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There is now a deeper understanding of the biology of hormone receptor-positive (HR+) early breast cancer (EBC) that can be used to inform assessment of risk and prognosis, and also guide more effective adjuvant systemic therapies. For postmenopausal HR+ EBC endocrine therapy remains the mainstay of treatment with extended duration up to 10 years for some, the addition of targeted CDK 4/6 inhibitors for those with node-positive high-risk disease, and de-escalation of chemotherapy use for those in whom it is unlikely to be of benefit. As such, systemic adjuvant therapy is now highly tailored and individualized.

Adjuvant abemaciclib plus endocrine therapy previously showed a significant improvement in invasive disease-free survival and distant relapse-free survival in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2; also known as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we report updated results from an interim analysis to assess overall survival as well as invasive disease-free survival and distant relapse-free survival with additional follow-up.In monarchE, an open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence with an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 603 sites including hospitals and academic and community centres in 38 countries. Patients were randomly assigned (1:1) by means of an interactive web-based response system (block size of 4), stratified by previous chemotherapy, menopausal status, and region, to receive standard-of-care endocrine therapy of physician's choice for up to 10 years with or without abemaciclib 150 mg orally twice a day for 2 years (treatment period). All therapies were administered in an open-label manner without masking. High-risk disease was defined as either four or more positive axillary lymph nodes, or between one and three positive axillary lymph nodes and either grade 3 disease or tumour size of 5 cm or larger (cohort 1). A smaller group of patients were enrolled with between one and three positive axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature (cohort 2). This was a prespecified overall survival interim analysis planned to occur 2 years after the primary outcome analysis for invasive disease-free survival. Efficacy was assessed in the intention-to-treat population. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03155997, and is ongoing.Between July 17, 2017, and Aug 12, 2019, 5637 patients were randomly assigned (5601 [99·4%] were women and 36 [0·6%] were men). 2808 were assigned to receive abemaciclib plus endocrine therapy and 2829 were assigned to receive endocrine therapy alone. At a median follow-up of 42 months (IQR 37-47), median invasive disease-free survival was not reached in either group and the invasive disease-free survival benefit previously reported was sustained: HR 0·664 (95% CI 0·578-0·762, nominal p0·0001). At 4 years, the absolute difference in invasive disease-free survival between the groups was 6·4% (85·8% [95% CI 84·2-87·3] in the abemaciclib plus endocrine therapy group vs 79·4% [77·5-81·1] in the endocrine therapy alone group). 157 (5·6%) of 2808 patients in the abemaciclib plus endocrine therapy group died compared with 173 (6·1%) of 2829 patients in the endocrine therapy alone group (HR 0·929, 95% CI 0·748-1·153; p=0·50). The most common grade 3-4 adverse events were neutropenia (in 548 [19·6%] of 2791 patients receiving abemaciclib plus endocrine therapy vs 24 [0·9%] of 2800 patients in the endocrine therapy alone group), leukopenia (318 [11·4%] vs 11 [0·4%]), and diarrhoea (218 [7·8%] vs six [0·2%]). Serious adverse events occurred in 433 (15·5%) of 2791 patients receiving abemaciclib plus endocrine therapy versus 256 (9·1%) of 2800 receiving endocrine therapy. There were two treatment-related deaths in the abemaciclib plus endocrine therapy group (diarrhoea and pneumonitis) and none in the endocrine therapy alone group.Adjuvant abemaciclib reduces the risk of recurrence. The benefit is sustained beyond the completion of treatment with an absolute increase at 4 years, further supporting the use of abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative early breast cancer. Further follow-up is needed to establish whether overall survival can be improved with abemaciclib plus endocrine therapy in these patients.Eli Lilly.

PURPOSE To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline. METHODS An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. RESULTS Fifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations. RECOMMENDATIONS Alpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians should use next-generation sequencing in tumor tissue or cell-free DNA in plasma to detect PIK3CA mutations. If no mutation is found in cell-free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations. There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for HR-positive, HER2-negative MBC. For BRCA1 or BRCA2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-naïve HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Purpose: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2− breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers. Experimental Design: 307 postmenopausal women with ER+/HER2− primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1. Results: Higher baselines ER and PgR were significantly associated with a greater chance of complete cell-cycle arrest (CCCA: Ki67 Conclusions: High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3–9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the “off” week of its schedule.

Purpose: In MONARCH 2, abemaciclib plus fulvestrant significantly prolonged progression-free survival (PFS) and overall survival (OS) versus placebo plus fulvestrant in patients with hormone receptor positive (HR+), HER2− advanced breast cancer. This exploratory analysis assessed the efficacy of abemaciclib plus fulvestrant across subgroups of patients receiving study therapy as first- or second-line treatment for metastatic disease. Patients and Methods: Improvements were estimated using Cox models, and a test of interactions of subgroups with treatment was performed. Results: The benefit in PFS [first-line, HR, 0.57; 95% confidence interval (CI), 0.45–0.73; second-line, HR, 0.48; 95% CI, 0.36–0.64] and OS (first-line, HR, 0.85; 95% CI, 0.64–1.14; second-line, HR, 0.66; 95% CI, 0.46–0.94) was observed across both subgroups, consistent with the intent-to-treat (ITT) population. In first-line patients (abemaciclib arm, n = 265; placebo arm, n = 133), the numerically largest effect on PFS and OS was observed in patients with primary resistance to endocrine therapy (ET; PFS, HR, 0.40; 95% CI, 0.26–0.63; OS, HR, 0.58; 95% CI, 0.35–0.97) and visceral disease (PFS, HR, 0.54; 95% CI, 0.39–0.73; OS, HR, 0.82; 95% CI, 0.58–1.20). In second-line patients (abemaciclib arm, n = 170; placebo arm, n = 86), a numerical benefit in PFS and OS was observed across primary and secondary ET resistance, with numerically more pronounced effects observed in patients with visceral disease (PFS, HR, 0.39; 95% CI, 0.27–0.57; OS, HR, 0.51; 95% CI, 0.33–0.81). Prolongation of time to second disease progression, time to chemotherapy, and chemotherapy-free survival was observed in both subgroups. Conclusions: Consistent with the ITT population, a benefit in PFS and OS was observed across the first- and second-line subgroups in MONARCH 2.

In MONARCH 3, continuous dosing of abemaciclib with an aromatase inhibitor (AI) conferred significant clinical benefit to postmenopausal women with HR+, HER2− advanced breast cancer. We report data for clinically prognostic subgroups: liver metastases, progesterone receptor status, tumor grade, bone-only disease, ECOG performance status, and treatment-free interval (TFI) from an additional 12-month follow-up (after final progression-free survival [PFS] readout). In the intent-to-treat population, after median follow-up of approximately 39 months, the updated PFS was 28.2 versus 14.8 months (hazard ratio [HR], 0.525; 95% confidence interval, 0.415–0.665) in abemaciclib versus placebo arms, respectively. Time to chemotherapy (HR, 0.513), time to second disease progression (HR, 0.637), and duration of response (HR, 0.466) were also statistically significantly prolonged with the addition of abemaciclib to AI. Treatment benefit was observed across all subgroups, as evidenced by objective response rate change from the addition of abemaciclib to AI, with the largest effects observed in patients with liver metastases, progesterone receptor-negative tumors, high-grade tumors, or TFI

Endocrine therapy (ET) is recommended as first-line therapy for the majority of patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative advanced breast cancer (ABC); however, the efficacy of ET in patients with visceral metastases (VM) versus patients whose disease is limited to non-visceral metastases (non-VM) is debated. Meta-analyses including available data from randomised controlled trials of first- and second-line endocrine monotherapies for patients with HR+ ABC were performed to address this question. In one and two-stage meta-analyses, progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and duration of clinical benefit (DoCB) outcomes were analysed. In the first-line meta-analysis (seven trials; n = 1988) tamoxifen and fulvestrant significantly improved PFS, OS and CBR for patients with non-VM versus those whose disease included VM. The most substantial hazard ratios were observed for fulvestrant 500 mg; 0.56 (95% confidence interval [CI] 0.45−0.70) and 0.55 (95% CI 0.42−0.72) for PFS and OS, respectively. In the second-line meta-analysis (seven trials; n = 2324), all ET combined was more effective (in terms of PFS, OS and DoCB) for non-VM versus VM. In both meta-analyses, patients with non-liver VM had better clinical outcomes than patients with liver VM for all types of ET. Patients whose disease included non-VM sites had better clinical outcomes with endocrine monotherapy compared with patients whose disease included VM. These findings may facilitate better informed treatment decision-making.

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.

Patients selected to receive neoadjuvant chemotherapy (NAC) are usually those at higher risk of relapse, and there is a need to find better therapeutic options for these patients.To determine the efficacy and safety outcomes for patients with hormone receptor (HR)-positive, ERBB2 (formerly HER2)-, high-risk early breast cancer enrolled in the randomized clinical trial monarchE who received NAC.The monarchE randomized clinical trial was a multicenter, phase 3, open-label study that evaluated adjuvant treatment with abemaciclib plus endocrine therapy (ET) compared with ET alone in patients with HR+, ERBB2-, and node-positive early breast cancer who were at high risk of recurrence. Patients were recruited between July 2017 and August 2019 from 603 sites in 38 countries. This subgroup analysis was performed with primary outcome data, with a cutoff date of July 8, 2020.Enrolled patients were randomized (1:1) to receive standard of care ET for at least 5 years with or without treatment with abemaciclib (150 mg, twice daily) for 2 years (treatment period) or until criteria were met for discontinuation.Prior chemotherapy (NAC vs adjuvant vs none) was a stratification factor in monarchE, and and a prespecified exploratory analysis included outcomes in patients who received NAC. The data presented in this article are from the primary outcome analysis (395 invasive disease-free survival [IDFS] events; cutoff date, July 8, 2020; median follow-up 19 months [IQR, 15.6-23.9 months]). Invasive disease-free survival (the primary end point of monarchE) and distant relapse-free survival (DRFS) were evaluated using the Cox proportional hazard model and Kaplan-Meier method.Of the 5637 patients (mean [SD] age, 49.9 [10.6] years; 2046 women [99.5%]; 462 Asian [22.8%], 54 Black [2.7%], and 1473 White participants [70.8%]) enrolled in monarchE, 2056 (37%) received treatment with NAC. In this subgroup, treatment with abemaciclib and ET demonstrated clinically meaningful benefit in IDFS (hazard ratio, 0.61; 95% CI, 0.47-0.80) and DRFS (hazard ratio, 0.61; 95% CI, 0.46-0.81), which corresponded with an absolute improvement of 6.6% in 2-year IDFS rates and 6.7% in 2-year DRFS rates. A consistent treatment benefit was observed across subgroups of pathological breast tumor size or number of positive lymph nodes at surgery.In the randomized clinical trial monarchE, treatment with adjuvant abemaciclib combined with ET demonstrated a clinically meaningful improvement in IDFS and DRFS for patients with HR+, ERBB2-, node-positive, high-risk early breast cancer who received NAC before trial enrollment.ClinicalTrials.gov Identifier: NCT03155997.

The monarchE Cohort 1 patient population was enrolled based on high-risk clinicopathological features that can easily be identified as part of routine clinical breast cancer evaluation. Efficacy data from Cohort 1 demonstrate substantial evidence of benefit for adjuvant abemaciclib+ET in patients with HR+, HER2− early breast cancer at high risk of recurrence (ClinicalTrials.gov: NCT03155997 [monarchE]).

Purpose: ESR1 mutations are acquired frequently in hormone receptor–positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane. Experimental Design: The phase III EFECT and SoFEA trials randomized patients with hormone receptor–positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies. Results: ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0–2.6] on exemestane and 3.9 months (95% CI, 3.0–6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39–0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7–6.2) on exemestane and 4.1 months (95% CI, 3.6–5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81–1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%–75%) on exemestane and 80% (95% CI, 68%–87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%–85%) on exemestane and 81% (95% CI, 74%–87%) on fulvestrant (P = 0.69). Conclusions: Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.

Background: Abemaciclib plus nonsteroidal aromatase inhibitors (AI) demonstrated efficacy with a tolerable safety profile as initial treatment for postmenopausal women with HR+, HER2− advanced breast cancer in the MONARCH 3 trial. In the intent-to-treat (ITT) population, the updated progression-free survival (PFS) with 12 months of additional follow-up was 28.2 versus 14.8 months (HR [95% CI]: 0.525 [0.415, 0.665]; p Methods: In MONARCH 3, a randomized, double-blind, phase III trial, 493 postmenopausal women with HR+, HER2− advanced breast cancer and no prior systemic therapy in the advanced setting, received an AI (anastrozole or letrozole) plus abemaciclib or placebo. From the October 31, 2018 cutoff, secondary endpoints including objective response rate ([ORR], complete response [CR] + partial response [PR]), time to response (TTR), and duration of response ([DoR], time from a confirmed CR or PR until disease progression or death) were assessed in the ITT population and exploratory subgroups previously reported as significantly prognostic. Waterfall plots will be used to illustrate the magnitude of change in tumor size for each subgroup (to be presented). Results: In patients with measurable disease, the ORR was 62.5% (95% CI: 56.7, 68.2) in the abemaciclib plus AI arm and 44.7% (95% CI: 36.2, 53.2) in the placebo plus AI arm (p≤.001). Additional follow-up confirmed that all prognostic subgroups received benefit from the addition of abemaciclib to AI, consistent with the ITT population, as evidenced by change in ORR, with the largest effects observed in subgroups of patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or treatment-free interval of Conclusions: Extended follow-up in the MONARCH 3 trial further confirmed that the addition of abemaciclib to AI is associated with durable tumor responses, including those in patients with clinically poor prognostic characteristics. References: Di Leo A et al. NPJ Breast Cancer. 2018;4:41. Clinical trial information: NCT02246621 This study was funded by Eli Lilly and Company Table: Objective Response RateAbemaciclib + AIPlacebo + AIORR ChangeNn (%)Nn (%)%Measurable disease population269168 (62.5)13259 (44.7)17.8Liver metastasesYes4727 (57.45)306 (20.00)37.45No222141 (63.51)10253 (51.96)11.55Progesterone receptor statusNegative6137 (60.66)298 (27.59)33.07Positive206130 (63.11)10351 (49.51)13.60Treatment-free interval Citation Format: Joyce O’Shaughnessy, Stephen Johnston, Miguel Martin, Jens Huober, Masakazu Toi, Valerie AnneMarie Andre, Holly Rene Martin, Molly Catherine Hardebeck, Angelo Di Leo, Matthew Philip Goetz. Updated subgroup tumor response of abemaciclib plus aromatase inhibitor for hormone receptor positive (HR+), HER2 negative advanced breast cancer (MONARCH 3) [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 P1-19-09.

Background: Abemaciclib is an oral selective inhibitor of cyclin-dependent kinases 4 and 6 approved for hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer. In the randomized, 3-arm, phase 2 study monarcHER (NCT02675231) for HR+, HER2+ advanced breast cancer (ABC), abemaciclib in combination with trastuzumab (T) and fulvestrant (F) significantly improved investigator-assessed progression-free survival (whereas abemaciclib + T did not) versus (vs) T + physician’s choice of chemotherapy and demonstrated a tolerable safety profile. Here, patient-reported HRQoL, functioning, and symptoms are reported. Methods: In monarcHER, 237 postmenopausal (surgical, natural, or chemical ovarian suppression) women with ABC and ≥2 prior HER2+ directed therapies in the advanced setting were randomized 1:1:1 to abemaciclib (150 mg PO Q12H every 21 days) + T (IV infusion on D1 every 21 days) with F (500 mg IM on Cycle 1 D1 and D15 and Cycle 2 D8, then Q4W; Arm A) or without F (Arm B) vs T + physician’s choice of chemotherapy (per label every 21 days; Arm C). Supportive measures to manage diarrhea were permitted. Patient-reported outcomes were measured at baseline and at each cycle using the modified Brief Pain Inventory-short form (mBPI-sf) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The EuroQol 5-Dimension 5 Level (EQ-5D 5L) questionnaire was also collected. Higher scores on EORTC QLQ-C30 functional and health status/QoL scales indicate improvement whereas higher scores on EORTC QLQ-C30 symptom scales and mBPI-sf indicate worsening of symptoms/pain. The EQ-5D 5L index score was calculated from a set of item weights to derive a score of 0-1, with 1 representing the best health status. Treatment arm comparisons of change from baseline (all post-baseline visits) were conducted using a mixed model repeated measure, with .05 considered statistically significant. Clinical meaningfulness was defined as a ≥10-point score change from baseline (on a 0-100 scale) for EORTC QLQ-C30 and a 2-point score change from baseline for mBPI-sf. Results: Patient-reported outcome compliance rates were ≥90% through Cycle 15; the range for median duration of each treatment component of each arm was 7.5-10.0 cycles. Overall, no statistically significant or clinically meaningful changes from baseline differences were observed between treatment arms for mBPI-sf pain scores or EORTC QLQ-C30 global health score, function scales, or for symptoms of fatigue, dyspnea, appetite loss, or financial difficulties. Least square (LS) mean change from baseline differences showed statistically significant improvements in Arm A vs C for EORTC QLQ-C30 symptoms of pain (-6.81; p=.026) and insomnia (-6.39; p=.041). Worsening for the symptom of nausea/vomiting was statistically significant but not clinically meaningful in Arm A vs C (4.08; p=.043). Diarrhea showed a statistically significant and clinically meaningful worsening in Arm A vs C (19.27; p Conclusions: Quality of life was maintained for patient-reported pain, global health, functioning, and most symptoms when abemaciclib was added to T + F compared with physician’s choice of chemotherapy in patients with HR+, HER2+ ABC. Gastrointestinal-related symptoms were transient and consistent with the manageable, reversible adverse event profile. Citation Format: Sara M Tolaney, Andrew M Wardley, Stefania Zambelli, John F. Hilton, Tiffany A Troso-Sandoval, Francesco Ricci, Seock-Ah Im, Sung-Bae Kim, Stephen RD Johnston, Arlene Chan, Shom Goel, Kristen Catron, Zhengyu Yang, M. Corona Gianford, Gregory L Price, Fabrice André. Health-related quality of life (HRQoL) in monarcHER: Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in HR+, HER2+ advanced breast cancer [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 P3-11-10.

Background: In MONARCH 2 (M2), abemaciclib, an oral selective cyclin dependent kinase 4 & 6 inhibitor, demonstrated significant progression-free survival (PFS) improvement in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer when added to fulvestrant. Treatment with abemaciclib plus fulvestrant provided a statistically significant and clinically meaningful median overall survival (OS) benefit of 9.4 months (hazard ratio 0.757; 95% confidence interval, 0.606, 0.945; p=0.0137).1 High grade tumors, progesterone receptor (PgR) negativity, liver metastases, and absence of bone-only disease were identified as independent poor prognostic disease characteristics.2 In a retrospective analysis of M2, among subgroups analyzed, patients within those poor prognostic subgroups numerically received the largest improvement from the addition of abemaciclib to endocrine therapy (ET) with PFS hazard ratios in the range of 0.4 to 0.5.2 Methods: M2 (NCT02107703) was a global, randomized, double-blind Phase 3 trial of abemaciclib + fulvestrant (N=446) or placebo + fulvestrant (N=223) in women with ET resistant HR+, HER2- advanced breast cancer. Investigator-assessed PFS was the primary objective and OS was a key secondary endpoint. Here, we present exploratory OS results conducted within the previously described prognostic subgroups.2 Hazard ratios were estimated using Cox models with a test of interactions of subgroups with treatment performed. Results: As of the data cut-off (20 June 2019), OS prolongation was consistent across all subgroups; a numerically greater OS effect was observed in patients with previously identified negative prognostic factors including patients with high tumor grade, PgR negativity, baseline liver metastases, and absence of bone-only metastases, relative to their complementary subgroups (Table). However, no statistically significant interaction between these prognostic factors and treatment effect were observed. Similar to OS, a more pronounced effect for abemaciclib plus fulvestrant for patients with high tumor grade, PgR negativity, baseline liver metastases, and absence of bone-only metastases was also observed when examining the time to chemotherapy or death, whichever is earlier (chemotherapy free survival [CFS]). Conclusions: Consistent with the statistically significant and clinically meaningful benefit observed in the overall study population, abemaciclib plus fulvestrant improved OS across all exploratory subgroups, with the largest OS effects observed in patients with poor prognostic factors, consistent with previously reported PFS data. Refernces: 1. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer. Abstract to be presented at: European Society for Medical Oncology 2019; Barcelona, Spain. 2. Di Leo A, O’Shaughnessy J, Sledge GW Jr, et al. Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy. NPJ Breast Cancer. 2018;4:41. Abbreviations: CFS, chemotherapy free survival; HR, hazards ratio; N, number in overall study population; n, number in specified subgroup; OS, overall survival; PgR, progesterone receptor. n (%) N=669Overall Survival Hazard Ratio (95% CI)Chemotherapy Free Survival Hazard Ratio (95% CI)Tumor gradeHigh169 (25.26)0.66 (0.44, 1.01)0.52 (0.36, 0.75)Low/intermediate345 (51.57)0.79 (0.58, 1.08)0.78 (0.60, 1.02)Unknown155 (23.17)0.83 (0.52, 1.31)0.50 (0.34, 0.76)PgR statusNegative141 (21.08)0.66 (0.41, 1.05)0.59 (0.39, 0.89)Positive509 (76.08)0.79 (0.61, 1.01)0.68 (0.55, 0.85)Baseline liver metastasesYes174 (26.01)0.73 (0.49, 1.08)0.60 (0.42, 0.85)No495 (73.99)0.76 (0.58, 0.99)0.64 (0.51, 0.81)Bone-only metastasesYes180 (26.91)0.91 (0.56, 1.46)0.69 (0.46, 1.01)No486 (72.65)0.72 (0.57, 0.93)0.64 (0.52, 0.80) Citation Format: Patrick Neven, Stephen Johnston, Masakazu Toi, Joohyuk Sohn, Kenichi Inoue, Xavier Pivot, Olga Burdaeva, Meena Okera, Norikazu Masuda, Peter A Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Yi Lu, Nadine Haddad, Karla Hurt, Antonio Llombart-Cussac, George W Sledge. MONARCH 2: Interim analysis of overall survival in patients with poor prognostic factors [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 P3-08-01.

Background: Combination treatments of CDK4 & 6 inhibitors (CDK4 & 6i) with endocrine therapy (ET) have improved outcomes in patients with HR-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Aside from estrogen receptor positivity (ER+), predictive biomarkers of clinical benefit from CDK4 & 6i in combination with ET remain elusive. We assessed clinical outcomes by genomic alterations detected in baseline circulating tumor DNA (ctDNA) from patients treated with abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) versus placebo plus NSAI in the Phase 3 study MONARCH 3 (NCT02246621). Methods: MONARCH 3 randomized 493 postmenopausal women with HR+, HER2- ABC who had no prior systemic therapy in the advanced setting to treatment with abemaciclib plus NSAI or placebo plus NSAI. Biomarker analysis of baseline ctDNA was an exploratory objective; plasma was analyzed by the Guardant360 next-generation sequencing (NGS)-based assay to identify potential tumor-related (i.e., somatic) genomic alterations including point mutations (SNV), indels, amplifications, and fusions in over 70 cancer-related genes. Genomic alterations detected in baseline ctDNA were associated with clinical outcomes including progression-free survival (PFS) and objective response rate (ORR). Results: Baseline ctDNA results were available for 295 patients (201 abemaciclib; 94 placebo) with 83% of patients harboring one or more detectable genomic alterations. Commonly altered genes of interest (% frequency) detected in baseline ctDNA included: PIK3CA (38%); TP53 (26%); EGFR (15%); FGFR1 (12%); NF1 (12%); MYC (9%); CCND1 (9%); ESR1 (5%).Overall, patients treated with placebo plus NSAI who harbored detectable ctDNA genomic alterations had shorter median PFS compared to patients without detectable genomic alterations, as shown in the Table (14.9 months [95% CI: 11.0-23.1] vs 19.2 months [95% CI 9.4-NR]). Moreover, genomic alterations in EGFR, FGFR1, MYC, and CCND1 were associated with median PFS Conclusions: In this exploratory subgroup analysis, the presence of detectable ctDNA genomic alterations was associated with shorter PFS with placebo plus NSAI. Consistently, abemaciclib added to NSAI improved outcomes for genomically identified subgroups. In contrast to prior studies, there was no subgroup (e.g., patients harboring FGFR1 alterations) that did not derive benefit from abemaciclib, supporting the efficacy of abemaciclib, including in difficult to treat tumors. These findings are hypothesis-generating and warrant further investigations in clinical studies of CDK4 & 6i in combination with ET. TableAbemaciclib + NSAIPlacebo + NSAIEvents, n/NMedian PFS (95% CI)Events, n/NMedian PFS (95% CI)Hazard Ratio (95% CI)OVERALLITT population170 / 32828.2 (23.7 - 33.9)123 / 16514.8 (11.2 - 19.2)0.52 (0.42 - 0.66)TR population93 / 20138.7 (31.1 - NR)71 / 9416.5 (11.7 - 23.1)0.45 (0.33 - 0.61)Any Gene AlterationDetected83 / 16634.1 (27.2 - 40.0)62 / 7914.9 (11.0 - 23.1)0.47 (0.34 - 0.66)Not detected10 / 35NR (36.4 - NR)9 / 1519.2 (9.40 - NR)0.31 (0.13 - 0.78)TP53Detected29 / 5327.0 (14.1 - NR)19 / 2315.4 (5.7 - 30.4)0.53 (0.30 - 0.95)Not detected64 / 14839.9 (34.1 - NR)52 / 7117.5 (11.7 - 24.2)0.42 (0.29 - 0.60)EGFRDetected10 / 26NR (32.4 - NR)16 / 1710.9 (2.1 - 24.7)0.20 (0.09 - 0.47)Not detected83 / 17536.4 (27.7 - NR)55 / 7717.6 (14.6 - 25.5)0.52 (0.37 - 0.73)FGFR1Detected15 / 2532.8 (10.1 - NR)10 / 117.6 (1.9 - 15.4)0.37 (0.16 - 0.85)Not detected78 / 17639.9 (31.1 - NR)61 / 8319.2 (14.6 - 26.5)0.45 (0.32 - 0.63)NF1Detected10 / 2435.9 (27 - NR)8 / 1014.6 (1.6 - 33.4)0.33 (0.13 - 0.84)Not detected83 / 17738.7 (30.8 - NR)63 / 8417.5 (11.7 - 24.2)0.47 (0.33 - 0.65)MYCDetected11 / 1720.1 (5.5 - NR)9 / 106.5 (1.2 - 15.7)0.33 (0.13 - 0.86)Not detected82 / 18438.9 (32.9 - NR)62 / 8419.2 (14.6 - 26.5)0.45 (0.32 - 0.63)CCND1Detected8 / 1632.8 (5.5 - NR)10 / 107.2 (3.6 - 9.0)0.28 (0.10 - 0.77)Not detected85 / 18538.7 (31.1 - NR)61 / 8417.6 (14.6 - 25.5)0.48 (0.34 - 0.67)n = number of patients with events; N = total number of patients in the corresponding population and treatment arm; NR = not reached. TR population consists of patients in the ITT population from whom a valid baseline ctDNA result has been obtained. Citation Format: Matthew P Goetz, J. Thaddeus Beck, Mario Campone, Sara Hurvitz, Seock-Ah Im, Stephen Johnston, Antonio Llombart-Cussac, Miguel Martin, Joohyuk Sohn, Masakazu Toi, Lacey M Litchfield, Hillary T Graham, Hong Wang, Sameera R Wijayawardana, Valerie M Jansen, Angelo Di Leo. Efficacy of abemaciclib based on genomic alterations detected in baseline circulating tumor DNA from the MONARCH 3 study of abemaciclib plus nonsteroidal aromatase inhibitor [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 PD2-06.

Purpose: Advanced breast cancer (ABC) has not been subjected to the same degree of molecular scrutiny as early primary cancer. Breast cancer evolves with time and under the selective pressure of treatment, with the potential to acquire mutations with resistance to treatment and disease progression. To identify potentially targetable mutations in advanced breast cancer, we performed prospective molecular characterization of a cohort of patients with ABC. Experimental Design: Biopsies from patients with advanced breast cancer were sequenced with a 41 genes targeted panel in the ABC Biopsy (ABC-Bio) study. Blood samples were collected at disease progression for circulating tumor DNA (ctDNA) analysis, along with matched primary tumor to assess for acquisition in ABC in a subset of patients. Results: We sequenced 210 ABC samples, demonstrating enrichment compared with primary disease for potentially targetable mutations in HER2 (in 6.19% of samples), AKT1 (7.14%), and NF1 (8.10%). Of these enriched mutations, we show that NF1 mutations were frequently acquired in ABC, not present in the original primary disease. In ER-positive cancer cell line models, loss of NF1 resulted in endocrine therapy resistance, through both ER-dependent and -independent mechanisms. NF1 loss promoted ER-independent cyclin D1 expression, which could be therapeutically targeted with CDK4/6 inhibitors in vitro. Patients with NF1 mutations detected in baseline circulating tumor DNA had a good outcome on the CDK4/6 inhibitor palbociclib and fulvestrant. Conclusions: Our research identifies multiple therapeutic opportunities for advanced breast cancer and identifies the previously underappreciated acquisition of NF1 mutations.

Invasive lobular breast carcinomas (ILC) account for approximately 15% of breast cancer diagnoses. They can be difficult to diagnose both clinically and radiologically, due to their infiltrative growth pattern. The pattern of metastasis of ILC is unusual, with spread to the serosal surfaces (pleura and peritoneum), retroperitoneum and gastrointestinal (GI)/genitourinary (GU) tracts and a higher rate of leptomeningeal spread than IDC. Routine staging and response assessment with computed tomography (CT) can be undertaken quickly and measurements can be reproduced easily, but this is challenging with metastatic ILC as bone-only/bone-predominant patterns are frequently seen and assessment of the disease status is limited in these scenarios. Functional imaging such as whole-body MRI (WBMRI) allows the assessment of bone and soft tissue disease by providing functional information related to differences in cellular density between malignant and benign tissues. A number of recent studies have shown that WBMRI can detect additional sites of disease in metastatic breast cancer (MBC), resulting in a change in systemic anti-cancer therapy. Although WBMRI and fluorodeoxyglucose-positron-emission tomography-computed tomography (FDG-PET/CT) have a comparable performance in the assessment of MBC, WBMRI can be particularly valuable as a proportion of ILC are non-FDG-avid, resulting in the underestimation of the disease extent. In this review, we explore the added value of WBMRI in the evaluation of metastatic ILC and compare it with other imaging modalities such as CT and FDG-PET/CT. We also discuss the spectrum of WBMRI findings of the different metastatic sites of ILC with CT and FDG-PET/CT correlation. KEY POINTS: • ILC has an unusual pattern of spread compared to IDC, with metastases to the peritoneum, retroperitoneum and GI and GU tracts, but the bones and liver are the commonest sites. • WBMRI allows functional assessment of metastatic disease, particularly in bone-only and bone-predominant metastatic cancers such as ILC where evaluation with CT can be challenging and limited. • WBMRI can detect more sites of disease compared with CT, can reveal disease progression earlier and provides the opportunity to change ineffective systemic treatment sooner.

Background Endocrine therapies are still the main strategy for the treatment of oestrogen receptor-positive (ER+) breast cancers (BC), but resistance remains problematic. Cross-talk between ER and PI3K/AKT/mTORC has been associated with ligand-independent transcription of ER. We have previously reported the anti-proliferative effects of the combination of everolimus (an mTORC1 inhibitor) with endocrine therapy in resistance models, but potential routes of escape via AKT signalling can lead to resistance; therefore, the use of dual mTORC1/2 inhibitors has met with significant interest. Methods To address this, we tested the effect of vistusertib, a dual mTORC1 and mTORC2 inhibitor, in a panel of endocrine-resistant and endocrine-sensitive ER+ BC cell lines, with varying PTEN, PIK3CA and ESR1 mutation status. End-points included proliferation, cell signalling, cell cycle and effect on ER-mediated transcription. Two patient-derived xenografts (PDX) modelling endocrine resistance were used to assess the efficacy of vistusertib, fulvestrant or the combination on tumour progression, and biomarker studies were conducted using immunohistochemistry and RNA-seq technologies. Results Vistusertib caused a dose-dependent decrease in proliferation of all the cell lines tested and reduced abundance of mTORC1, mTORC2 and cell cycle markers, but caused an increase in abundance of EGFR, IGF1R and ERBB3 in a context-dependent manner. ER-mediated transcription showed minimal effect of vistusertib. Combined therapy of vistusertib with fulvestrant showed synergy in two ER+ PDX models of resistance to endocrine therapy and delayed tumour progression after cessation of therapy. Conclusions These data support the notion that models of acquired endocrine resistance may have a different sensitivity to mTOR inhibitor/endocrine therapy combinations.

CDK 4/6 inhibitors have given patients with estrogen receptor (ER)-positive/HER2-negative (ER+/HER2ࢤ) advanced metastatic breast cancer important new therapeutic options. Abemaciclib is different to the other two licensed and approved CDK 4/6 inhibitors, palbociclib and ribociclib, both in dosing schedule (continuous vs intermittent) and toxicity profile (less neutropenia, more diarrhea), yet the magnitude of clinical benefit seen in first- and second-line studies is very similar. One of the key issues for clinicians is when to use these therapies. Ultimately, the biggest impact of abemaciclib could be in the adjuvant setting if the current MONARCH-E trial in high-risk node-positive patients is positive. The emerging biomarker work in the early breast cancer setting (i.e., neoMONARCH) may determine which tumors are most sensitive to abemaciclib.

Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) for breast cancer predicts the risk of recurrence and increasingly may indicate the need for additional therapy postoperatively. We identified non-metastatic breast cancer patients receiving NACT during 2013–2017. Patients’ and disease characteristics, rates of pCR (ypT0-is ypN0), toxicities, dose delays and reductions, and survival outcomes were recorded. 789 patients had median age of 50 years. 67.8% had stage II disease, 71.1% had grade 3 , and 91.8% had ductal histopathology. 32.8% had estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 25.5% had triple-negative (TN), and 38.0% HER2-positive disease. 6.8% received platinum. 48.2% of the HER2-positive patients received trastuzumab and pertuzumab and 51.8% received trastuzumab. Overall pCR rate was 33.5% and differed according to disease subtype, receptor status, grade, histology, and early discontinuation, but not according to age, dose reductions/delays, or year of treatment. The addition of pertuzumab to trastuzumab marginally improved the pCR rates. Survival outcomes were better following pCR. In our analysis, pCR rates are consistent with the published data. Even with contemporary therapies, many patients have residual disease following NACT, suggesting a significant risk of recurrence, and may benefit from additional postoperative systemic therapy.

BaCe1 − xYxO3 − δ (BCY) and BaCe0.8 − yZryY0.2O3 − δ (BCZY) perovskite mixed metal oxides were synthesised by an aqueous sol-gel technique to be investigated for their suitability in intermediate-temperature catalytic applications such as Electrochemical Promotion of Catalysis. The hydration capacity and the stability under CO2 environments of the samples were studied using thermogravimetric analysis. Based on the evaluation of these properties, BaCe0.6Zr0.2Y0.2O3 − δ (BCZ20Y20) was selected as the membrane support for wireless Electrochemical Promotion for CO oxidation on Pt. In a dual-chamber reactor, the use of H2/H2O flow in the sweep side induced promoting species supply to the catalyst in the reaction side of the reactor. Moderate promotion of the catalytic rate up to 10% was observed for temperatures up to 650 °C, while this promotional effect was reversible and repeatable. The encouraging preliminary catalytic experiments together with the membrane’s stability under the applied conditions reinforce the candidacy of BCZY membranes for intermediate-temperature applications in catalytic membrane reactors.

Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Programme previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the Programme across ten institutions in the United Kingdom. We retrospectively identified HR-positive HER2-negative ABC patients on the Programme between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher’s exact test, χ2 method and Cox regression were used. 118 patients identified had a median age of 59. 82.2% were postmenopausal and 92.4% performance status 0–1. 81.4% had visceral involvement and 6.8% bone-only disease after a median of 5 prior treatments and 3 prior chemotherapies. Clinical benefit rate was 47.5%, overall response rate 15.8%, median PFS 4.5 months and median OS 15.8 months. Longer progression-free survival on prior endocrine therapy was a predictor of longer PFS and OS. 89.7% developed neutropenia (grade ≥ 3 in 56.8%). 5.1% experienced febrile neutropenia. 48.3% had dose reductions and 3.4% discontinued Palbociclib following toxicity. No statistically significant difference in grade ≥ 3 neutropenia was observed according to metastatic sites nor previous treatments. This is the most extensive analysis of palbociclib in ≥ 4th-line setting. Clinical benefit was confirmed particularly for endocrine-sensitive, predominantly bony disease and in earlier lines of treatment. Safety was similar to PALOMA trials with higher febrile neutropenia rate.

Treatment with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with letrozole or fulvestrant endocrine therapies. However, limited information exists on its cutaneous adverse effects (AE). Hence, we conducted a retrospective cohort study to investigate the prevalence and management of cutaneous AE during palbociclib and endocrine therapy. We included 324 adult patients with advanced breast cancer who received palbociclib between March 2016 and August 2020 within a tertiary comprehensive cancer centre. Patient demographics, details of previous and concurrent treatments, as well as treatment-related cutaneous AE were recorded from electronic records. The incidence of treatment-related cutaneous AE was 14.2% (46 from a total of 324 patients). The most frequent cutaneous reactions included maculopapular rash (41%), asteatosis (37%), pruritus and urticaria (20%), and bullous dermatitis reactions (9%). We identified two patients with treatment-induced subacute cutaneous lupus erythematosus, one case of bullous pemphigoid, and a single erythema multiforme. Patients received an average of 9 cycles of treatment, completing an average of 6 cycles before developing cutaneous AE, which persisted for a median of 43 days. Only 15% (n = 7) of affected patients required temporary suspension, and 4% (n = 2) required discontinuation. The majority were managed with potent topical steroids, with oral corticosteroids being required in 3 patients, and one patient required hydroxychloroquine. Our study describes both the spectrum of cutaneous AE of palbociclib and endocrine therapy, and approaches to management. Prompt management may limit the negative impact on patients, facilitating beneficial continuation of palbociclib and endocrine therapy.

In MONARCH 2, abemaciclib plus fulvestrant significantly prolonged progression-free survival (PFS) and overall survival (OS) versus placebo plus fulvestrant in patients with hormone receptor positive (HRImprovements were estimated using Cox models, and a test of interactions of subgroups with treatment was performed.The benefit in PFS [first-line, HR, 0.57; 95% confidence interval (CI), 0.45-0.73; second-line, HR, 0.48; 95% CI, 0.36-0.64] and OS (first-line, HR, 0.85; 95% CI, 0.64-1.14; second-line, HR, 0.66; 95% CI, 0.46-0.94) was observed across both subgroups, consistent with the intent-to-treat (ITT) population. In first-line patients (abemaciclib arm,Consistent with the ITT population, a benefit in PFS and OS was observed across the first- and second-line subgroups in MONARCH 2.

Càncer de mama precoç; Teràpia endocrina; Abemaciclib Cáncer de mama precoz; Terapia endocrina; Abemaciclib Early Breast Cancer; Endocrine Therapy; Abemaciclib PURPOSE Many patients with HR+, HER2− early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2− advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting. METHODS This open-label, phase III study included patients with HR+, HER2−, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse–free survival, overall survival, and safety. RESULTS At a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone (P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib. CONCLUSION Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2− node-positive EBC at high risk of early recurrence. Funded and sponsored by Eli Lilly and Company. Additional support provided by National Institute for Health Research funding to the Royal Marsden and Institute of Cancer Research Biomedical Research Center.

Many patients with ER+ HER2− primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER 10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2− breast cancer during and in the aftermath of the COVID-19 crisis.

Background MONARCH 3, a phase III trial (NCT02246621) of postmenopausal women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), previously demonstrated significantly improved progression‐free survival in patients receiving abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI). This study evaluated patient‐reported outcomes, including global health‐related quality of life (HRQoL), functioning, and symptoms. Methods Patients were randomly assigned 2:1 to receive abemaciclib (150 mg twice daily; n = 328) or placebo (n = 165), plus 1 mg anastrozole or 2.5 mg letrozole daily. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Breast Cancer–Specific Quality of Life Questionnaire HRQoL instruments were administered at baseline, every two cycles during cycles 2 through 19 (each cycle being 28 days), every three cycles thereafter, and once at a short‐term posttherapy follow‐up visit (approximately 30 days after discontinuation). Longitudinal mixed regression and Cox proportional hazards models evaluated postbaseline change and time to sustained deterioration (TTSD), respectively. Results Baseline scores were similar between treatment arms. Although select scores statistically favored the placebo arm, global HRQoL, most symptoms, and functioning scales did not meet the threshold for clinically meaningful differences between treatment arms. Only diarrhea favored the placebo arm with statistically and clinically meaningful differences. There were no TTSD differences between treatment arms for global HRQoL, most symptoms (except diarrhea), or functioning. Conclusion Over a 2‐year period, there were no clinically meaningful differences in global HRQoL, functioning, and most symptoms for patients receiving abemaciclib plus NSAI compared with NSAI alone. Only diarrhea favored the placebo arm, consistent with prior safety data, which has been shown to be manageable and reversible. Combined with clinical efficacy, results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2− ABC. Implications for Practice The addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) was not associated with a clinically meaningful detriment in patient‐reported global health‐related quality of life, functioning, and most symptoms in postmenopausal women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC). Prior studies have also demonstrated clinical efficacy of abemaciclib plus NSAI compared with NSAI alone, including improved progression‐free survival and objective response rate. These results also complement previously reported toxicity data, as measured by investigator‐assessed adverse events. Taken together, these results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2− ABC., Previous reports have detailed the efficacy and toxicity of abemaciclib, but results detailing patient‐reported health‐related quality of life have not yet been published. This report assesses the effect of abemaciclib plus NSAI compared with placebo plus NSAI on patient‐reported global health‐related quality of life, functioning, and symptoms in postmenopausal women with HR+, HER2− advanced breast cancer in the phase III MONARCH 3 trial.

Because incidence of breast cancer and comorbidities increase with age, it is important to determine treatment benefit in elderly patients. We evaluated outcomes with palbociclib plus endocrine therapy in patients aged ≥65 years.Data were pooled from three randomised studies (NCT00721409, NCT01740427 and NCT01942135) of women with HR+/HER2- advanced breast cancer (ABC). In PALOMA-1 (open-label) and PALOMA-2 (double-blind, placebo-controlled), treatment-naïve patients received palbociclib plus letrozole or letrozole alone. In PALOMA-3 (double-blind, placebo-controlled), patients with endocrine-resistant disease received palbociclib plus fulvestrant or fulvestrant alone.Among 528 patients treated with palbociclib plus letrozole and 347 treated with palbociclib plus fulvestrant, 218 (41.3%) and 86 (24.8%), respectively, were aged ≥65 years. Versus endocrine therapy alone, median progression-free survival was significantly improved in patients aged 65-74 years (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.45-0.97; P = 0.016) and ≥75 years (HR, 0.31; 95% CI, 0.16-0.61; P0.001) receiving palbociclib plus letrozole and in patients aged 65-74 years (HR, 0.27; 95% CI, 0.16-0.48; P0.001) receiving palbociclib plus fulvestrant; few patients aged ≥75 years received palbociclib plus fulvestrant (HR, 0.59; 95% CI, 0.19-1.8; P = 0.18). Patient-reported functioning and quality of life was maintained. No clinically relevant differences in palbociclib exposure were observed between age groups. Although myelosuppression was more common among patients aged ≥75 years, incidence of grade ≥III myelosuppression was similar across age groups, and febrile neutropenia was uncommon (≤2.4%); no new safety concerns were identified in older patients.Palbociclib plus endocrine therapy is an effective, well-tolerated treatment for older patients with ABC.

Resistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80–90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit. In order to address this, we assessed the impact of abiraterone on cell-viability, cell-death, ER-mediated transactivation and recruitment to target promoters. together with ligand-binding assays in a panel of ER+ breast cancer cell lines that were either oestrogen-dependent, modelling endocrine-sensitive disease, or oestrogen-independent modelling relapse on an aromatase inhibitor. The latter, harboured wild-type (wt) or naturally occurring ESR1 mutations. Similar to oestrogen, abiraterone showed paradoxical impact on proliferation by stimulating cell growth or death, depending on whether the cells are hormone-dependent or have undergone prolonged oestrogen-deprivation, respectively. Abiraterone increased ER-turnover, induced ER-mediated transactivation and ER-degradation via the proteasome. Our study confirms the oestrogenic activity of abiraterone and highlights its differential impact on cells dependent on oestrogen for their proliferation vs. those that are ligand-independent and harbour wt or mutant ESR1. These properties could impact the clinical efficacy of abiraterone in breast cancer.

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER. Electronic supplementary material The online version of this article (10.1186/s13058-018-0983-1) contains supplementary material, which is available to authorized users.

Background: CDK4-6 inhibitors are now considered the standard of care for advanced ER-positive HER2-negative advanced breast cancer (ABC) in combination with endocrine therapy (ET). During the first wave of the COVID-19 pandemic, clinicians were uncertain what impact CDK4-6 inhibitor-induced immunosuppression may have on the risk of contracting COVID-19 or the severity of infection. Some clinicians pre-emptively reduced doses, altered schedules, or even withheld treatment, continuing ET alone. There is currently no evidence that CDK4-6 inhibitors increase the risk or severity of COVID-19 infection, although there have reports of protracted illness. We describe our experience of 203 patients receiving CDK4-6 inhibitors during the first wave and demonstrate the safety of continuing treatment during this period. Methods: Epidemiological and clinical data were collected prospectively for patients at the Royal Marsden Hospital (RMH) and one network hospital with a ER-positive HER2-negative ABC that were receiving a CDK4-6 inhibitor between April 1st and June 30th 2020. Results: 200 patients received a CDK4-6 inhibitor in combination with ET, of which of 65/200 fulfilled local criteria to be screened with COVID-19 PCR testing and 6/65 were swab-positive. Two patients required hospital admission but there were no ICU admissions or COVID-19-associated deaths. Only 12 patients (6%) had treatment adjustments in the form of dose reduction (3/12), regime adjustment (2/12), or temporary interruption (7/12). In 9/12 cases this was a prophylactic measure due to additional risk factors;age (n=1), co-morbidities(n=3), patient choice (n=1) or overall concerns (n=4) to reduce the risk of contracting COVID-19. Results on dispensing >2 cycles at a time, telephone clinics, deferred CT scans and complications relating due to remote monitoring will also be reported. Conclusions: Based on this snapshot during the first wave of the COVID-19 pandemic, we conclude that continuation of CDK4-6 inhibitors appears safe. This project is helping to drive a UK-wide review of CDK4-6 inhibitor treatment continuation, adjustment during the pandemic, assessing the risk of acquiring clinically severe COVID-19 infection, and subsequent cancer-related outcomes for these patients. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: S.R.D. Johnston: Advisory/Consultancy: Eli Lilly;Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca;Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer;Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis;Speaker Bureau/Expert testimony: Eisai;Research grant/Funding (institution), Clinical Trials: Roche/Genentech;Research grant/Funding (institution), Clinical Trials: Eli Lilly;Research grant/Funding (institution), Clinical Trials: Pfizer;Research grant/Funding (institution), Clinical Trials: AstraZeneca;Research grant/Funding (institution), Clinical Trials: Novartis;Research grant/Funding (institution), Laboratory studies: Pfizer;Research grant/Funding (institution), Laboratory studies: Puma Biotechnology. A. Okines: Research grant/Funding (self): Pfizer;Honoraria (self): Leo Pharma;Speaker Bureau/Expert testimony: Seagen;Advisory/Consultancy: Roche;Research grant/Funding (self): Roche;Honoraria (self): AstraZeneca;Advisory/Consultancy: Seagen. S. McGrath: Speaker Bureau/Expert testimony: Pfizer. All other authors have declared no conflicts of interest.

Introduction: Detection of circulating tumor DNA (ctDNA) presents a strategy to identify Molecular Residual Disease (MRD) in patients with breast cancer. Tools capable of detecting ctDNA at lower concentrations are needed to increase sensitivity and lengthen lead time between ctDNA detection and relapse. We present results from a highly sensitive personalized sequencing approach for ctDNA detection of MRD based on multiple patient specific mutations. Methods: 22 early breast cancer patients (12 hormone receptor positive HER2 negative (HR+HER2-), 7 HER2+ and 3 triple negative breast cancer (TNBC)) enrolled in the ChemoNEAR sample collection study were included. Tumor DNA from FFPE samples was Whole Exome Sequenced to identify patient specific mutations and design personalized Residual Disease and Recurrence (RaDaRTM) multiplex PCR assays. Cell free DNA was extracted from 147 plasma samples (median volume 4ml, range 0.5-5ml) and sequenced with RaDaR assays, with 10-61 variants (median 41) per panel, to 100,000x per locus. A matched single timepoint buffy coat was sequenced to identify confounding CHIP mutations. A proprietary algorithm was used to identify ctDNA. Tumor Sequencing of multiple biopsy timepoints was carried out for 14 patients (mean 2.8 samples per patient) and clonal populations estimated with Pyclone. For clusters of greater than 10 mutations, RaDaR panels were supplemented with additional variants for clonal tracking. Results: At a median follow-up of 24.6 months post-surgery, MRD was identified in 100% (17/17) of relapsed patients, and in none of the 54 time points in the 5 patients that did not relapse (p=0.0002, Log rank test). Detection of ctDNA levels ranged from 7.4 parts per million (ppm), equivalent to Allele Frequency (AF) of 0.0007%, to 13,195ppm (1.3%) (median 625ppm and 0.06% AF). Median lead-time from ctDNA detection to clinical relapse in patients with extracranial disease relapse was 12.89 months (range 3.72-26.04). In three patients with brain only relapse, ctDNA was detected prior to relapse in all patients (3/3, 100%) albeit with a reduced lead time over clinical relapse (3.85, 4.21 and 5.65 months), which was not previously achievable with single mutation dPCR MRD-detection assays. In 8/14 patients with multiple tumor samples sequenced, multiple clones (mean 3.4 clones/patient) were identified, with heterogenous polyclonal relapse in 4/8 patients, and a single clone detectable in 4/8 patients. Conclusions: In a retrospective, multi-center, proof-of-principle study of early stage breast cancer patients with personalized sequencing assays, ctDNA-detected MRD associates with relapse free survival and long lead time over clinical relapse. Sequencing based ctDNA testing can detect patients with brain-only relapses, with increased sensitivity over first generation dPCR-based ctDNA assays. Citation Format: Rosalind J. Cutts, Maria Coakley, Isaac Garcia-Murillas, Lara Ulrich, Karen Howarth, Warren Emmett, Malcolm Perry, Pete Ellis, Charlene Knape, Stephen R. Johnston, Alistair Ring, Simon Russell, Abigail Evans, Anthony Skene, Duncan Wheatley, Mitch Dowsett, Ian E. Smith, Nicholas C. Turner. Molecular residual disease detection in early stage breast cancer with a personalized sequencing approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 536.

Purpose Leptomeningeal disease (LMD) is an uncommon complication of advanced breast cancer. The prognosis is poor, and although radiotherapy (RT), systemic and intra-thecal (IT) chemotherapy are accepted treatment modalities, efficacy data are limited. This study was designed to evaluate potential predictors of survival in this patient group. Methods Breast cancer patients with LMD diagnosed by MRI in a 10-year period (2004–2014) were identified from electronic patient records. PFS and OS estimates were calculated using Kaplan-Meier method, with planned sub-group analysis by treatment modality. Cox regression was employed to identify significant prognostic variables. Results We identified 182 eligible patients; all female, median age at LMD diagnosis 52.5 years (range 23–80). Ninety patients (49.5%) were ER positive/HER2 negative; 48 (26.4%) were HER2 positive, and 27 (14.8%) were triple negative. HER2 status was unknown in 17 (9.3%). Initial management of LMD was most commonly whole or partial brain RT in 62 (34.1%), systemic therapy in 45 (24.7%) or supportive care alone in 37 (20.3%). Fourteen patients (7.7%) underwent IT chemotherapy, of whom two also received IT trastuzumab. From diagnosis of LMD, the median PFS was 3.9 months (95%CI 3.2–5.0) and median OS was 5.4 months (95%CI 4.2–6.6). Patients treated with systemic therapy had the longest OS (median 8.8 months, 95%CI 5.5–11.1), compared to RT; 6.1 months (95%CI 4.2–7.9 months), IT therapy; 2.9 months (95%CI 1.2–5.8) and supportive care; 1.7 months (95%CI 0.9–3.0). On multivariable analysis, triple negative histology, concomitant brain metastases, and LMD involving both the brain and spinal cord were associated with poor OS. Conclusions Breast cancer patients with triple negative LMD, concomitant brain metastases or LMD affecting both the spine and brain have the poorest prognosis. Clinical trials to identify more effective treatments for these patients are urgently needed.

Summary Background Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. Methods This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1–21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov ( NCT02675231 ) and is ongoing for long-term survival follow-up. Findings Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7–25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9–12·6) and group C (5·7 months, 5·4–7·0; HR 0·67 [95% CI 0·45–1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2–7·2) and group C (HR 0·94 [0·64–1·38]; p=0·77). The most common grade 3–4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. Interpretation The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. Funding Eli Lilly and Company.

Approximately 70% of breast cancers are estrogen-receptor positive. Tamoxifen and aromatase inhibitors have been the mainstay of endocrine therapy and have improved breast cancer survival. However, a large number of patients experience disease recurrence either during or following completion of endocrine therapy. Recent improvements in our understanding of the various mechanisms underlying the development of endocrine resistance have led to a dramatic change in the landscape of current endocrine treatment with the introduction of new drugs targeting molecular pathways involved in endocrine resistance. Over the past years we have witnessed the use of combination endocrine therapy with mammalian target of rapamycin antagonists, whilst most recently the introduction of cyclin-dependent kinase 4/6 inhibitors has significantly improved response to endocrine therapy. Whilst not a formal systematic review, this article will provide historical background and summarise key clinical trials and current strategies in both first-line and second-line endocrine therapy.

PURPOSECDK4/6 inhibitors are used to treat estrogen receptor (ER)–positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy.PATIENTS AND METHODSPostmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase.RESULTSThree hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (−4.1 v −2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of −97.4% versus −88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (−0.80 v −0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia.CONCLUSIONAdding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.

At the MONARCH 3 interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (AI) significantly improved progression-free survival (PFS) and objective response rate (ORR) with a tolerable safety profile as initial treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). MONARCH 3 is a randomized, phase III, double-blind study of abemaciclib/placebo (150 mg twice daily, continuous) plus nonsteroidal AI (1 mg anastrozole or 2.5 mg letrozole, daily). A total of 493 postmenopausal women with HR+, HER2− ABC with no prior systemic therapy in this setting were enrolled. The primary endpoint was investigator-assessed PFS (final analysis after 240 events); other endpoints included response and safety evaluations. Here we analyze the final PFS data and update secondary endpoints. The abemaciclib arm had a significantly longer median PFS than the placebo arm (28.18 versus 14.76 months; hazard ratio [95% confidence interval], 0.540 [0.418–0.698]; p =.000002). The ORR was 61.0% in the abemaciclib arm versus 45.5% in the placebo arm (measurable disease, p =.003). The median duration of response was longer in the abemaciclib arm (27.39 months) compared to the placebo arm (17.46 months). The safety profile was consistent with previous reports. The most frequent grade ≥ 3 adverse events in the abemaciclib versus placebo arms were neutropenia (23.9% versus 1.2%), diarrhea (9.5% versus 1.2%), and leukopenia (8.6% versus 0.6%). Abemaciclib plus a nonsteroidal AI was an effective initial treatment with an acceptable safety profile for HR+, HER2− ABC., SCOPUS: ar.j, info:eu-repo/semantics/published

e13025 Background: H3B-6545, a highly Selective ERα Covalent Antagonist (SERCA), inactivates both wild-type and mutant ERα by targeting cysteine 530 and enforcing a unique antagonist conformation. At the dose of 450 mg daily, H3B-6545 has a manageable safety profile and demonstrated preliminary single-agent antitumor activity in heavily pretreated ER+, HER2- mBC patients (Hamilton et al, San Antonio Breast Cancer Symposium, 2020). Methods: The study evaluates the safety, pharmacokinetics (PK), and efficacy of H3B-6545 in combination with palbociclib in patients with ER+, HER2- metastatic breast cancer (MBC). The escalation phase enrolls patients with 2 or more prior therapies in the metastatic setting. Up to one prior chemotherapy and up to one prior CDK4/6 inhibitor were allowed. Results: As of January 31, 2021, 10 patients were enrolled; 7 in Cohort 1 (H3B-6545 300 mg QD and palbociclib 100 mg QD) and 3 in Cohort 2 (H3B-6545 300 mg QD and palbociclib 125 mg QD). One patient in Cohort 1 was not evaluable for dose limiting toxicity (DLT) assessment and no DLT was observed in the 6 evaluable patients. One patient discontinued study treatment because of progression and no patients discontinued study treatment due to adverse events (AE). Grade 3 or 4 neutropenia and thrombocytopenia were observed in 4 patients and 1 patient, respectively. One patient had grade 3 hypercalcemia, generalized muscle weakness, hypophosphatemia, fall, and anemia and one patient had grade 3 lipase increase. Four patients had grade 1 bradycardia or sinus bradycardia (asymptomatic) 1 patient had grade 2 sinus bradycardia (symptomatic, no intervention required). Preliminary PK analysis suggested no clinically relevant drug-drug interactions between H3B-6545 and palbociclib, to be confirmed with data from additional cohorts. Recruitment is currently ongoing in Cohort 2. Updated results will be presented. Conclusions: H3B-6545, in combination with palbociclib, was well-tolerated. Clinical trial information: NCT04288089.

1018 Background: H3B-6545, a selective, small molecule covalent antagonist of ERα demonstrated preclinical and preliminary clinical activity against ER+ breast cancer (Hamilton EP, SABCS, 2020). This study evaluated the activity and tolerability of H3B-6545 in patients (pts) with metastatic ER+, HER2-, breast cancer refractory to endocrine therapy. Methods: Patients received H3B-6545 once daily at the recommended phase II dose of 450 mg. The primary objective of the phase II is to estimate the objective response rate (ORR), progression-free survival (PFS), clinical benefit rate (CBR) and secondary objectives include safety. Results: 83 pts were treated with 450 mg in the phase II part of the trial. Additionally, 11 pts were treated with 450 mg in the phase I part of the trial and are included in this analysis. Median age was 62 years (range: 38 to 87 years), 81% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 8). Prior CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, and chemotherapy were received by 85%, 80%, 72%, and 50% of the pts, respectively. 58 pts (62%) had detectable ESR1 mutations in liquid biopsies, including 10 (11%) and 19 pts (20%) who had clonal Y537S and clonal D538G mutation, respectively. As of January 29, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), fatigue (16%), nausea (17%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (38%), hemoglobin decrease (37%), bilirubin increase (12%), ALT increase (14%), AST increase (13%), and creatinine increase (11%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 34% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in the table below. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, CDK4/6 inhibitor, and/or chemotherapy in the metastatic setting. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was observed in pts with ESR1 mutations. Clinical trial information: NCT03250676 .[Table: see text]