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Background: Although few patients with breast cancer experience tumor progression during neoadjuvant systemic therapy (NST), their extremely poor outcomes are similar to patients who fail to achieve pathological complete response (pCR). No reports have compared patients with pCR, non-pCR, and progression during NST to determine the survival outcomes.Methods: This retrospective chart review of patients with stage I–III breast cancer was conducted between January 2001 and December 2018. pCR was defined as no invasive cancer or in situ residuals in the breast and lymph nodes (ypT0 ypN0). Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier methods.Results: Of the 595 patients who received NST, 167 (29.2%) had pCR (pCR group), 404 (70.8%) responded to NST but did not have pCR (non-pCR group), and 24 (4.0%) experienced tumor progression during NST (PD group). The median DFS was 6.0 months, 154.0 months, and not reached in the PD, non-pCR, and pCR groups, respectively. The PD group had significantly shorter DFS than patients without tumor progression in the pCR and non-pCR groups [hazard ratios (HR) 13.0, 95% CI: 8.1–21.0, p < 0.01]. The median OS was 13.6 months (95% CI: 10.4–35.5) in the PD group and was not reached in the pCR and non-pCR (non-PD) groups. The OS was significantly poorer in the PD group than in the non-PD group (HR 15.8, 95% CI: 9.2–27.1, p < 0.01).Conclusion: The PD group had the poorest survival outcomes even after recurrence, thus warranting new treatment targets.

Purpose A known barrier to getting breast cancer survivors (BCSs) to engage in habitual exercise is a lack of information on recommended physical activity levels provided to them by oncology care providers (OCPs). However, the actual situation in Japan remains unclear. This study sought to clarify OCPs’ awareness and practice related to Japan’s physical activity recommendation for BCSs and to ascertain barriers to routine information provision. Methods We conducted a web-based survey involving members of the Japanese Breast Cancer Society (JBCS) and the Japanese Association of Cancer Rehabilitation between Dec. 2018 and Feb. 2019. Results Of 10,830 members, 1,029 (9.5%) responded. Only 19.1% were aware of the details of the JBCS physical activity recommendation, and only 21.2% routinely provided physical activity information to BCSs. Factors related to being aware of the recommendation details were 1) availability of the guidelines, 2) experience reading relevant parts of the guidelines, and 3) involvement in multidisciplinary team case meetings. Barriers to routine information provision were 1) absence of perceived work responsibility, 2) underestimation of survivors’ needs, 3) lack of resources, 4) lack of self-efficacy about the recommendation, and 5) poor knowledge of the recommendation. Conclusions Only one fifth of the OCPs routinely provided physical activity information. Barriers to provision were poor awareness, self-efficacy, and attitudes and unavailable resources. The physical activity recommendation needs to be disseminated to all OCPs and an information delivery system needs to be established for BCSs to receive appropriate information and support to promote their engagement in habitual physical activity.

Background This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Methods Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety. Results In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380–1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390–1.463). Conclusions Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population. Clinical trial registration NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703.

Breast cancer, the most common malignancy among women, is closely associated with mutations in the tumor suppressor gene BRCA. DSS1, a component of the TRanscription-EXport-2 (TREX-2) complex involved in transcription and mRNA nuclear export, stabilizes BRCA2 expression. DSS1 is also related to poor prognosis in patients with breast cancer owing to the induction of chemoresistance. Recently, BRCA2 was shown to be associated with the TREX-2 component PCID2, which prevents DNA:RNA hybrid R-loop formation and transcription-coupled DNA damage. This study aimed to elucidate the involvement of these TREX-2 components and BRCA2 in the chemosensitivity of breast carcinomas. Our results showed that compared with that in normal breast tissues, DSS1 expression was upregulated in human breast carcinoma, whereas PCID2 expression was comparable between normal and malignant tissues. We then compared patient survival time among groups divided by high or low expressions of DSS1, BRCA2, and PCID2. Increased DSS1 expression was significantly correlated with poor prognosis in recurrence-free survival time, whereas no differences were detected in the high and low BRCA2 and PCID2 expression groups. We performed in vitro analyses, including propidium iodide nuclear staining, single-cell gel electrophoresis, and clonogenic survival assays, using breast carcinoma cell lines. The results confirmed that DSS1 depletion significantly increased chemosensitivity, whereas overexpression conferred chemoresistance to breast cancer cell lines; however, BRCA2 expression did not affect chemosensitivity. Similar to DSS1, PCID2 expression was also inversely correlated with chemosensitivity. These results strongly suggest that DSS1 and PCID2 depletion is closely associated with increased chemosensitivity via BRCA2-independent DNA damage. Together with the finding that DSS1 is not highly expressed in normal breast tissues, these results demonstrate that DSS1 depletion confers a druggable trait and may contribute to the development of novel chemotherapeutic strategies to treat DSS1-depleted breast carcinomas independent of BRCA2 mutations.

Background In MONARCH 2, abemaciclib plus fulvestrant significantly improved median progression-free survival (PFS, 16.4 vs 9.3 months, hazard ratio [HR] 0.553) and overall survival (OS, 46.7 vs 37.3 months; HR 0.757) compared with placebo plus fulvestrant in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC) patients who were endocrine therapy (ET) resistant, regardless of menopausal status. Here, we report findings in the premenopausal subgroup of the MONARCH 2 trial. Methods The premenopausal subgroup included patients with natural menstrual bleeding who received a gonadotropin-releasing hormone agonist at least 4 weeks prior to study treatment start date and for the entire study duration. Of the 669 patients enrolled in the MONARCH 2 trial, 114 were premenopausal (abemaciclib plus fulvestrant, n = 72; placebo plus fulvestrant, n = 42), and were included in this analysis. The primary objective was investigator-assessed PFS and secondary objectives were OS, objective response rate, and safety and tolerability. Exploratory analyses included time to second disease progression (PFS2), time to chemotherapy (TTC), and chemotherapy-free survival (CFS). Results At the primary objective cutoff (February 14, 2017), median PFS was not reached for the abemaciclib plus fulvestrant arm versus 10.52 months for the placebo plus fulvestrant arm (HR 0.415; 95% CI 0.246–0.698). At the pre-specified OS interim cutoff (20-June-2019), median PFS was 28.6 months in the abemaciclib plus fulvestrant arm compared with 10.26 months in the placebo plus fulvestrant arm (HR 0.477; 95% CI 0.302–0.755). A numerical OS benefit was observed with abemaciclib plus fulvestrant compared to fulvestrant alone (HR 0.689; 95% CI 0.379–1.252, median, not reached vs 47.3 months). Improvements were also observed for the exploratory outcomes of PFS2 (HR 0.599), TTC (HR 0.674), and CFS (HR 0.642) with the addition of abemaciclib to fulvestrant. The safety profile was generally consistent with results disclosed previously. Conclusions Results of the premenopausal subgroup in the MONARCH 2 trial were consistent with the improved clinical outcomes observed in the intent-to-treat population. The analysis provides support for the use of abemaciclib plus fulvestrant (with ovarian suppression) as an effective treatment option for premenopausal patients with HR+, HER2- ABC who are ET-resistant. Clinical trial registration: NCT02107703. Registered April 08, 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02107703.

The standard first-line treatment for patients with human epidermal growth factor 2-positive metastatic breast cancer is a combination therapy of trastuzumab, pertuzumab and docetaxel, and the standard second-line treatment is trastuzumab emtansine. However, it may be difficult for the elderly to maintain sufficient intensity of treatment due to severe adverse events of trastuzumab, pertuzumab and docetaxel. The aim of this trial is to confirm the non-inferiority of trastuzumab emtansine over trastuzumab, pertuzumab and docetaxel in terms of overall survival in elderly (65-year-old or more) patients with human epidermal growth factor 2-positive metastatic breast cancer. If improved overall survival and fewer toxicities are observed, trastuzumab emtansine may be a feasible new standard first-line treatment for elderly patients with human epidermal growth factor 2-positive metastatic breast cancer. A planned total 330 patients will be enrolled from 45 institutions over 6.5 years. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000030783 [http://www.umin.ac.jp/ctr/index.htm].

PURPOSE In the phase III SOLAR-1 trial ( NCT02437318 ), the PI3Kα-selective inhibitor and degrader alpelisib significantly improved median progression-free survival when added to fulvestrant in patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA)–mutated, hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. We assessed health-related quality of life using patient-reported outcome measures in these patients. MATERIALS AND METHODS In the PIK3CA-mutant cohort, 341 patients were randomly assigned 1:1 to receive alpelisib 300 mg daily or placebo plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Patient-reported outcomes were evaluated with the European Organisation for Research and Treatment of Cancer QoL of Cancer Patients and Brief Pain Inventory-Short Form questionnaires. Changes from baseline and time to 10% deterioration were analyzed using repeated measurement models and Cox models, respectively. RESULTS Global Health Status/QoL and functional status were maintained from baseline (mean changes < 10 points) in the alpelisib (overall change from baseline [95% CI], −3.50 [−8.02 to 1.02]) and placebo arms (overall change from baseline [95% CI], 0.27 [−4.48 to 5.02]). Overall treatment effect in Global Health Status/QoL was not significantly different between arms (−3.77; 95% CI, −8.35 to 0.80; P = .101). Time to 10% deterioration for Global Health Status/QoL was similar between arms (hazard ratio, 1.03; 95% CI, 0.72 to 1.48). Compared with placebo, deterioration in social functioning and in diarrhea, appetite loss, nausea or vomiting, and fatigue symptom subscales occurred with alpelisib. Numerical improvement in Worst Pain was observed with alpelisib versus placebo (42% v 32%, week 24; P = .090). CONCLUSION In SOLAR-1, there was no statistical difference in deterioration of Global Health Status/QoL between arms, whereas symptom subscales favored placebo for diarrhea, appetite loss, nausea or vomiting, and fatigue, known side effects of alpelisib. Treatment decisions must consider efficacy and tolerability; taken with clinical efficacy, these results support the benefit-risk profile of alpelisib in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative PIK3CA-mutated advanced breast cancer.

Background The most frequently reported treatment‐related adverse event in clinical trials with the cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (i.e., end of week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Materials and Methods ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib‐treated patients from PALOMA‐2 (n = 584) and PALOMA‐3 (n = 442). SNP, race, and cycle 1 day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n = 122) and non‐Asian (n = 530) ethnicity. Median progression‐free survival (mPFS) was estimated using the Kaplan‐Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed. Results ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non‐Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR], 6.033, 95% confidence interval [CI], 2.615−13.922, p < .0001; Non‐Asians: OR, 6.884, 95% CI, 4.138−11.451, p < .0001). ABCB1_rs1128503 (C/C vs. T/T: OR, 0.57, 95% CI, 0.311−1.047, p = .070) and ERCC1_rs11615 (A/A vs. G/G: OR, 1.75, 95% CI, 0.901−3.397, p = .098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non‐Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype. Conclusion This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135). Implications for Practice Palbociclib plus endocrine therapy improves hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy‐induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (p, The most frequently reported treatment‐related adverse event in clinical trials with the cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. In this study, pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms in the ABCB1 and ERCC1 genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia.

Background In the phase III IMpassion130 study, atezolizumab plus nab-paclitaxel (A+nP) showed clinical benefit in advanced or metastatic triple-negative breast cancer patients who were programmed death-ligand 1 (PD-L1)+ (tumor-infiltrating immune cells [IC] ≥1%) using the SP142 immunohistochemistry assay. Here we evaluate 2 other PD-L1 assays for analytical concordance with SP142 and patient-associated clinical outcomes. Methods Samples from 614 patients (68.1% of intention-to-treat population) were centrally evaluated by immunohistochemistry for PD-L1 status on IC (VENTANA SP142, SP263, Dako 22C3) or as a combined positive score (CPS; 22C3). Results Using SP142, SP263, and 22C3 assays, PD-L1 IC ≥1% prevalence was 46.4% (95% confidence interval [CI] = 42.5% to 50.4%), 74.9% (95% CI = 71.5% to 78.3%), and 73.1% (95% CI = 69.6% to 76.6%), respectively; 80.9% were 22C3 CPS ≥1. At IC ≥1% (+), the analytical concordance between SP142 and SP263 and 22C3 was 69.2% and 68.7%, respectively. Almost all SP142+ cases were captured by other assays (double positive), but several SP263+ (29.6%) or 22C3+ (29.0%) cases were SP142– (single positive). A+nP clinical activity vs placebo+nP in SP263+ and 22C3+ patients (progression-free survival [PFS] hazard ratios [HRs] = 0.64 to 0.68; overall survival [OS] HRs = 0.75 to 0.79) was driven by double-positive cases (PFS HRs = 0.60 to 0.61; OS HRs = 0.71 to 0.75) rather than single-positive cases (PFS HRs = 0.68 to 0.81; OS HRs = 0.87 to 0.95). Concordance for harmonized cutoffs for SP263 (IC ≥4%) and 22C3 (CPS ≥10) to SP142 (IC ≥1%) was subpar (approximately 75%). Conclusions 22C3 and SP263 assays identified more patients as PD-L1+ (IC ≥1%) than SP142. No inter-assay analytical equivalency was observed. Consistent improved A+nP efficacy was captured by the SP142 PD-L1 IC ≥1% subgroup nested within 22C3 and SP263 PD-L1+ (IC ≥1%) populations.

Background Neoplastic seeding (NS) can occur after tissue biopsy, which is a clinical issue especially in mastectomy with immediate reconstruction. This is because postoperative radiation is not usually given and local recurrence of preserved skin flap may increase. The purpose of this study is to investigate the importance of preoperative evaluation of NS and the validity of biopsy scar excision. Patients and methods We retrospectively analysed 174 cases of mastectomy with immediate breast reconstruction. The primary endpoint is the frequency of clinical and pathological NS and the secondary endpoint is the problem of excision of needle biopsy site. Results Three cases (1.7%) had preoperative clinical findings of NS. Pathological examination revealed NS in all three cases. Biopsy scars could be excised in 115 cases among 171 cases without clinical NS. Pathological NS was found in 1 of 66 (1.5%) cases of which pathological examination was performed. Biopsy scars could not be excised in the remaining 56 cases: the biopsy scar could not be identified in 41 cases, and there was concern about a decrease in flap blood flow after excision in 15 cases. In 12 of these 15 cases, the scars were close to the skin incision; excision of these scars might have triggered skin necrosis between the incision and the biopsy scar excision site. No postoperative complications were observed. Conclusions It is important to preoperatively evaluate clinical NS, and biopsy scars should be excised in clinical NS cases. Even in cases without clinical NS, biopsy scar excision should be considered. It is also important to perform a biopsy in consideration of the incision design for reconstructive surgery., It is important to evaluate clinical neoplastic seeding (NS) due to biopsy. Biopsy scars should be excised in clinical NS cases. Excision should be considered even without clinical NS.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2‐negative (HER2−) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double‐blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent‐to‐treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression‐free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P, Abemaciclib in combination with endocrine therapy (ET) in the East Asian populations of MONARCH 2 and MONARCH 3 improved efficacy for patients with HR+, HER2− advanced breast cancer.

In April 2016, the Japanese government introduced health technology assessment as a response to rising medical expenses due to ‘medical innovation’. This study investigates how Japanese breast cancer patients who received treatment in Japan consider the financial value (willingness-to-pay; WTP) for their life and health by using the contingent valuation method (CVM) prospectively. First, 168 patients (84 primary breast cancer patients and 84 metastatic breast cancer patients) were pre-examined their WTP with dichotomous-choice method survey form. Next, 1,596 patients (798 primary breast cancer patients and 798 metastatic breast cancer patients) will be surveyed to their WTP for hypothetical scenarios in CVM. Based on our results, we will construct an evaluation axis from the patients’ viewpoint for the cost-effectiveness of clinical trials to establish standard treatments for breast cancer. We believe this research can contribute to create a meaningful healthcare system for patients, clinicians, industries, and healthcare policymakers., This study investigated how Japanese breast cancer patients who received treatment in Japan consider the willingness-to-pay for their life and health by using the contingent valuation method prospectively.

Background We conducted a prospective study with the intention to omit surgery for patients with ductal carcinoma in situ (DCIS) of the breast. We aimed to identify clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with DCIS. Patients and methods We retrospectively analyzed patients with DCIS diagnosed through biopsy between April 1, 2010 and December 31, 2014, from 16 institutions. Clinical, radiological, and histological variables were collected from medical records. Results We identified 2,293 patients diagnosed with DCIS through biopsy, including 1,663 DCIS (72.5%) cases and 630 IDC (27.5%) cases. In multivariate analysis, the presence of a palpable mass (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.2–2.6), mammography findings (≥ category 4; OR 1.8; 95% CI 1.2–2.6), mass formations on ultrasonography (OR 1.8; 95% CI 1.2–2.5), and tumor size on MRI (> 20 mm; OR 1.7; 95% CI 1.2–2.4) were independent predictors of IDC. Among patients with a tumor size on MRI of ≤ 20 mm, the possibility of postoperative upstaging to IDC was 22.1%. Among the 258 patients with non-palpable mass, nuclear grade 1/2, and positive for estrogen receptor, the possibility was 18.1%, even if the upper limit of the tumor size on MRI was raised to ≤ 40 mm. Conclusion We identified four independent predictive factors of upstaging to IDC after surgery among patients with DCIS diagnosed by biopsy. The combined use of various predictors of IDC reduces the possibility of postoperative upstaging to IDC, even if the tumor size on MRI is larger than 20 mm.

Background: In the phase 2 KEYNOTE-086 study (NCT02447003), pembrolizumab monotherapy had durable antitumor activity in a subset of patients with previously treated mTNBC (cohort A; n = 170) and in patients with previously untreated PD-L1-positive mTNBC (cohort B; n = 84). In this exploratory analysis of KEYNOTE-086, we evaluated the association between several biomarkers and response to pembrolizumab. Methods: Cohort A enrolled patients regardless of PD-L1 expression who had documented disease progression following ≥1 systemic therapy for metastatic disease. Cohort B enrolled patients with PD-L1-positive (combined positive score [CPS] ≥1) tumors who had not received prior systemic therapy for metastatic disease. Immunohistochemistry was used to measure PD-L1 CPS and CD8 density; H&E staining for percentage of stromal tumor infiltrating lymphocytes (sTILs); RNA-sequencing for 18-gene T-cell-inflamed gene expression profile (GEP), angiogenesis, and glycolysis signatures; and whole exome sequencing (paired tumor and germline) for TMB (TMB-H defined as ≥175 mut/exome), HRD-LOH (DNA damage), Signature 3, and APOBEC. Biomarkers were analyzed as continuous variables in cohorts A and B combined and individually. Area under the receiver operating characteristic curve was estimated between each biomarker and overall response rate (ORR). Wald test P-values were calculated using logistic regression adjusted for cohort and Eastern Cooperative Oncology Group performance status. Germline and somatic BRCA1/2 mutations were pooled; one-sided P-value was calculated using Fisher’s exact test. Spearman’s correlation was used for correlations. Results: Biomarker data were available in the following number of patients: 253 (99.6%; PD-L1), 204 (80.3%; CD8), 187 (73.6%; GEP), 171 (67.3%; TMB/HRD), 228 (89.8%; sTILs), 163 (64.2%; Signature 3/APOBEC), and 132 (52.0%; angiogenesis/glycolysis). When data from cohorts A and B were combined, PD-L1 CPS (median 2; IQR 0-10), CD8 (median 159; IQR 62-319), GEP (median -0.34; IQR -0.57 to -0.11), TMB (median 82 mut/exome; IQR 50-139), and sTILs (median 5; IQR 2-20) were significantly associated with ORR (Table). There were moderate correlations between PD-L1 and GEP (r = 0.532), PD-L1 and sTILs (r = 0.451), and GEP and sTILs (r = 0.490). No correlation was observed between TMB and PD-L1 (r = 0.038), GEP (r = -0.035), and sTILs (r = -0.031). When cohorts were combined, TMB was significantly associated with ORR, PFS, and OS after adjustment for PD-L1, GEP, CD8, or sTILs. HRD-LOH score, Signature 3, and APOBEC were not significantly associated with ORR (Table); P for BRCA1/2 was 0.2385. The angiogenesis signature was associated with lack of response while the glycolysis signature was associated with response to pembrolizumab (Table). Conclusions: In this exploratory biomarker analysis from KEYNOTE-086, higher levels of PD-L1, GEP, TMB, CD8 IHC, sTILs, and the glycolysis signature were associated with increased response to pembrolizumab monotherapy. These findings may help identify patients with mTNBC who are most likely to respond to pembrolizumab. Table. Association of Biomarkers as Continuous Variables With Pembrolizumab Objective ResponseBiomarkerCombined Cohorts AUCCombined Cohorts P*Combined Cohorts Multitest corrected PCohort A AUCCohort B AUCPD-L10.6740.040-0.5440.654GEP0.7480.003-0.8370.561TMB0.6270.007-0.5480.710CD8 IHC0.760.000020.000120.850.68sTILs0.6710.012-0.6320.641HRD0.3940.874-0.5220.316Signature 30.6830.072-0.6970.736APOBEC0.5280.537-0.6740.623Angiogenesis0.6770.0090.0450.6610.731Glycolysis0.6120.0090.0360.8590.459AUC, area under the curve.*One-sided P-values are shown for all biomarkers except for Signature 3 and APOBEC, for which 2-sided P-values are shown. Citation Format: Sherene Loi, Peter Schmid, Javier Cortes, David W. Cescon, Eric P. Winer, Deborah L. Toppmeyer, Hope S. Rugo, Michelino De Laurentiis, Rita Nanda, Hiroji Iwata, Ahmad Awada, Antoinette R. Tan, Roberto Salgado, Vassiliki Karantza, Petar Jelinic, Anran Wang, Lingkang Huang, Razvan Cristescu, Lakshman Annamalai, Jennifer Yearley, Jennifer Yearley, Sylvia Adams. Association between biomarkers and response to pembrolizumab in patients with metastatic triple-negative breast cancer (mTNBC): Exploratory analysis from KEYNOTE-086 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-07.

Background Trastuzumab deruxtecan (T-DXd, DS-8201) is an antibody-drug conjugate with a HER2 antibody, tetrapeptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2 positive metastatic breast cancer (MBC) and supported regulatory approval in the US and Japan. Updated longer-term safety and efficacy results are presented here. Methods All patients were required to have MBC that progressed on or after T-DM1. 253 patients were enrolled and 184 received T-DXd 5.4 mg/kg, representing the primary analysis set. The primary endpoint was ORR. Additional endpoints included duration of response, PFS, and OS. Results Patients had received a median of 6 previous lines of treatment for MBC. In this updated data cutoff (8 June 2020) compared to the prior data cutoff (1 Aug 2019), median duration of follow-up has increased from 11.1 to 20.5 mo; 37 patients (20.1%) remain on treatment. Confirmed ORR was 61.4% (12 CRs) with a median duration of response of 20.8 mo; the disease control rate was 97.3% (95% CI, 93.8-99.1). The updated mPFS was 19.4 mo (95% CI, 14.1 mo-NE). Estimated OS was 85% (95% CI, 79%-90%) at 12 months and 74% (95% CI, 67%-80%) at 18 months. The preliminary mOS is 24.6 mo (estimated at 35% maturity with only 17 patients at risk at 24 months). The safety profile of T-DXd was similar as that previously reported; with an additional 9 mo follow-up, only 3 new cases of T-DXd-related interstitial lung disease (ILD) were reported. Results are summarized in the table below. Conclusion Consistent with prior results, T-DXd demonstrated high rates of durable responses in a heavily pretreated population of patients with MBC. From this single-arm, phase 2 study, the PFS and immature OS results are encouraging; these endpoints will be further evaluated in the ongoing randomized controlled studies of T-DXd. For patients who remained on treatment for this longer duration (double that of the previous report), the rate of discontinuation or ILD did not notably increase. Continued attention to pulmonary symptoms and careful monitoring is warranted. Updated Results for DESTINY-Breast011 Aug 2019 datacut8 Jun 2020 datacutPatients remaining on treatment, n/N (%)79/184 (42.9%)37/184 (20.1%)Median duration of follow-up11.1 months20.5 monthsORR60.9%61.4%CR6.0%6.5%PR54.9%54.9%SD36.4%35.9%Duration of response, median (95% CI)14.8 months (13.8-16.9)20.8 months (15.0-NE)PFS, median (95% CI)16.4 months (12.7-NE)19.4 months (14.1-NE)OSMedian (95% CI)NE (NE-NE)24.6 months (23.1-NE)Point estimate at 12 mo (95% CI)86.2% (79.8-90.7)85% (79-90)Point estimate at 18 mo (95% CI)–74% (67-80)SafetyPatients with a TEAE, n (%)183 (99.5%)183 (99.5%)Grade ≥3105 (57.1%)113 (61.4%)Associated with discontinuation28 (15.2%)34 (18.5%)Associated with death10 (5.4%)10 (5.4%)Drug-related ILD per ILD adjudication committeea25 (13.6%)28 (15.2%)Grade 5 drug-related ILD per ILD adjudication committee4 (2.2%)5 (2.7%)a1 grade 1 and 1 grade 3 event are pending adjudication and are not included. Citation Format: Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Yali Liu, Lin Zhang, Javad Shahidi, Antoine Yver, Jose Baselga, Ian E Krop. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd ) in HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-06.

Introduction: The PI3K pathway is often hyperactivated in cancer as a result of an altered PI3K isoform and/or loss of phosphatase and tensin homolog function. Approximately 40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) have tumors with mutations in PIK3CA, which encodes the α-isoform of PI3K, p110α. These mutations are known to cause hyperactivation of the PI3K pathway, which contributes to cell proliferation, drug resistance, and poor prognoses. Alpelisib (ALP) is an α-selective PI3K inhibitor that, in combination with fulvestrant (FUL), prolonged median progression-free survival (mPFS) in pts with HR+, HER2−, PIK3CA-mutant ABC following progression on/after prior aromatase inhibitor in the phase 3 SOLAR-1 trial. In SOLAR-1, prospective PIK3CA mutation testing was performed on tumor tissue using PCR-based assays. Through retrospective analysis, efficacy of ALP was demonstrated in subgroups of pts with PIK3CA alteration(s) in tumor tissue and mutation(s) in ctDNA, detected by next-generation sequencing (NGS) and PCR, respectively. In this exploratory biomarker analysis, we assessed clinical outcomes of pts with PIK3CA alteration(s), detected in ctDNA by NGS.Methods: SOLAR-1 is a phase 3, randomized, double-blind, placebo-controlled study of ALP 300 mg vs placebo taken daily with FUL 500 mg every 28 days + Cycle 1 Day 15 in men and postmenopausal women with HR+, HER2- ABC. Retrospectively, the full exonic region of the PIK3CA gene was sequenced using the Foundation Medicine 324-gene ctDNA panel in plasma ctDNA collected at baseline. mPFS was assessed using Kaplan-Meier methodology per investigator assessment.Results: Of 572 pts in SOLAR-1, 381 pts (66.6%) across both PIK3CA-mutant and nonmutant cohorts had valid plasma ctDNA data. Of these pts, 193 (50.7%) had a PIK3CA alteration; 168 (87%) had PCR-detectable mutations and 147 (76%) had a single alteration. A total of 70 (36%) and 102 (53%) pts had alterations in exons 9 and 20, respectively. ALP plus FUL prolonged mPFS in pts with PIK3CA alterations detected in plasma ctDNA by NGS (n=101; Table). Clinical benefit was also observed in pts with PCR-detectable mutations (n=88), single mutations (n=83), and pts with mutations in exon 9 (n=34) and exon 20 (n=54). Pt numbers were low, and wide 95% CIs were observed in groups with alterations not detectable by PCR (n=13) and in pts with multiple alterations. Some limitations of this retrospective plasma analysis include that this is a subgroup (66.6%) of the SOLAR-1 pt population and that the subgroup of pts with non-altered PIK3CA included pts with a PIK3CA mutation in their tumor tissue. Conclusions: ALP plus FUL demonstrated clinical benefit in pts with PIK3CA mutations detected in plasma ctDNA by NGS, in pts with single alterations, and in pts with alterations in exons 9 and 20. Results were consistent across pt groups, except in those with alterations not detectable by PCR. In conclusion, these data demonstrate a consistent clinical benefit of ALP plus FUL in various groups of pts with PIK3CA alterations detected in ctDNA by NGS. Clinical Outcomes of Patients With PIK3CA Alterations Detected in Plasma ctDNA by NGS in SOLAR-1Alpelisib + fulvestrantPlacebo + fulvestrantHR (95% CI)Events/N (%)mPFS, mo (95% CI)Events/N(%)mPFS, mo (95% CI)PIK3CA altered vs non-alteredAltered58/101(57.4)11.04(7.72-16.16)73/92(79.3)3.65(2.86-6.80)0.47(0.33-0.67)Non-altered40/87(46.0)10.87(5.59-16.76)60/101(59.4)5.45(3.75-9.00)0.60(0.40-0.91)PIK3CA: alteration detectable by PCR vs alteration not detectable by PCRDetectable52/88(59.1)12.48(7.36-18.37)66/80(82.5)3.58(2.37-5.65)0.44(0.30-0.64)Not detectable6/13(46.2)8.48(2.69-NA)7/12(58.3)7.39(1.87-12.98)1.12(0.35-3.56)PIK3CA: number of alterationsSingle45/83(54.2)12.88(7.36-18.50)50/64(78.1)3.58(1.87-6.11)0.43(0.28-0.65)Multiple13/18(72.2)9.00(3.68-18.37)23/28(82.1)4.63(3.48-9.63)0.55(0.25-1.20)PIK3CA alterations in exon 9 or exon 20Exon 918/34(52.9)15.21(7.03-NA)29/36(80.6)3.66(2.86-7.36)0.31(0.16-0.61)Exon 2034/54(63.0)10.91(5.72-18.37)40/48(83.3)3.52(1.87-6.11)0.51(0.31-0.82)CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; mPFS, median progression-free survival; mo, months; NA, not available; NGS, next-generation sequencing. Citation Format: Eva M. Ciruelos, Sibylle Loibl, Ingrid A. Mayer, Mario Campone, Hope S. Rugo, Monica Arnedos, Hiroji Iwata, Pier Franco Conte, Fabrice André, Albert Reising, Chong Ma, Michelle Miller, Naveen Babbar, Dejan Juric. Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing: Biomarker analysis from the SOLAR-1 study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-06.

BackgroundIn 2019, the Japanese government has decided to introduce the economic valuation to healthcare system. However, the threshold for determining cost-effectiveness-analysis has yet to be adequately studied. Therefore, we have designed a study to examine the financial value of “life” and “health” based on willingness-to-pay (WTP) considered by approximately 1,800 patients with primary and metastatic breast cancer (PBC and MBC) in Japan. Preliminary study has been conducted to set the amount of WTP prior to the main study. Methods This study is conducted by six leading hospitals under the Breast Cancer Study Group of Japan Clinical Oncology Group (JCOG). 168 patients (84 patients with PBC and 84 patients with MBC) from 20 to 79 years of age paying medical costs were examined their WTP for setting up the dichotomous-choice method survey form. Virtual scenario-specific treatments to avoid the recurrence and death of breast cancer for one year for PBC patients, and to prolong the survival period for one year for the patients with MBC were presented. The patients were evaluated how much money would pay to receive the treatment in a self-written answer. The amount of WTP that will be presented in the main study was determined by calculating the median price from these responses based on the protocol. In addition, we conducted surveys of quality-of-life by EQ-5D-5L, social background on patients, and of breast cancer medical condition on doctors. Results Completed surveys were collected from 166 doctors (98.8%) and 139 patients (82.7%). The range of the amount of WTP for scenario-specific treatments among the patients with the patients with PBC was from 0 to 5 million Japanese yen (JPY) (50,000 USD), and among the patients with MBC was from 0 to 10 million JPY (100,000 USD). In accordance with the criteria set forth in advance in the protocol, the amount of WTP that will be presented in the main study was set at 5 million JPY in both PBC and MBC patients. Conclusion We have fixed the cost that will be presented in the main study based on the findings of our preliminary study. The main study will commence around September 2020. Citation Format: Tsuguo Iwatani, Fumikata Hara, Tadahiko Shien, Masato Takahashi, Norikazu Masuda, Hiroyuki Yasojima, Yasuaki Sagara, Tomonori Mizutani, Keita Sasaki, Kenichi Nakamura, Haruhiko Fukuda, Takaru Shiroiwa, Hiroji Iwata. Estimation of willingness-to-pay for breast cancer treatments through contingent valuation method in Japanese breast cancer patients (JCOG1709A); preliminary study findings [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-57.

Introduction: U3-1402 is a novel, investigational ADC directed against HER3, which is widely expressed in breast cancer. Safety and preliminary antitumor activity of U3-1402 was previously reported in this ongoing, phase 1/2 clinical trial (NCT02980341/JapicCTI-163401). Here we report updated safety data from the dose escalation/dose finding (DE/DF) and phase 2 dose expansion parts, and we present for the first time efficacy data for patients in the expansion part with HR+/HER2− MBC with high or low levels of HER3 expression. Methods: In DE/DF, U3-1402 was administered intravenously (IV) Q2W or Q3W at doses ranging from 1.6 to 8.0 mg/kg. Patients had HER3-expressing advanced/unresectable disease refractory/intolerant to standard treatment or for which no standard treatment was available. In the expansion part, U3-1402 was administered IV Q3W to patients with HER3-high (4.8 or 6.4 mg/kg) or HER3-low (6.4 mg/kg) HR+/HER2− MBC or with HER3-high triple-negative breast cancer (TNBC; 6.4 mg/kg). Primary objectives included safety and efficacy of U3-1402; secondary objectives included correlative biomarker and pharmacokinetics analyses. Archival or pretreatment tissue obtained in the 6 months prior to U3-1402 treatment was analyzed by IHC for HER3 expression. Results: As of March 2020, all 4 expansion cohorts had completed enrollment. In the DE/DF and expansion parts combined, 172 patients received ≥1 dose of U3-1402 (114 [66%] had HR+/HER2− MBC). Median age was 56 y (range, 30-83 y); 123 (72%) and 49 (28%) patients had an ECOG PS of 0 or 1, respectively. Patients received a median of 6 (range, 1-14) prior systemic therapies. Median treatment duration of U3-1402 was 5 mo (range, 1-30 mo). 101 patients (59%) discontinued because of progressive disease, and 15 (9%) discontinued because of an AE. The most common grade ≥3 treatment-emergent AEs reported were decreased neutrophil count (43 patients [25%]), decreased platelet count (39 patients [23%]), decreased white blood cell count (28 patients [16%]), and anemia (31 patients [18%]). Nine patients (5%) experienced treatment-related interstitial lung disease according to central adjudication, including one grade 5 event. At data cutoff, 85 patients in the HR+/HER2− expansion part were evaluable for efficacy by blinded independent central review. Among 33 patients with HR+/HER2− HER3-high MBC treated with 4.8 mg/kg, 10 (30%) had a response (all partial responses [PRs]), with a clinical benefit rate (CBR; complete response + PR + stable disease for ≥6 mo) of 45% (15/33). Among 31 patients with HER3-high MBC treated with 6.4 mg/kg, 3 (10%) had a response (all PR) with a CBR of 16% (5/31). Among 21 patients with HER3-low MBC treated with 6.4 mg/kg, 6 (29%) had a response (all PRs) with a CBR of 33% (7/21). TNBC data are immature at the time of abstract data cutoff; efficacy by HR status will be provided in the presentation. Membrane HER3 expression levels were dynamic; they varied between archival and pretreatment biopsies and decreased on treatment with U3-1402. Across the doses evaluated, the U3-1402 AUC and Cmax of the total antibody, intact ADC, and released payload were approximately dose proportional, with minimal accumulation after multiple doses; the released payload Cmax was highest in cycle 1 and decreased in later cycles. Conclusions: In this heavily pretreated MBC population, U3-1402 demonstrated clinically meaningful antitumor activity in HR+/HER2− MBC with high or low levels of HER3 expression. The safety profile of U3-1402 was consistent with that previously reported, with 9% of patients discontinuing because of AEs. Clinical data pertaining to patients with TNBC and correlative analyses (including association of HER3 expression with response) will be presented. Citation Format: Ian Krop, Kan Yonemori, Shunji Takahashi, Kenichi Inoue, Takahiro Nakayama, Hiroji Iwata, Tatsuya Toyama, Yutaka Yamamoto, Masato Takahashi, Akihiko Osaki, Shigehira Saji, Yasuaki Sagara, Joyce O’Shaughnessy, Tiffany Traina, Shoichi Ohwada, Zhenhao Qi, Yang Qiu, Hiroshi Onuma, Om Sharma, Sabeen Mekan, Norikazu Masuda. Safety and efficacy results from the phase 1/2 study of U3-1402, a human epidermal growth factor receptor 3 (HER3)-directed antibody drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-09.

Background: Patients (pts) with HER2-positive locallyadvanced/metastatic breast cancer (LA/MBC) previously treated with pertuzumab(P)-containing regimens have few therapeutic options. The efficacy of Pre-treatment combined with trastuzumab (T)+chemotherapy as 3 or 4 -line chemotherapy was examined in such pts. Methods: Pts previously treated with P-containing regimens as1st/2nd-line treatment for LA/MBC were randomly assigned 1:1 to two groups(P+T+chemotherapy based on physicians’ choice (C) (PTC), and T+C (TC)),stratified by estrogen receptor status, previous P treatment duration, numberof previous chemotherapy regimens, and presence or absence of visceralmetastasis. The primary endpoint was investigator-assessed progression-freesurvival (PFS). Superiority of PTC to TC will be tested using a stratifiedlog-rank test that accounts for all stratification factors, and a one-sidedP-value of less than 0.05 will be considered an indicator of superiority. Thedistribution of PFS will be estimated using the Kaplan-Meier method. In addition,the hazard ratio and one-sided 95% CI of the therapeutic effect between thegroups will be calculated using the Cox proportional hazard model. Secondaryendpoints included independent reviewer assessed PFS, PFS in pts treated withT-DM1 as the latest regimen (PFS after T-DM1), objective response rate (ORR),overall survival (OS), safety, and health-related quality of life (HR-QoL). Results: Of the 219 pts enrolled, 217 (108 PTC, 109 TC) wereincluded in the intent-to-treat analysis. At the data cutoff (July 31, 2019),PFS and OS events were 184 (84.8%) and 84 (38.7%), respectively. Medianfollow-up time was 14.2 months (mo). Investigator-assessed PFS wassignificantly better in the PTC group (median PFS 5.3 vs. 4.2 mo; HR = 0.755[One-sided 95%CI upper limit, 0.967]; One-sided stratified log-rank test p =0.0217). Median PFS after T-DM1 (5.3 vs. 4.2 mo; HR = 0.801 [One-sided 95%CIupper limit, 1.061]; One-sided log-rank test p = 0.0952) and OS (28.8 vs. 23.4mo; HR = 0.713, [One-sided 95%CI upper limit, 1.026], One-sided log-rank test p= 0.062) tended to be longer in the PTC group, though further follow-up isneeded. The ORR with measurable disease (PTC (n = 90) 18.9% vs. TC (n = 92)19.6%) did not differ between the groups. The serious adverse event rate didnot differ between the groups (17.9% vs. 21.3%). There were no new safetysignals included cardiac events in the groups. In the comparison of HR-QoL bytime to deterioration analysis, there was no significant difference between thegroups in FACT-B trial outcome index (PTC 2.8 mo vs. TC 4.3 mo; HR = 1.274,log-rank test p = 0.2289).Conclusions: P re-treatment as 3 or 4 -line chemotherapy wasactive and feasible. P re-treatment can be a standard treatment option forpatients with HER2-positive LA/MBC previously treated with P.(ClinicalTrials.gov number: NCT02514681) Citation Format: Yutaka Yamamoto, Hiroji Iwata, Taira Naruto, Norikazu Masuda, Masato Takahashi, Tetsuhiro Yoshinami, Takayuki Ueno, Tatsuya Toyama, Takashi Yamanaka, Toshimi Takano, Masahiro Kashiwaba, Koichiro Tsugawa, Yoshie Hasegawa, Kenji Tamura, Hiroshi Tada, Fumikata Hara, Shigehira Saji, Satoshi Morita, Masakazu Toi, Shinji Ohno, Japan Breast Cancer Research Group. A randomized, open-label, phase III trial of pertuzumab re-treatment in HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab, and chemotherapy: The Japan Breast Cancer Research Group-M05 (PRECIOUS) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-11.

Background: In the Phase III SOLAR-1 trial (NCT02437318), ALP (PI3Kα inhibitor) + fulvestrant (FUL) significantly improved progression-free survival vs FUL alone in patients (pts) with HR+/HER2− advanced breast cancer with PIK3CA mutations (André et al. N Engl J Med. 2019;380:1929-1940). Hyperglycemia was identified as an expected adverse event (AE) with ALP and was the most frequent grade (G) 3/4 AE in SOLAR-1 (G3, 32.7%; G4, 3.9%). A protocol amendment was implemented during the study to provide additional detailed guidance on hyperglycemia and rash management. Additionally, conditions at baseline such as prediabetic or diabetic glycemic status, body mass index (BMI) ≥30, and age ≥75 years have been identified as risk factors for ALP-induced hyperglycemia. Here we present a case report highlighting 4 examples of early intervention and different management approaches for ALP-induced hyperglycemia in SOLAR-1. Methods: According to the protocol, glycemic status was assessed at baseline and over time using fasting plasma glucose and glycated hemoglobin. Hyperglycemia was regularly assessed per the National Cancer Institute CTCAE v4.03. In addition to concomitant medications for hyperglycemia, dose interruptions or reductions by one level were recommended for both G3 and G4 hyperglycemia, per protocol. If G4 hyperglycemia had not improved within 24 hours and confounding factors could be excluded, pts should be permanently discontinued from ALP. Pts from this case report were selected on the basis of hyperglycemia events of interest to the community: (1) not well controlled on metformin alone; (2) required hospitalization; (3) no risk factors for hyperglycemia at baseline; (4) no action taken at initial presentation of hyperglycemia. Results: In SOLAR-1, 284 pts were randomized to ALP + FUL and 187 (66%) developed hyperglycemia; 163 of these pts received concomitant medications for hyperglycemia, and most received metformin as part of their treatment (87%). Three cases exhibited examples of early intervention for ALP-induced hyperglycemia. The first pt was prediabetic and had a BMI >30. She presented with G2 hyperglycemia on day 8 and received metformin and a DPP-4 inhibitor but then had a G3 event 2 weeks later, managed by an ALP dose interruption. Another G2 event led to addition of an SGLT2 inhibitor and a sulfonylurea, which allowed her to stay on ALP treatment (>43.3 mo). The second pt was prediabetic and had a BMI >30. She had G3 hyperglycemia leading to hospitalization on day 8, started metformin, and then received rescue insulin. She continued to be managed with dose adjustments of metformin and addition of a sulfonylurea until disease progression (11.2 mo). The third pt had a normal glycemic status at baseline and a BMI 40.5 mo). A case example of late intervention for ALP-induced hyperglycemia was a pt who had a normal glycemic status at baseline and a BMI Citation Format: Ingrid Mayer, Azeez Farooki, Hope S. Rugo, Hiroji Iwata, Eva Ciruelos, Mario Campone, Sibylle Loibl, Pierfranco Conte, Dejan Juric, Farhat Ghaznawi, Ines Lorenzo, Huilin Hu, Fiorenza Gaudenzi, Fabrice Andre. Early intervention for and management of alpelisib (ALP)-induced hyperglycemia: Case studies from the phase III SOLAR-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-35.

Background Understanding the impact of the tumor immune microenvironment and BRCA1/2-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help optimize both patient and treatment selection in metastatic triple-negative breast cancer. In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA1/2 alterations were evaluated for association with clinical benefit with atezolizumab and nab-paclitaxel (A+nP) vs placebo and nP in unresectable (P+nP) locally advanced or metastatic triple-negative breast cancer. Methods Patients were randomly assigned 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) and atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival and overall survival were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells, intratumoral CD8, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutations. Results PD-L1 IC+ in either primary or metastatic tumor tissue was linked to progression-free survival and overall survival benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and stromal tumor-infiltrating lymphocytes positivity (sTIL+) were associated with PD-L1 IC+ status; improved outcomes were observed with A+nP vs P+nP only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% [89 of 612 patients]) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status. Conclusions Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.

Background Advance care planning (ACP) is a process that supports adults in understanding and sharing their personal values, life goals, and preferences regarding future medical care. We examined the current status of ACP and end‐of‐life (EOL) communication between oncologists and patients with metastatic breast cancer. Materials and Methods We conducted a survey among 41 institutions that specialize in oncology by using an online tool in October 2019. Participants (118 physicians) from 38 institutions completed a 39‐item questionnaire that measured facility type and function; physicians’ background and clinical approach, education about EOL communication, and understanding about ACP; and the current situation of ACP and EOL discussions. Results Ninety‐eight responses concerning physicians’ engagement in ACP with patients were obtained. Seventy‐one (72%) answered that they had engaged in ACP. Among these, 23 (33%) physicians used a structured format to facilitate the conversation in their institutions, and only 6 (8%) settled triggers or sentinel events for the initiation of ACP. In the multivariable analysis, only the opportunity to learn communication skills was associated with physicians’ engagement with ACP (odds ratio: 2.8, 95% confidence interval: 1.1–7.0). The frequency and timing of communication about ACP and EOL care with patients substantially varied among the oncologists. Communication about patients’ life expectancy was less frequent compared with other topics. Conclusion The opportunity to improve EOL communication skills promoted physicians’ engagement with ACP among patients with metastatic/advanced breast cancer. However, there were still substantial variabilities in the method, frequency, and timing of ACP and EOL communication among the oncologists. Implications for Practice This study found that the opportunity to improve end‐of‐life (EOL) communication skills promoted physicians’ engagement in advance care planning (ACP) among patients with metastatic/advanced breast cancer. All oncologists who treat said patients are encouraged to participate in effective education programs concerning EOL communication skills. In clinical practice, there are substantial variabilities in the method, frequency, and timing of ACP and EOL communication among oncologists. As recommended in several clinical guidelines, the authors suggest a system that identifies patients who require conversations about their care goals, a structured format to facilitate the conversations, and continuous measurement for improving EOL care and treatment., The purpose of advance care planning is to enable individuals to make plans about their future health care and improve discussions about end‐of‐life care and treatment. This article examines the current status of advance care planning for patients with advanced metastatic breast cancer to determine factors associated with physician engagement in institutions that specialize in oncology.

PURPOSE Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)–positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. This updated article reflects minor numerical corrections in some secondary efficacy analyses that resulted from programming errors and that do not change the major conclusions of the study. METHODS Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) plus TRAS plus AI, TRAS plus AI, or LAP plus AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP plus TRAS plus AI versus TRAS plus AI. Secondary end points were PFS (comparison of other arms), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. RESULTS Three hundred fifty-five patients were included in this analysis: LAP plus TRAS plus AI (n = 120), TRAS plus AI (n = 117), and LAP plus AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP plus TRAS plus AI versus TRAS plus AI (median PFS, 11 v 5.6 months; hazard ratio, 0.62 [95% CI, 0.45 to 0.88]; P = .0063). A consistent PFS benefit was observed in predefined subgroups. ORR, CBR, and OS also favored LAP plus TRAS plus AI. The median PFS with LAP plus AI versus TRAS plus AI was 8.3 versus 5.6 months (hazard ratio, 0.85 [95% CI, 0.62 to 1.17]; P = .3159). Common adverse events (AEs; ≥ 15%) with LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the 3 groups, and AEs leading to discontinuation were lower with LAP plus TRAS plus AI. CONCLUSION Dual HER2 blockade with LAP plus TRAS plus AI showed superior PFS benefit versus TRAS plus AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.

Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer.We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969.Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [1%]), and fatigue (six [1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis.These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer.Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Over the past 10 years, immunotherapy with immune checkpoint inhibitors has revolutionized the management of various cancers. However, immunotherapy in breast cancer has not been successful. Breast cancer has long been recognized as an immunologically ‘cold’ tumor, although a higher frequency of tumor-infiltrating lymphocytes present in certain subtypes and an association between tumor-infiltrating lymphocytes and favorable prognosis have been reported. In March 2019, the combination of atezolizumab and nanoparticle albumin-bound paclitaxel was granted accelerated approval in the United States for the treatment of programmed death-ligand 1-positive advanced or metastatic triple-negative breast cancer. This finally opened the door for immune checkpoint blockade therapy for breast cancer. Several clinical trials have been conducted using different combinations of immune checkpoint inhibitors and chemotherapy or targeted agents in various treatment settings for metastatic breast cancer and early-stage breast cancer. In this review, we summarize recent advances in immune checkpoint blockade therapy and predictive biomarkers in breast cancer.

BackgroundIn the double-blind, phase 3 PALOMA-2 and PALOMA-3 studies, palbociclib plus endocrine therapy (ET) demonstrated significant improvement in progression-free survival versus placebo plus ET in patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer. This analysis assessed subsequent treatment patterns after palbociclib therapy in Japanese patients enrolled in the PALOMA-2 and PALOMA-3 studies.MethodsPALOMA-2 included postmenopausal women who had not received prior systemic therapy for advanced disease. PALOMA-3 included pre- or postmenopausal women who had progressed on previous ET. Types of subsequent therapy were assessed, and treatment durations of subsequent therapy were estimated using the Kaplan–Meier method.ResultsJapanese patients were enrolled in PALOMA-2 (n = 46) and PALOMA-3 (n = 35). In both studies, the most common first subsequent therapy was ET (PALOMA-2, 77% in the palbociclib group and 75% in the placebo group; PALOMA-3, 55% and 43%, respectively), followed by chemotherapy (PALOMA-2, 18% and 8%; PALOMA-3, 32% and 57%). The median (95% CI) duration of first subsequent therapy was 6.4 (2.3‒13.9) months with palbociclib plus letrozole and 6.7 (2.8‒13.0) months with placebo plus letrozole in PALOMA-2 and 3.8 (2.4‒5.7) months with palbociclib plus fulvestrant and 9.7 (1.0‒not estimable) months with placebo plus fulvestrant in PALOMA-3.ConclusionsThe types of first subsequent therapy received by Japanese patients in the palbociclib plus ET and placebo plus ET groups were similar. Further evaluation of subsequent therapy data in the real-world setting is warranted considering the small sample size of this analysis.

Purpose The CKD4/6 inhibitor abemaciclib is related to adverse events such as hematological toxicity and increase in serum creatinine levels associated with abemaciclib pharmacokinetics. Increase in serum creatinine levels is considered a result of competition with abemaciclib via organic cation transporter 2 and multidrug and toxic compound extrusion. Therefore, we evaluated the association among serum creatinine levels, serum abemaciclib concentrations, and adverse events and whether increase in serum creatinine levels is a useful indicator for predicting the onset of the adverse events of abemaciclib. Methods In total, the data of 12 patients with breast cancer who were treated with abemaciclib (150 mg twice daily) were evaluated to determine the association between increased serum creatinine levels and abemaciclib concentrations and hematological toxicity. Results Grade 3 neutropenia, thrombocytopenia, and anemia were observed at 4 weeks in four (33%), two (17%), and one (8%) patients, respectively. A significant association was observed between steady-state abemaciclib concentrations and the rate of decrease in neutrophil and platelet counts (r = - 0.80, P = 0.003 and r = - 0.70, P = 0.016, respectively). Compared with baseline levels (0.61 [0.53-0.82] mg/mL), serum creatinine levels significantly increased and reached a steady state in at least 2 weeks (0.84 [0.61-1.02] mg/mL, P = 0.01). However, we did not find a significant association between increase in serum creatinine levels and abemaciclib concentrations and hematological toxicity. Conclusions Abemaciclib concentrations are associated with neutropenia and thrombocytopenia. However, increase in serum creatinine levels may not be a useful predictor for estimating abemaciclib pharmacokinetics and hematological toxicity.

Background Bevacizumab is an antiangiogenic agent, and that synergizes with chemotherapeutic drugs. When used in combination therapies, Bevacizumab is associated with adverse events such as hemorrhage, gastrointestinal perforation, delayed wound healing, and pneumothorax. However, the molecular mechanisms underlying these adverse events are not fully understood. Case summary A 45-year-old female with multiple lung metastases that were derived from primary breast cancer, was placed on Bevacizumab + paclitaxel therapy, since this combination has a potent antitumor effect. She reported dyspnea before cycle 3, day 1 and we therefore ran a chest X-ray, which detected a right pneumothorax. The coronal plane computed tomography revealed that one solid mass rapidly necrosed and was replaced by a cavity that passed through the bronchus in the right lower lobe. The cavity eventually ruptured the pleura and made the bronchopleural fistula that led to this pneumothorax. Thoracic cavity drainage using an intercostal catheter was performed. On the 7th day of drainage, the patient was discharged from our hospital on recovery. Recurrence of pneumothorax was not reported, and continuation of chemotherapy was made possible by changing the regimen. Conclusion Patients with lung metastases surrounding the bronchi and on the pleura should be monitored for pneumothorax by Bevacizumab-containing chemotherapies.

Purpose Anti-human epidermal growth factor receptor 2 (HER2) therapies are associated with interstitial lung disease (ILD), also referred to as pneumonitis. In this literature review, we describe the incidence of ILD among patients with HER2-positive metastatic breast cancer (MBC) receiving anti-HER2 therapies, and we describe existing recommendations for monitoring and managing drug-induced ILD among these patients. Methods We searched PubMed and Embase to identify clinical trials and postmarket observational studies that investigated anti-HER2 therapies for HER2-positive MBC, reported on ILD, and were published during January 1, 2009 to July 15, 2019. Articles were screened by two researchers; data were extracted from the full-text articles. Results The 18 articles selected for this review assessed 9,886 patients who received trastuzumab (8 articles), lapatinib (4 articles), trastuzumab emtansine (3 articles), trastuzumab deruxtecan (2 articles), or trastuzumab duocarmazine (1 article). The overall incidence of all-grade ILD was 2.4% (n = 234), with 66.7% (n = 156) occurring as grade 1–2 events, 0.5% grade 3–4 (n = 54; incidence), and 0.2% grade 5 (n = 16; incidence). The highest ILD incidence (21.4%) was among patients receiving trastuzumab combined with everolimus and paclitaxel. Ten studies indicated that ILD events were managed via dose interruption, dose reduction, or treatment discontinuation; two studies included detailed guidelines on managing drug-induced ILD. Conclusions ILD is a well-described adverse drug reaction associated with several anti-HER2 drugs. Published ILD management guidelines are available for few anti-HER2 treatment regimens; however, guidance for monitoring for anti-HER2 drug-induced ILD is lacking.

PURPOSE Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−) breast cancer (ClinicalTrials.gov identifier: NCT02564900 ) are reported. PATIENTS AND METHODS Eligible patients had advanced/metastatic HER2-low–expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd–induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

The utility of regional nodal irradiation (RNI) is being considered in cases of 1-3 axillary node metastases after breast-conserving surgery (BCS) with axillary lymph-node dissection (ALND). Therefore, we examined the necessity of RNI by examining the sites of recurrences in cases at our institution. We retrospectively analyzed 5,164 cases of primary breast cancer between January 2000 and December 2014 at the Aichi Cancer Centre, identifying local and distant recurrences in 152 patients with primary breast cancer treated with BCS and ALND and who had 1-3 positive axillary nodes. All patients received whole-breast irradiation (WBI) and adjuvant systemic therapy with either chemotherapy or anti-endocrine therapy with or without anti-human epidermal growth factor receptor 2 therapy. The present study excluded patients with ipsilateral breast tumor recurrence, contralateral breast cancer, neoadjuvant chemotherapy, T4 tumors or N2-3 nodes and distant metastasis. From the database of our institution, we identified 152 cases that met the defined criteria. The median follow-up period was 71 months (1-176). Isolated locoregional recurrences were found in three patients (2.0%) and were recurrent only in the breast. Only one patient had local lymph node recurrence with distant recurrence. The 10-year rates of isolated regional disease-free survival (DFS), DFS, and overall survival were 95.41, 89.50 and 96.75%, respectively, which was better compared with previous studies. We conclude that the addition of RNI to WBI is not necessary for Japanese patients who have 1-3 positive axillary nodes and ALND.

Breast cancer is highly sensitive to systemic therapy. High probability of pathological complete response suggests a clinical question that omitting surgery is an effective alternative to surgery in breast cancer showing clinical complete response to primary systemic therapy. However, the validity of omitting surgery for early breast cancer after primary systemic therapy has not been sufficiently established; thus, even if pathological complete response is expected in patients showing clinical complete response, excision of the primary tumor site remains the standard treatment of breast cancer. Inappropriate omitting surgery increases the incidence of local recurrence, which can be the risk of a subsequent distant metastasis and reduced overall survival. To achieve acceptable local control rate, omitting surgery should be investigated in patients with early breast cancer where a high percentage of pathological complete response, a high concordance rate between clinical complete response and pathological complete response and an acceptable local control rate are expected. This review presents concept and ongoing clinical trials for omitting surgery for patients with breast cancer showing clinical complete response to primary systemic therapy.

Palbociclib is a highly selective, reversible, oral inhibitor of cyclin‐dependent kinases 4 and 6 that is approved to treat hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer. An open‐label, single‐arm, Japanese phase 2 study was conducted to investigate the efficacy and safety of palbociclib plus letrozole as first‐line treatment in 42 postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer. The probability of progression‐free survival originally reported at 1 year was 75.0% (90% confidence interval, 61.3‐84.4), but median progression‐free survival was not attained at the primary analysis. In this report, updated efficacy and safety results with a longer follow‐up period are presented. The median duration of treatment in the updated analysis was 33.0 months (range, 1.8‐49.2). The probability of progression‐free survival at 1 year was 75.6% (90% confidence interval, 62.4‐84.7). Median progression‐free survival was 35.7 months (95% confidence interval, 21.7‐46.7). Objective response rate and disease control rate were 47.6% (95% confidence interval, 32.0‐63.6) and 85.7% (95% confidence interval, 71.5‐94.6), respectively. Common treatment‐related adverse events (all grades; grade 3/4) were neutropenia (100%; 93%), leukopenia (83%; 60%), and stomatitis (76%; 0%). Treatment‐related febrile neutropenia was reported in one patient. In general, no clinically meaningful deterioration in health‐related quality of life was observed. Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer in this updated analysis., With longer follow‐up of an open‐label, single‐arm, Japanese phase 2 study conducted to investigate the efficacy and safety of palbociclib plus letrozole as first‐line treatment in postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer, median progression‐free survival was 35.7 months (95% CI, 21.7‐46.7). Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer.

The OlympiAD Phase III study (NCT02000622) established the clinical benefits of olaparib tablet monotherapy (300 mg twice daily) over chemotherapy treatment of physician’s choice (TPC) in patients with a germline BRCA1/2 mutation (gBRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who had received ≤2 chemotherapy lines in the metastatic setting. Here, we report pre-specified analyses of data from Asian (China, Japan, Korea and Taiwan) patients in the study. All patients were randomized 2:1 to olaparib tablets (300 mg twice daily) or single-agent chemotherapy TPC (21-day cycles of either capecitabine, eribulin or vinorelbine). The primary endpoint was progression-free survival assessed by blinded independent central review. The prevalence of gBRCAm in the OlympiAD Asian subgroup screened for study recruitment was 13.5%. Patient demographics and disease characteristics of the Asian subgroup (87/302 patients) were generally well balanced between treatment arms. Asian patients in the olaparib arm achieved longer median progression-free survival, assessed by blinded independent central review, versus the chemotherapy TPC arm (5.7 vs 4.2 months; HR = 0.53 [95% CI: 0.29–0.97]), which was consistent with findings in the global OlympiAD study population. Findings on secondary efficacy and safety/tolerability outcome measures in Asian patients were also similar to those observed in the global OlympiAD study population. The OlympiAD study was not powered to detect race-related differences between treatment groups; however, the consistency of our findings with the global OlympiAD study population suggests that previously reported findings are generalizable to Asian patients.

Purpose We present the English version of The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition. Methods The JBCS formed a task force to update the JBCS Clinical Practice Guidelines, 2015 edition, according to Minds Handbook for Clinical Practice Guideline Development 2014. First, we set multiple outcomes for each clinical question (CQ). Next, quantitative or qualitative systematic review was conducted for each of the multiple outcomes, and the strength of recommendation for the CQ was taken into consideration during meetings, with the aim of finding a balance between benefit and harm. Finalized recommendations from each session were confirmed through discussion and voting at the recommendation decision meeting. Results The recommendations, the strength of recommendation and the strength of evidence were determined based on systemic literature reviews and the meta-analyses for each CQ. Conclusion The JBCS updated the Clinical Practice Guidelines for systemic treatment of breast cancer.

Background: Paclitaxel (PTX) is one of the key drugs for primary and metastatic breast cancer. The management of PTX induced peripheral neuropathy (PN) is not easy regardless of several reports about the prevention of chemotherapy-induced peripheral neuropathy (CIPN). Recently, the effectiveness of compression therapy for nanoparticle albumin-bound-paclitaxel induced PN using surgical gloves (SG) was reported from Japan. However, we consider the accurate assessment of CIPN is difficult because it is evaluated by mainly subjective symptoms, therefore, some biases such as performance bias and detection bias occurred easily. Additionally, it is difficult to confirm the reproducibility of the assessment. In this study, we assess the effectiveness of compression therapy using SG (same procedure as previous reports) for the prevention of CIPN based on the complete blind for patients and assessing physician which means the study design to minimize the biases. Methods: The early and recurrence breast cancer patients who started chemotherapy of weekly PTX 80mg/m2(± Trastuzumab or Bevacizumab or Pertuzumab±Trastuzumab) were enrolled. Each patient installed SG on both hands at every PTX infusion. Two one-size smaller SG was installing on one hand (study side) and two just fitted SG was installing on another hand (control side) during 90 minutes from 30 minutes before the infusion to 30 minutes after the end of the infusion. Study side and control side are blind for both patients and physicians according to the determination of the study side by research nurses in the chemotherapy unit. The primary outcome is the difference in the frequency of CIPN (motor/sensory) between the study side and the control side determined by the physician using the CTCAE v4.0. Grade 2 or more were considered to be CIPN. The secondary outcome is the difference in the frequency of CIPN (motor/sensory) assessed by the patients using Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE). For the severity assessment, ‘moderate’ or more and for the interfering with the daily activities assessment, ’somewhat’ or more was considered as an event. We planned sample size as follows. We assessed the frequency of more than grade2 PN in the control hand is 30% based on previous reports. According to the previous study of compression therapy, we expected 15% difference between each side with 80 % power and a significance level for a two-sided test of 0.05. We consider 5% of the dropout rate, the planned total sample size was 55 patients. McNemar Chi-squared test was used to assess the primary and secondary outcome. Results: Between July 11, 2017 and November 26, 2018, 56 patients were enrolled from our institution. Two patients who complained uncomfortableness of installing SG and unmatched five patients for the inclusion criteria were excluded. As a result, 49 patients were evaluated. For the patient characteristics, median age was 53, 43(87.8%) were early and 6(12.2%) were recurrence breast cancer patients. 21 patients underwent axillary dissection. At the end of the PTX regimen, Grade 2 or more PN (sensory) was observed 34.7% and 34.7% in the study and control side, respectively (McNemar p=1.0). PN (motor) was observed 24.5% and 26.5 % in the study and control side, respectively (McNemar p=1.0). No statistically significant difference of primary endpoint was observed between the control side and the study side. For the Pro-CTCAE assessment, there was also no difference between the study and control side both in the grade of numbness (McNemar p=1.0) and the effect for life. (McNemar p=1.0) Conclusions: SG compression therapy was not effective for decreasing the incidence of PTX induced PN. Citation Format: Haruru Kotani, Nanae Horisawa, Kayoko Sugino, Ayumi Kataoka, Yayoi Adachi, Naomi Gondou, Akiyo Yoshimura, Masaya Hattori, Masataka Sawaki, Mitsuo Terada, Hiroji Iwata. A double-blind phase 2 trial of preventative use of surgical gloves for paclitaxel-induced peripheral neuropathy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-25.

Background: In the Phase 3 IMpassion130 (NCT02425891) trial in metastatic triple-negative breast cancer (mTNBC), first-line atezolizumab + nab-paclitaxel (A+nP) significantly improved PFS vs placebo + nab-paclitaxel (P+nP) in the intent-to-treat (ITT) and PD-L1+ (PD-L1-stained immune cells [IC] ≥ 1% of the tumor area by VENTANA PD-L1 SP142 assay) populations. SP142 is currently the only validated assay for selecting patients who may derive benefit with A+nP. In post-hoc analyses of IMpassion130 (Rugo, ESMO 2019, submitted), PD-L1 status was also evaluated by Dako 22C3 and VENTANA SP263 assays. The SP142+ population (IC ≥ 1%; 46% prevalence) was captured within the 22C3 (CPS ≥ 1, 81% prevalence) and SP263 (IC ≥ 1%, 75% prevalence) subgroups, which identified more patients (pts) with PD-L1+ tumors. A+nP clinical activity was highest in pts identified as PD-L1+ by both SP142 and 22C3/SP263. HRs for clinical activity were lower in pts identified as PD-L1+ by 22C3/SP163, but PD-L1- by SP142. There was no suggestion of clinical benefit in pts identified as PD-L1- by both SP142 and 22C3/SP263. In the current retrospective exploratory analysis, we attempted to harmonize the PD-L1 assays by identifying cutoffs for 22C3 or SP263 that replicate the SP142 IC ≥ 1% population. Methods: Samples from IMpassion130 were assessed by a central laboratory for PD-L1 expression using VENTANA SP142 or SP263 IHC assays or Dako 22C3 IHC assay. Optimal cutoffs for 22C3 and SP263 were identified as those that maximize the analytical concordance (defined as overall percentage agreement; OPA) with the clinically validated SP142 IC 1% cutoff as the reference standard. Association with clinical activity was analyzed in the biomarker-evaluable population (BEP) in tumor samples from pts evaluated by the three PD-L1 assays. Results: In the BEP (n = 614; 68% of ITT), the intraclass correlation index (Spearman r) between SP142 IC and 22C3 CPS or SP263 IC was 0.57 and 0.69, respectively. The model-derived cutoffs with highest OPA (75%) for SP142 IC ≥ 1% were CPS 10 for 22C3 and IC 4% for SP263. Compared with our previous analyses at standard cutoffs (22C3 CPS 1; SP263 IC 1%), model-derived cutoffs resulted in negative percentage agreement increases from 45% to 74% (22C3) and from 34% to 77% (SP263), accompanied by positive percentage agreement reductions from 98% to 74% (22C3) and to 73% (SP263). These data suggest that the SP142 assay may identify a different population from the 22C3 or SP263 assays. For 22C3 at CPS 10, 36% of pts were SP142+/22C3+, but 10% were SP142+/22C3-, and 17% SP142-/22C3+. For SP263 at IC 4%, 34% of pts were SP142+/SP263+, but 12% were SP142+/SP263-, and 12% SP142-/SP263+. See table for prevalences, medians and HR point estimates for PFS and OS with the model-derived cutoffs. Conclusions: The suboptimal OPAs achieved with the model-derived cutoffs indicate that the assays could not be harmonized. Differences in SP142+ vs 22C3+ or SP263+ populations at model-derived cutoffs suggest that SP142, 22C3 and SP263 may not identify the same tumor biology. Additional data are required to understand these differences. Findings from these hypothesis-generating, post-hoc exploratory analyses based on mathematical modeling should be interpreted with caution. Currently, the VENTANA PD-L1 SP142 IHC assay (IC ≥ 1%) is the only clinically validated companion assay to select pts with mTNBC for A+nP treatment. Populationn (%)Median PFS, moPFS HRMedian OS, moOS HRA+nPP+nP(95% CI)A+nPP+nP(95% CI)BEP614 (100)7.45.40.7221.119.20.84(0.61, 0.86)(0.68, 1.03)SP142IC ≥ 1%285 (46)8.34.10.627.317.90.74(0.47, 0.78)(0.54, 1.01)IC < 1%329 (54)5.75.60.8620.820.70.95(0.68, 1.09)(0.72, 1.27)22C3CPS ≥ 10325 (53)7.55.50.712218.70.77(0.56, 0.91)(0.57, 1.03)CPS < 10289 (47)5.85.40.7320.219.40.94(0.57, 0.93)(0.69, 1.26)SP263IC ≥ 4%286 (47)8.75.50.6428.919.60.71(0.49, 0.83)(0.51, 0.98) Citation Format: Hope Rugo, Sherene Loi, Sylvia Adams, Peter Schmid, Andreas Schneeweiss, Carlos H Barrios, Hiroji Iwata, Véronique Diéras, Eric P Winer, Mark M Kockx, Dieter Peeters, Stephen Y Chui, Jennifer C Lin, Anh Nguyen Duc, Guiseppe Viale, Luciana Molinero, Leisha A Emens. Exploratory analytical harmonization of PD-L1 immunohistochemistry assays in advanced triple-negative breast cancer: A retrospective substudy of IMpassion130 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-07.

Background: Triple-negative breast cancer (TNBC) generally has an aggressive clinical course, including distant metastases and increased likelihood of death within 5 years of diagnosis compared with non-TNBCs. Therapeutic options for metastatic TNBC patients are limited to sequential chemotherapy, although recent advances with novel agents have been made for specific subgroups (PD-L1 inhibitor atezolizumab in combination with nab-paclitaxel in patients with PD-L1-positive tumors and PARP inhibitors in germline BRCA-mutant patients). However, improvements in progression-free survival (PFS) derived from immune-oncology and PARP inhibitors are still insufficient in terms of informing patient selection and overall magnitude of benefit. Developing novel treatments in both early and advanced TNBC settings remains a significant unmet need in the management of advanced breast cancer. The PI3K/AKT/PTEN signaling pathway is often activated in TNBC, mainly through activating mutations in PIK3CA or AKT1 and/or inactivating alterations in PTEN. The Phase II PAKT study (NCT02423603) demonstrated that addition of the oral AKT inhibitor capivasertib to first-line paclitaxel resulted in significantly longer PFS and overall survival (OS) in patients with advanced TNBC, especially in patients with PIK3CA/AKT1/PTEN-altered tumors (Schmid, 2018). The Phase III trial we report (NCT03997123) will further evaluate the efficacy and safety of capivasertib in combination with paclitaxel in first-line treatment of patients with metastatic TNBC in an unselected population and will also explore potential predictive markers of sensitivity to the combination of paclitaxel and capivasertib. Methods: Eligible patients for this double-blind, randomized, placebo-controlled trial must have metastatic TNBC or locally advanced disease not amenable to resection with curative intent. Patients must be candidates for single-agent taxane therapy and have received no prior systemic therapy for locally advanced inoperable or metastatic disease. Prior chemotherapy in the (neo)adjuvant setting must be completed ≥12 months prior to enrollment. Patients will be randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8 and 15) with either capivasertib 400 mg twice daily or placebo (days 2-5, 9-12, 16-19) every 28 days until objective radiologic disease progression as defined by RECIST 1.1, unacceptable toxicity, or death. Stratification factors will be prior adjuvant chemotherapy, visceral vs non-visceral disease, and geographic region. Post-randomization central testing of tumor tissue (collected prior to enrollment) will be carried out to identify predictive markers of sensitivity to treatment. The primary endpoints of this study are PFS and OS. Secondary endpoints include safety and tolerability, time to second progression or death, objective response rate, duration of response, and clinical benefit rate. Enrollment for this study opened in May 2019. Citation Format: Peter Schmid, Javier Cortes, Mark Robson, Hiroji Iwata, Roberto Hegg, Sunil Verma, Marina Nechaeva, Binghe Xu, Vincent Haddad, Esteban Rodrigo Imedio, Gaia Schiavon, Andrew Foxley, Yeon Hee Park. Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-08-02.

Background: Insulin-like growth factor receptor-1 (IGF-1R) signaling is implicated in cancer progression, prognosis, and treatment resistance. Cross-talk between IGF-1R signaling and cyclin-dependent kinase (CDK) 4 & 6 was reported in preclinical studies, and synergy was shown with concurrent inhibition of IGF-1R signaling and CDK 4 & 6. The CDK 4 & 6 inhibitor, abemaciclib, is FDA approved for hormone receptor-positive [HR+], HER2- advanced BC (ABC) in combination with an aromatase inhibitor as initial endocrine-based therapy, with fulvestrant for progression following endocrine therapy (ET), and as monotherapy for progression following ET and prior chemotherapy in the metastatic setting. NCT03099174 is a prospective, open-label study investigating the safety and tolerability of concurrent inhibition of IGF/IGF-1R signaling with the IGF-1/2-neutralizing monoclonal antibody, xentuzumab, plus abemaciclib (provided by Eli Lilly), with or without ET. Methods: 4 dose-finding cohorts were evaluated in 2 parts using a Bayesian Logistic Regression Model with overdose control, fitted to toxicity outcomes. Part 1 (Cohort A) included pts with solid tumors who had failed/were intolerant of prior treatments, or had no other option available. The starting dose was xentuzumab 1000 mg i.v. weekly plus abemaciclib 150 mg orally (p.o.) every 12 h (Q12h). Part 1 determined the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) prior to starting Part 2. Part 2 included postmenopausal women with HR+, HER2- BC who had received 0-2 prior lines of chemotherapy in the metastatic setting and were eligible for ET. One of 3 ETs was combined with xentuzumab plus abemaciclib (doses determined in Part 1): Cohort B, letrozole; Cohort C, anastrozole; Cohort D, fulvestrant. Previous CDK 4 & 6 inhibitor therapy was not permitted. Treatment was given until progression, lack of tolerability, or withdrawal. Primary endpoints were MTD and dose-limiting toxicities (DLTs) during the first 28-day cycle. Tumor response and progression-free survival (PFS) were also assessed. Results: 27 pts were treated (26 female [96.3%]; median age, 58 years [range 34-70]); 9 pts remained on treatment at the time of analysis. Cohorts A/B/C/D included 6/7/6/8 pts. Cohort A included pts with ABC (n=3), and lung cancer, sarcoma, and colorectal cancer (n=1 each). In total, 23 pts were evaluable for MTD. MTD was xentuzumab 1000 mg i.v. weekly plus abemaciclib 150 mg p.o. Q12h in Cohorts A, B, and D (Cohort C is ongoing). During Cycle 1, 4 DLTs were reported (Cohort A: grade 3 neutrophil count decrease, n=1; Cohort B: grade 3 neutrophil count decrease, n=1; Cohort C: grade 4 thrombocytopenia, n=1; Cohort D: grade 3 neutropenia, n=1). The most common drug-related AEs (DRAEs) in Cohort A were diarrhea and decreased appetite (66.7% each), and nausea, vomiting, and asthenia (50% each). The most common DRAEs in Cohorts B/C/D were diarrhea (90.5%), asthenia (66.7%), anemia (61.9%), neutropenia (57.1%), and nausea (52.4%). Most were reversible and grade 1/2. The most common grade 3/4 DRAEs were diarrhea (16.7/0%) in Cohort A, and neutropenia (19.0/14.3%) and diarrhea (14.3/0%) in Cohorts B/C/D. 4 pts had a best overall response of partial response (Cohorts A and B, n=1; Cohort D, n=2) and 10 pts had stable disease (Cohort A/B/C/D, n=1/3/1/5; duration currently Citation Format: Douglas Yee, Mafalda Oliveira, Hiroji Iwata, Anthony Gonçalves, Javier García-Corbacho, Marie Paule Sablin, Aleix Prat, Molly Catherine Hardebeck, Marta Puig, Dennis Chin-Lun Huang, Mingchi Hsu, Patricia LoRusso. A phase Ib multi-cohort study of xentuzumab and abemaciclib in patients (pts) with solid tumors and breast cancer (BC) - Initial report of four dose-finding cohorts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-05.

Background: Medical expenses are on an increasing trend due to "medical innovation". The Japanese government introduced health technology assessment (HTA) in April 2016. HTA is the systematic evaluation process of scientific value, economic, social and ethical issues related to medical technology with fair and robust methods while ensuring transparency. Two achievements are expected in our research. First, we establish the evaluation standard for the interpretation of the results of cost-effectiveness analysis (CEA) of clinical trials for a standard treatment for breast cancer. Next, we can re-evaluate the HTA's decision making based on the viewpoint of general Japanese population from the perspective of cancer patients. We believe this research can contribute to the creation of a healthcare system that is meaningful to patients, clinicians, industries, and healthcare policymakers. Specific Aims: The aim of this study is to prove how Japanese breast cancer patients who received treatment in Japan consider the financial value (willingness to pay; WTP) for their life and health by using the Contingent Valuation Method (CVM), prospectively. Based on our results, we will construct an evaluation axis from patients’ viewpoint for the cost effectiveness of clinical trials to establish standard treatments for breast cancer. Key Eligibility Criteria: For Japanese breast cancer patients aged 20 to 79 who meet the followings. Unilateral breast cancer patients who fulfill either i) or ii) below i) Primary breast cancer of clinical stage 0 through III for which surgery and/ or chemotherapy and / or radiotherapy has been completed as initial treatment and that is currently undergoing regular follow-up observations or postoperative endocrine therapy. ii) Undergoing endocrine therapy or first-line through third-line chemotherapy for metastatic or recurrent cancer at least 2 months. Trial Design: This study will be conducted by the Breast Cancer Study Group of the Japan Clinical Oncology Group (JCOG). We will investigate WTP for hypothetical scenarios for primary breast cancer patients (PBC) and metastatic breast cancer patients (MBC), using a two-step dichotomous-choice method in CVM. For PBC, we will evaluate the monetary value of the prevention of recurrent cancer. Therefore, to investigate WTP, we will present hypothetical new treatments for preventing breast cancer death to these patients. In MBC, new treatments for extending survival time is presented as hypothetical scenarios and the patients’ WTP is investigated. Statistical Methods: Questionnaire data that is returned by 4 weeks (postmark deadline) after enrollment is completed at the facility and will be considered valid and analyzed. While the WTP amounts of individual responders are not clarified with the two-step dichotomous-choice method, analyses will proceed considering the obtained responses as follows. With the two-step dichotomous-choice method, if the first stage response is yes, a higher amount will be displayed for the second stage. If the first stage response is no, a lower amount will be shown for the second stage. Target Accrual: The study will be conducted in two stages. First, 168 patients (84 patients with PBC and 84 patients with MBC) will be examined to determine their WTP for setting up the dichotomous-choice method survey form. Next, 1,596 patients (798 patients with PBC and 798 patients with MBC) will be surveyed on their WTP for hypothetical scenarios in CVM. Approximately 1800 patients with primary breast cancer and stable metastatic breast cancer are enrolled. Contact information for people with a specific interest in the trial: Tsuguo Iwatani, MD, PhD. Department of Breast Surgery, National Cancer Center Hospital East tiwatani@east.ncc.go.jp Citation Format: Tsuguo Iwatani, Fumikata Hara, Hiroji Iwata, Tadahiko Shien, Takashi Hojo, Yasuaki Sagara, Norikazu Masuda, Masato Takahashi, Shigehira Saji, Tomomi Fujisawa, Naoto Kondo, Akihiko Shimomura. Estimation of willingness-to-pay for breast cancer treatments through contingent valuation method in Japanese breast cancer patients (JCOG1709A) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-13-01.

[Backgrounds] Many breast cancer survivors (BCSs) still remain physically inactive. Lack of receiving physical activity (PA) information from oncology care providers (OCPs) is known as one of patient-reported barriers to get exercise habits. [Methods] To clarify OCPs’ attitudes, practices, barriers and facilitators of PA promotion in BCSs, we conducted web-based surveys for all members of Japanese Breast Cancer Society (JBCS) and Japanese Association of Cancer Rehabilitation from Dec. 2018 to Feb. 2019. [Results] Of 10,830 OCPs who asked to answer the web-based survey, 1,029 (9.5%) responded. Of those, 17% recognized contents about PA recommendation in JBCS guidelines in detail. And, 23% informed BCSs about benefits of PA routinely. Logistic regression analysis showed that the associated factors about OCPs’ routinely informing about benefits of PA were as follows: 1) recognition that explaining to BCSs about PA includes in OCPs’ own job roles (OR: 5.9, 95% confident interval (95%CI)=2.48-14.02, p Citation Format: Yoichi Shimizu, Katsunori Tsuji, Eisuke Ochi, Ryo Okubo, Taichi Shimazu, Noriatsu Tatematsu, Naomi Sakurai, Hiroji Iwata, Yutaka Johnnie Matsuoka. Oncology care providers’ attitudes, practices, barriers and facilitators of physical activity promotion in breast cancer survivors: A nation-wide cross sectional web-based survey [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-21.

Introduction: Hyperactivation of the phosphoinositide-3-kinase (PI3K) pathway is a frequent event in human cancers and can be a result of phosphatase and tensin homolog (PTEN) loss, activation of receptor tyrosine kinases, or alterations in PI3K isoforms. About 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) breast cancers harbor alterations in the PIK3CA gene, which encodes the alpha subunit of PI3K (p110α). Mutations in PIK3CA can cause PI3K pathway hyperactivation, which may contribute to endocrine resistance. Alpelisib (ALP) is an α-selective PI3K inhibitor that, in combination with fulvestrant (FUL), demonstrated improved median progression-free survival (PFS) vs placebo (PBO) + FUL (11.0 vs 5.7 mo, respectively; hazard ratio [HR] 0.65; 95% confidence interval [CI], 0.50-0.85; P Methods: SOLAR-1 is a phase 3, randomized, double-blind study of ALP 300 mg (or PBO) once daily + FUL 500 mg every 28 days + Cycle 1 Day 15 in men and postmenopausal women with HR+, HER2- ABC. Retrospectively, PIK3CA alterations (mutations and amplifications) were assessed by NGS and PTEN levels were assessed by immunohistochemistry. PTEN loss was defined based on an H-score Results: Of 572 pts in SOLAR-1, 341 (60%) had a PIK3CA mutation in tumor tissue by PCR, valid NGS results were available for 404 (71%), and PTEN levels were available for 401 (70%). Of the pts with available PTEN results, 34 (8%) had PTEN loss. PFS results and HRs, by PIK3CA alteration status as detected by NGS and PTEN status, are shown in the Table. In pts whose tumors had any PIK3CA alteration (n=239), which included a small group of pts with alterations not detectable by the PCR-based test used for screening in SOLAR-1 (n=31), mPFS was improved in the ALP + FUL vs PBO + FUL arms. In the small group of pts (n=19) whose tumors had PTEN loss but no PIK3CA alteration, ALP showed an improved mPFS and favorable HR vs the placebo arm. In pts whose tumors had multiple alterations (n=44), HR and mPFS benefits of ALP were observed, albeit with wide 95% CIs. Conclusions: These data demonstrate the efficacy of ALP in pts whose tumors harbor PIK3CA alterations as detected by NGS, including alterations that were not detectable by the PCR-based test used in SOLAR-1. Additional analyses suggest that ALP is also effective in pts with single and multiple PIK3CA mutations and in those whose tumors do not harbor a PIK3CA alteration but do have PTEN loss; however, low patient numbers in the PTEN loss subgroups may limit conclusions. Alpelisib + FulvestrantPlacebo + FulvestrantHR (95% CI)Events/N (%)mPFS, mo (95% CI)Events/N(%)mPFS, mo (95% CI)PIK3CA:altered vs non-altered (by NGS)Altered68/121 (56.2)11.01 (8.05 - 15.21)85/118 (72.0)5.52 (3.55 - 7.36)0.59 (0.43 - 0.82)Non-altered36/82 (43.9)7.29 (5.22 - 9.17)39/83 (47.0)7.16 (5.03 - 11.01)0.99 (0.62 - 1.57)PIK3CA:single vs multiple alterations (by NGS)Single60/100 (60.0)11.01 (7.49 - 14.55)66/94 (70.2)4.63 (3.38 - 7.39)0.59 (0.41 - 0.84)Multiple8/20 (40.0)9.36 (6.31 - NA)19/24 (79.2)7.29 (2.07 - 12.85)0.56 (0.23 - 1.33)PIK3CA: alteration detectable by PCR vs alteration not detectable in SOLAR-1 (by NGS)Detectable64/105 (61.0)11.01 (7.49 - 15.21)79/103 (76.7)3.81 (3.52 - 7.29)0.56 (0.40 - 0.79)Not detectable4/16* (25.0)8.48 (5.55 - NA)6/15 (40.0)12.98 (3.38 - NA)0.75(0.21 - 2.73)PIK3CA alterations (by NGS) and/or PTEN loss (by IHC)PIK3CA non-altered, PTEN non-loss31/72 (43.1)7.39 (5.16 - 9.26)32/71 (45.1)7.16 (5.06 - 11.01)1.03 (0.62 - 1.70)PIK3CA altered, PTEN non-loss63/113 (55.8)11.01 (8.31 - 15.21)78/111 (70.3)5.52 (3.61 - 7.39)0.63 (0.45 - 0.88)PIK3CA non-altered, PTEN loss5/9 (55.6)6.23 (2.79 - NA)7/10 (70.0)1.86 (1.64 - NA)0.50 (0.13 - 1.89)PIK3CA altered, PTEN loss5/8 (62.5)7.72 (2.69 - NA)7/7 (100.0)3.55 (1.05 - 7.23)0.24 (0.06 - 0.97)CI, confidence interval; HR, hazard ratio; IHC, immunohistochemistry; mPFS, median progression-free survival; NA, not available; NGS, next-generation sequencing; PTEN, phosphatase and tensin homolog.*These 16 alterations not detectable by PCR include 15 mutations and 1 PIK3CA amplification. Citation Format: Dejan Juric, Fabrice Andre, Christian F. Singer, Joohyuk Sohn, Mario Campone, Sibylle Loibl, Pierfranco Conte, Hiroji Iwata, Eva Ciruelos, Ingrid A. Mayer, Albert Reising, Chong Ma, Michelle Miller, Naveen Babbar, Hope S. Rugo. Clinical outcomes of alpelisib in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer by next-generation sequencing-detected PIK3CA alteration status and phosphatase and tensin homolog loss: Biomarker analysis from the SOLAR-1 study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-04.

BACKGROUND: Although long-term prognostic outcomes of primary breast cancer (PBC) patients have been improved remarkably in recent years, the disease recurrence remains a serious problem. We have previously investigated a role for oral fluoropyrimidines in postoperative adjuvant treatments.In this study, we aimed to verify the usefulness of S-1 in combination with adjuvant endocrine therapy for PBC patients having luminal disease. PATIENTS AND METHODS: This open-label, randomized, phase 3 trial was carried out in 139 centers in Japan. StageI-IIIPBC patients, who had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negativestatus and intermediate or higher risk of recurrence were randomly assigned (1:1) to receive standard endocrine therapy alone (control arm) or endocrine therapy plus S-1 (S-1 arm). Recurrence risk assessment was performed using anatomical stage, pathological findings such as histologic grade, and centrally confirmed proliferative marker status. S-1 was administered postoperatively in combination with standard endocrine therapy. For patients who underwent multi-drug postoperative adjuvant or preoperative neoadjuvant chemotherapy, S-1 was administered following the multi-drug chemotherapy. Cases having no residual cancer in the breast and axillary node after the preoperative chemotherapy were excluded from this study. The S-1 dosage was chosen among 80 mg/day, 100 mg/day, and 120 mg/day according to the body surface area of each patient, and S-1 was administered for one year with a 2 weeks on/1 week off administration schedule. The primary endpoint was invasive disease-free survival (iDFS), defined as time from randomization to invasive disease recurrence, occurrence of second invasive cancer event, or death, and was analyzed on an intent-to-treat basis. Secondary endpoints included DFS, distant DFS, overall survival, and safety profile. RESULTS: From Feb 2012 to Feb 2016, 1959 patients were enrolled and 1932 patients were included in the full analysis set (control arm, 973; S-1 arm, 959). The results of the prespecified interim analysis met the primary end point, and this trial was terminated early. Median follow-up was 51.4 months. S-1 significantly reduced invasive events; 153 iDFS events were reported in the control arm and 99 iDFS events were reported in the S-1 arm [hazard ratio, 0.63 (95%CI, 0.49-0.81); p-value, 0.0003]. The 5-year iDFS estimate was 81.5% in the control arm and 86.9% in the S-1 arm. Distant recurrence as the first disease event was observed in 6.8% of patients in the S-1 arm and in 9.5% of those in the control arm. The safety data in patients treated with S-1 was consistent with the known profile of S-1. The S-1 treatment was well tolerated and manageable. CONCLUSIONS: It was concluded that the postoperative adjuvant use of an oralfluoropyrimidine S-1 significantly reduced iDFS events and improved 5-year iDFS estimate in PBC patients having HR-positive and HER2-negative disease, in the combination with standard endocrine therapy, with a feasible safety profile. Funding: This study was funded by the Comprehensive Support Project (CSP) of the Public Health Research Foundation. The research fund was provided to CSP by Taiho Pharmaceutical Co., Ltd. This trial was conducted as a study of ‘Advanced Medical Care,’ the Ministry of Health, Labour and Welfare, Japan. JRCT ID: jRCTs051180057, UMIN000003969 Citation Format: Masakazu Toi, Shigeru Imoto, Takanori Ishida, Yoshinori Ito, Hiroji Iwata, Norikazu Masuda, Hirofumi Mukai, Shigehira Saji, Akira Shimizu, Takafumi Ikeda, Hironori Haga, Toshiaki Saeki, Kenjiro Aogi, Tomoharu Sugie, Takayuki Ueno, Takayuki Kinoshita, Yuichiro Kai, Masahiro Kitada, Yasuyuki Sato, Kenjiro Jimbo, Nobuaki Sato, Hiroshi Ishiguro, Masahiro Takada, Yasuo Ohashi, Shinji Ohno. Addition of S-1 to endocrine therapy in the post-operative adjuvant treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative primary breast cancer: A multicenter, open-label, phase 3 randomized trial (POTENT trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-09.

Background: The randomized controlled trial (RCT) is accepted as the standard clinical trial to decide a standard therapy, but it remains unclear whether or not elderly patients benefit as much as other patients from participation in an RCT. In the RESPECT study (NCT01104935), the relative value of trastuzumab (H) monotherapy as an adjuvant treatment was compared in an RCT with the standard combination treatment with chemotherapy (H+CT) in patients over 70 years old with HER2-positive invasive breast cancer (BC) who received curative surgery. This cohort study was aimed at comparing prognoses between RCT participants (RCT group) and non-participants (Cohort group). Methods: Patients were divided into RCT participants, and those who did not agree to participate in the RCT despite meeting the eligibility criteria and receiving the explanation given by the investigator. In the RCT group patients were randomized to H or H+CT; in the Cohort group treatment was selected for each patient based on the discretion of the treating physician and the patient's wishes without intervention. Treatment categories were divided into three groups: (1) trastuzumab monotherapy group (cH group), (2) trastuzumab plus chemotherapy group (cH+CT group), and (3) those who received either no therapy at all, or any other anticancer therapies without H (cOther group). The primary endpoint was disease-free survival (DFS). Secondary endpoints were overall survival (OS), relapse-free survival, safety, health-related quality of life (HRQOL) and comprehensive geriatric assessment. Results: A total of 275 patients in the RCT group and 123 patients in the Cohort group, in total 398 patients, were enrolled in this study between October 2009 and October 2014. The median age was 74.0 years in the RCT group, 74.5 years in the Cohort group and the median follow-up time was 4.1 years and 3.2 years, respectively. Patients were classified as Stage I: 41.8%, 42.5%; IIA: 41.5 %, 40.8%; IIB: 13.5%, 13.3%; and IIIA: 1.5%. 3.3%, respectively (P = 0.51), there were no significant differences between the two groups. Treatment categories in the Cohort group were: (1) cH group; 43% (n = 52), (2) cH+CT group; 30% (n = 36), cOther group; 27% (n = 32). The planned analysis showed that DFS at 3 years was 91.4% in the RCT group vs 89.3% in the Cohort group (adjusted hazard ratio (HR) = 1.30; 95%CI, 0.72-2.35, P = 0.38). In patients in the cH+CT, cH and cOther group, DFS at 3 years was 92.3%, 89.2% and 82.5%, respectively. DFS in patients in the cH+CT and the cH group was significantly better than that of the cOther group (adjusted HR = 3.79; 95%CI = 1.35-10.64, P = 0.01). DFS in the cH group showed a better tendency compared with cOther (adjusted HR = 2.59; 95%CI, 0.87-7.73, P = 0.08). The incidence of grade 3/4 non-hematological adverse events in the RCT group was relatively higher compared with the Cohort group (18.5% vs 10.8 %, P = 0.05). Conclusion: The prognosis did not vary between the RCT and Cohort groups. H-containing regimens are often chosen for elderly patients with HER2-positive breast cancer. The prognosis of patients who received any H-containing regimen, even H monotherapy, was better than those who were not treated with H. Citation Format: Shinichi Baba, Masataka Sawaki, Yukari Uemura, Tsuyoshi Saito, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Naruto Taira, Hiroji Iwata, Tatsuya Toyama, Koichiro Tsugawa, Yasuo Ohashi, Hirofumi Mukai. A cohort study to evaluate the efficacy and safety of postoperative adjuvant therapy in HER2-positive elderly breast cancer patients (RESPECT-cohort study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-02.

Background: The standard chemotherapy treatment strategy for patients with advanced/metastatic breast cancer (ABC) is the continuation of the same drug until tumor progression. However, despite continued antitumor effects, continuation of a drug often becomes difficult because of cumulative adverse events, such as peripheral neuropathy. Methods: This multicenter, randomized, Phase II study in patients with estrogen receptorpositive (ER+) human epidermal growth factor receptor 2-negative (HER2−) ABC aimed to compare 2 treatment strategies following induction therapy with 4-6 cycles of the combined use of weekly paclitaxel (wPTX) and bevacizumab (BV). Patients in Arm A continued with wPTX+BV, whereas patients in Arm B were switched from wPTX to maintenance endocrine therapy (endocrine+BV) until disease progression, followed by wPTX+BV re-induction. The primary endpoint was time to failure of strategy (TFS), defined as the time from randomization to a qualifying event (addition of a new agent not in the primary regimen, progressive disease during or after planned therapy, or death). Secondary endpoints were overall survival (OS), progression-free survival, safety, and quality of life (QoL). Sequential plasma and serum biomarkers were analyzed for predicting/monitoring the response. Result: Of 160 patients enrolled to receive induction therapy with wPTX+BV, 125 patients responded to treatment (complete response [CR], partial response [PR], or stable disease) and were randomized to either of the 2 treatment arms. Median follow-up was 21.3 months. Aromatase inhibitor (AI), fulvestrant, or AI with a luteinizing hormonereleasing hormone (LH-RH) analogue was used as maintenance endocrine therapy. The primary endpoint of TFS was 8.87 months (95% CI: 5.68-13.80) in the wPTX+BV continued group (Arm A) and 16.82 months (95% CI: 12.88-18.99) in the maintenance endocrine+BV group (Arm B) (hazard ratio [HR], 0.51; p Conclusion: This is the first study showing the benefit of maintenance endocrine therapy in patients with ER+ HER2− advanced breast cancer who responded to a fixed dose of chemotherapy. (UMIN: UMIN000012179; ClinicalTrials.gov: NCT01989780) Funding: Chugai Pharmaceutical CO., LTD. Citation Format: Shigehira Saji, Masahiro Kitada, Toshimi Takano, Masahiro Takada, Tohru Ohtake, Tatsuya Toyama, Yuichiro Kikawa, Yoshie Hasegawa, Tomomi Fujisawa, Masahiro Kashiwaba, Takanori Ishida, Rikiya Nakamura, Yutaka Yamamoto, Uhi Toh, Hiroji Iwata, Norikazu Masuda, Naruto Taira, Satoshi Morita, Shinji Ohno, Masakazu Toi. A randomized, multicenter, phase II study evaluating the efficacy of interventional maintenance endocrine therapy with bevacizumab following fixed cycles of bevacizumab plus paclitaxel in advanced/metastatic ER-positive HER2-negative breast cancer: JBCRG-M04 BOOSTER trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-01.

Background Previous large trials of trastuzumab (TZM) demonstrated improved outcomes in patients with HER2-positive early breast cancer. However, its effectiveness and safety in Japanese patients is not yet clear. Recently, new anti-HER2 agents were developed to improve treatment outcomes, but the patient selection criteria remain controversial. Purpose The aim of this study was to evaluate the long-term effectiveness of TZM therapy as perioperative therapy for HER2-positive operable breast cancer in daily clinical practice and to create a recurrence prediction model for therapeutic selection. Methods An observational study was conducted in Japan (UMIN000002737) to observe the prognosis of women (n = 2024) with HER2-positive invasive breast cancer who received TZM for stage I–III C disease between July 2009 and June 2011. Moreover, a recurrence-predicting model was designed to evaluate the risk factors for recurrence. Results The 5- and 10-year disease-free survival (DFS) rates were 88.9 (95% CI 87.5–90.3%) and 82.4% (95% CI 79.2–85.6%), respectively. The 5- and 10-year overall survival (OS) rates were 96% (95% CI 95.1–96.9%) and 92.7% (95% CI 91.1–94.3%), respectively. Multivariate analysis revealed that the risk factors for recurrence were an age of ≥ 70 years, T2 or larger tumors, clinically detected lymph node metastasis, histological tumor diameter of > 1 cm, histologically detected lymph node metastasis (≥ n2), and the implementation of preoperative treatment. The 5-year recurrence rate under the standard treatment was estimated to be > 10% in patients with a score of 3 or greater on the recurrence-predicting model. Conclusion The recurrence-predicting model designed in this study may improve treatment selection of patients with stage I–III C disease. However, further studies are needed to validate the scores generated by this model.

Background In establishing the 2018 Breast Cancer Practice Guidelines of the Japan Breast Cancer Society, we explored the optimal first-line endocrine therapy for advanced postmenopausal hormone receptor-positive breast cancer. Methods We performed a systematic review of relevant reports from randomized-controlled studies published prior to November 2016 found using medical journal search engines. The main outcomes which we evaluated were progression-free survival (PFS), objective response rate (ORR), disease control rate (CBR), and toxicity. Results Four controlled trials comparing aromatase inhibitors (AI) and cyclin-dependent kinase (CDK)4/6 inhibitor combination therapy to AI monotherapy, and two controlled trials comparing anastrozole to fulvestrant 500 mg were analyzed. AI/CDK4/6 inhibitor combination therapy significantly improved PFS (Risk Ratio: 0.67, 95%CI 0.60–0.73), increased ORR (Risk Difference: 0.11, 95% CI 0.07–0.16), and increased CBR (Risk Difference: 0.11, 95% CI 0.07–0.15), compared with AI monotherapy. Patients who received this combination therapy had a higher grade ≥ 3 adverse event rate more than those who received AI monotherapy (Risk Difference: 43%, 95%CI: 0.39–0.47). Fulvestrant 500 mg alone significantly improved PFS (risk ratio: 0.85, 95%CI 0.72–0.98), but ORR and CBR were similar to those of anastrozole alone. Conclusion In the first-line treatment for advanced postmenopausal hormone receptor-positive breast cancer, a combination therapy of CDK4/6 inhibitors and AI showed significant improvement of PFS, ORR, and CBR but with significant increased toxicities compared with AI alone. Fulvestrant 500 mg monotherapy significantly prolonged PFS compared with AI monotherapy. We must wait for the results of the studies with longer follow-up period.

Systemic therapies for operable breast cancer patients have improved outcomes and have thus become standard treatments. Recently, new molecular target drugs and regimens are being developed based on the predicted sensitivity for specific breast cancer histological types. Systemic therapy is selected according to recurrence risk, with the treatment for low-risk patients being de-escalated, while high-risk patients receive aggressive systemic treatment with an adequate dose and duration. Neoadjuvant systemic therapy has a different aim. The efficacy of systemic therapies, based on the sensitivities to drugs, is supported by improvements in the rate of breast-conserving therapy. The response to neoadjuvant systemic therapy is the most important factor for predicting outcomes and selecting the optimal adjuvant therapy. Novel biological markers unique to individual patients allow appropriate targeted therapy, which can achieve optimal efficacy.

The combination of bevacizumab and chemotherapy has greatly improved progression-free survival (PFS) and objective response rate (ORR) in HER2-negative metastatic breast cancer in many pivotal trials. However, risk–benefit balance related to bevacizumab addition could not be confirmed because of a lack of overall survival (OS) improvement. Therefore, we conducted a meta-analysis to evaluate multiple endpoints pertaining to bevacizumab use in metastatic breast cancer (MBC) treatment. We searched PubMed and Cochrane Library databases and included seven studies in our meta-analysis in which bevacizumab combined with chemotherapy was compared with chemotherapy alone in MBC. Compared to the chemotherapy-alone group, the combination treatment group had significantly improved PFS [hazard ratio (HR): 0.72, 95% CI 0.67–0.77, P

Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer.In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154.Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness.Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer.Amgen.