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Background: Triple negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, and despite recent treatment advances, clinical outcomes remain poor, particularly in the metastatic setting. TNBC is a biologically heterogeneous entity, and up to 50% of TNBC express the androgen receptor (AR). Gene expression subtyping has identified a subset of AR-TNBC with a luminal AR-driven (LAR) phenotype. Consequently, there has been great interest in translating androgen receptor signaling inhibitors (ARSIs) approved for use in prostate cancer such as enzalutamide and bicalutamide into the management of LAR-TNBC. However, early phase clinical trials of anti-androgens in metastatic AR-TNBC have had modest results. While multiple mechanisms of anti-androgen resistance have been identified in prostate cancer, including AR amplification and over-expression, emergence of AR splice variants (AR-Vs), and transition to AR independent growth, molecular determinants of anti-androgen resistance in TNBC remain poorly understood, and pre-clinical models to study acquired ARSI resistance in LAR-TNBC have been limited. Methods: A novel pre-clincial model of acquired ARSI resistance was derived from the LAR subtype MDA-MB-453 cell line through serial passaging with increasing concentrations of enzalutamide. Celltiter Blue viability assays were used to determine enzalutamide IC50 of parental and enzalutamide-resistant (EnzR) cell lines. RNA was extracted from the parental and resistant cells, reverse transcribed and expression of AR, splice-variants and canonical AR target genes were evaluated using RT-qPCR. Immunofluorescence was used to investigate the amount and nuclear localization of the AR protein within the parental and enzalutamide resistant cells. Results: EnzR MDA-MB-453 cells were derived through culture in increasing concentrations of enzalutamide for >6 months, and found to have a significant increase in enzalutamide IC50 compared to the parental cell line. EnzR MDA-MB-453 cells had a 4.5 fold increase in full-length AR expression at the transcriptional level compared to the parental cell line. AR protein expression and nuclear localization were also increased in EnzR cells compared to the parental cell line. Canonical AR targets including NKX3.1 were downregulated in response to enzalutamide in parental but not EnzR cells. While pathogenic AR splice variants (AR-Vs) implicated in ARSI resistance in prostate cancer were detected at low levels in MDA-MB-453 cells, no increase in AR-V expression was observed in the EnzR cell line. Conclusions: We have developed a novel pre-clinical model of anti-androgen/ARSI resistance in LAR-TNBC, and identified AR overexpression and persistent AR signaling associated with acquired enzalutamide resistance in LAR-TNBC. While pathogenic AR splice variants have been implicated in ARSI resistance in metastatic prostate cancer and are detected in the MDA-MB-453 cell line model, enzalutamide resistance was not associated with increased AR splice variant expression in this model. Future work will investigate mechanisms leading to AR overexpression as well as combination therapeutic strategies to overcome acquired ARSI resistance. Citation Format: Hannah Krause, Marina N. Sharifi, Serena K. Wolfe, Jamie M. Sperger, Kari B. Wisinski, Ruth O’Regan, Joshua Lang. Increased androgen receptor expression as a mechanism of acquired anti-androgen resistance in androgen receptor-positive triple negative breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-14.

Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. The benefit from the addition of OFS was most clinically meaningful for patients at higher clinico-pathologic risk of recurrence. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS and its resultant toxicities. The Breast Cancer Index (BCI) is a gene expression–based signature that stratifies patients based on the risk of overall (0-10 years) and late (post-5 years) distant recurrence (DR) and predicts the likelihood of benefit from extended endocrine therapy in early stage HR+ breast cancer. The purpose of this study is to assess BCI’s prognostic and predictive ability in premenopausal women randomly assigned to 5-years treatment with E+OFS or T+OFS vs T alone in the SOFT trial. Methods: All available FFPE tumor samples from the SOFT trial (n=1718 of 3047) were included in the study. BCI testing was performed blinded to clinical characteristics, treatment and outcome. Median follow-up was 13 years. Primary endpoint was breast cancer-free interval (BCFI). Secondary endpoints were distant recurrence-free interval (DRFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of BCI (H/I) status (High vs Low), and secondarily H/I as a continuous score. Hypothesis testing for interaction was performed by stratified log-rank tests. Results: Tumor samples from 1687 (98%) patients (30.4% < 40 years, 64.1% T1, 50.1% G2, 65.8% N0, 85.5%% HER2-, 53.3% received prior chemotherapy) were successful in BCI testing and included in the final analysis. Patient characteristics in the translational cohort are representative of the parent SOFT trial. 42.4% of patients’ tumors had H/I-High status. Prognostic and predictive analyses are ongoing and will be presented at the meeting. Citation Format: Ruth O’Regan, Yi Zhang, Gini F. Fleming, Prudence Francis, Roswitha Kammler, Giuseppe Viale, István Láng, Meritxell Bellet Ezquerra, Hervé R. Bonnefoi, Sherene Loi, Marco Colleoni, Catherine A. Schnabel, Kai Treuner, Meredith Regan. Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-06.

Background: Development of brain metastasis (BM) portends poor prognosis in patients (pts) with metastatic breast cancer (MBC) mainly due to lack of systemic therapy with strong activity in CNS. While survival in HER2+ BC BMs has improved due to development of various HER2 therapies with activity against BM, outcome for HER2- BC BMs remains dismal. A novel assay (CELsignia) which measures underlying HER2 signal (HS) of live cancer cells in response to HER2 agonists & antagonists showed that about 25% of BC deemed HER2- by standard methods have underlying abnormal HS. Preclinical data showed various HER2 therapies inhibit tumor growth of such HER2- BC with abnormal HS. Among tested HER2 inhibitors with known CNS activity, neratinib had the lowest IC50. We propose a trial which identifies HER2- BC BM pts with abnormal HS & assesses activity of neratinib based therapy. Design: This is a phase II single arm study with 2 steps- step 0 (biopsy) & step 1 (treatment). Pts eligible for Step 0 will be registered as “Immediate Treatment (IT)” (intent to register to Step 1 immediately) or “Future Treatment” [registration can be delayed up to 28 weeks (wks)] & undergo biopsy of most accessible extra CNS (eCNS) tumor. Tumor will be sent for CELsignia testing (2 wks turn around). Additional biopsies may be obtained for standard of care (SOC). IT pts can be treated with a brief course of capecitabine 1gm/m2 BID for 1 wk followed by 1 wk off while waiting for CELsigia result. Pts with BC having abnormal HS will be screened & registered to step 1. Enrolled pts will receive neratinib 240mg daily (with SOC antidiarrheal prophylaxis) + capecitabine 750mg/m2 BID for 2 wks in every 3 wks cycle (C). Tumor assessments will be done prior to C3, 5 & 7 then every 12 wks with MRI brain, CT chest abdomen pelvis & bone scan using RECIST1.1 (eCNS disease) and a modified BM RANO criteria (>5mm, measurable disease, CNS). In isolated CNS progression, investigators have option of treatment beyond progression after SOC local treatment of progressing BMs. Key Eligibility Criteria: Step 0: Inclusion Criteria (IC): histologically confirmed HER2- BC (primary or metastatic); has radiological evidence of BM; prior treatment with CDK4/6 inhibitor + endocrine therapy required for hormone receptor+ BC, no prior specific treatment required for triple negative BC; radiological evidence of eCNS measurable disease (RECIST1.1) accessible for biopsy. Exclusion Criteria (EC): prior use of capecitabine in metastatic setting; known/suspected leptomeningeal disease. Step 1: IC: Abnormal HS; New or progressing BM that is measurable (>5mm); minimum washout periods in wks: last chemotherapy 2, hormonal therapy 1 except fulvestrant 4, targeted therapies 3, eCNS radiation 1, any investigational treatment 4. ECOG performance status 0-2; adequate end organ functions. EC: whole brain radiation in last 3 months (m). Endpoints: Co-primary: Overall survival (OS) and CNS progression free survival (CNS PFS). Key Secondary: Objective response rate, clinical benefit rate and duration of response (CNS using BM RANO, eCNS using RECIST1.1), eCNS PFS, various feasibility endpoints. Safety. Statistical methods: To detect 70% improvement in this trial in CNS PFS and OS compared to historical control (BEACON trial BM subset) 2.7m vs. 4.6m and 4.8m vs. 8.2 m with 80% power and 1-sided 5% significance level, a sample size of 22 is required. About 88 patients will undergo biopsy to enroll 22 pts in step 1. One futility assessment is planned when the first 12 pts have been treated for at least 6 wks or have failed (died or progressed) prior to 6 wks. If 9 or more in the first 12 have died or progressed by 6 wks of treatment, the study will close for futility. PFS and OS will be analyzed using Kaplan-Meier survival functions. Contact: Ajay Dhakal MBBS, ajay_dhakal@urmc.rochester.edu NCT#: NCT04965064 Funding: Celcuity, Puma Biotechnology Status: IRB approved. Anticipated activation Aug 2022, Accrual duration: 2 years. Seeking participating sites. Citation Format: Ajay Dhakal, Ruth O’Regan, Carla Falkson, David Hicks, Douglas Hawkins, Bradley Turner, Nimish Mohile. Trial of Neratinib Plus Capecitabine in Subjects With HER2-Negative Metastatic Breast Cancer With Brain Metastases and Abnormally Active HER2 Signaling [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-10-02.

PURPOSE Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2– MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2– MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

Several anti-HER2 agents are approved for third-line treatment and beyond (after first-line and second-line); however, no specific treatment strategy is recommended for third-line and beyond. Although these agents improve disease outcomes, HER2-positive metastatic breast cancer remains incurable and there is an unmet need for effective therapies in the later line setting. This review focuses on the development of margetuximab-cmkb, a novel, Fc-engineered, anti-HER2 monoclonal antibody, and its role in the systemic treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Purpose:Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).Patients and Methods:Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods.Results:The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI.Conclusions:Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Supplementary Figure from Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2− Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial

Supplementary Table from Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2− Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial

Introduction: Overexpression of HER2 occurs in 15%-20% of early breast cancers (EBC) and is considered more aggressive than other types of breast cancer. Though HER2-targeted therapies have improved patient outcomes, up to 25% of patients will suffer relapse within 10 years, from which the majority of patients will die from incurable metastatic disease. Previous review articles have identified prognostic factors for recurrence for EBC, such as pathological complete response (pCR), hormone receptor (HR) status, and residual cancer burden (RCB). However, most of these were not specific for HER2+ EBC. The goal of this literature analysis was to confirm and identify patient and disease factors that correlate with recurrence in patients with HER2+ EBC. Methods: Primary research articles (inclusive of randomized controlled trials, retrospective cohort analyses, and database analyses) were identified using NCBI PubMed via the search criteria “HER2+ breast cancer,” followed by “early-stage” or “adjuvant” therapy, followed by “relapse” or “recurrence.” Search results were restricted to publications from 2019-2021 that were written in English to account for modern treatment options, including trastuzumab + pertuzumab, ado-trastuzumab emtansine, and neratinib. These same terms were applied to oncology abstracts presented at ASCO 2019-2021; ESMO 2019-2020; ESMO Breast 2019 and 2021; SABCS 2019 and 2020; and St Gallen 2019 and 2021. All results were analyzed for risk factors for recurrence associated with HER2+ EBC. Results: Using the search criteria, we identified 351 research articles, and listed conferences were searched for relevant abstracts. Of these, 53 journal articles and 57 abstracts that assessed risk factor terms, including “age at diagnosis,” “BMI,” “tumor size at diagnosis,” “lymph node status,” “hormone receptor status,” “pCR status,” “smoking history,” and/or “biomarkers,” were analyzed. These were evaluated individually, where possible. Various prognostic scoring methods were also evaluated for their ability to assess the risk factors of recurrence for HER2+ EBC. The RCB prognostic scoring system correlated most strongly to identifying EBC at risk of recurrence amongst all factors evaluated. We also confirmed the results of prior reviews listing non-pCR and fewer tumor-infiltrating lymphocytes (TILs) as risk factors for HER2+ EBC recurrence. HR status remained an important risk factor for recurrence, with HER2+/HR+ disease more likely to occur. In addition, patients with a lower BMI were more likely to have HR- EBC, but no conclusive relationship to risk of recurrence could be determined for BMI. Clinical factors including tumor size, involvement of ≥2 lymph nodes, and a younger age at diagnosis (≤50 years) were also risk factors for recurrence. Of the biomarkers identified, Ki67 represented the strongest association with recurrence. Further analyses of the risk factors identified by the literature review will be presented at the meeting. Conclusion: In this literature analysis, non-pCR, fewer TILs, HR status, younger age at diagnosis, and low Ki67 were identified as potential risk factors for HER2+ recurrence. Finally, RCB correlated strongly with a risk of progression in patients with HER2+ EBC. Patients who have these risk factors could potentially benefit from additional treatments for their early-stage disease in an effort to reduce their risk of recurrence. Citation Format: Joyce O'Shaughnessy, William Gradishar, Ruth O’Regan, Vijayakrishna Gadi. Assessment of risk factors for HER2+ breast cancer recurrence: A literature review [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-08.

Introduction: It is well established that multidisciplinary tumor boards improve the decision-making process for cancer patients. Tumor boards have been shown to improve the accuracy of diagnosis and staging, optimize patient outcomes, increase adherence to guidelines, and educate our peers and trainees. However, over 80% of patients in the United States receive their cancer care in the community setting, where access to multi-disciplinary tumor boards may not be readily available. This may particularly impact underserved populations who often lack the resources to travel to an academic center for second opinions or treatment. The problem is worse in low-resource countries. Virtual expert tumor boards could provide an effective solution. Methods: Preeminent breast oncology faculty from around the Unites States were assembled into virtual tumor board panels via an online platform to discuss challenging cases submitted by community providers and trainees. These tumor boards consisted of a moderator, a breast radiologist, a breast medical oncologist, a breast surgeon, and a breast radiation oncologist. The purpose of this ongoing endeavor is to educate community oncologists on how to best manage challenging cases. Following tumor board discussions, written recommendations were shared with submitting providers within 48 hours and recordings of the discussions were also later provided. After submitting providers watched the recording of their case discussion, we conducted a survey to determine their perceived benefit of the expert panel discussion. Results: From Sept 2020 to June 2021, ten breast cancer panels were virtually convened with 17 expert faculty panelists. During that time, 21 providers submitted 94 cases from the U.S. and around the world to be discussed by the expert panel. Thirty-three percent of the providers who submitted a case to be discussed have subsequently submitted an additional case to a later panel. Surveys were sent to all submitting providers and responses were recorded from 16/21 submitters (76.2%). Conclusion: With more than three out of four submitters responding, we learned that not only is it feasible to convene virtual expert breast tumor boards to discuss challenging cases, but the vast majority of respondents learned new information, changed management of their patients, and wanted to submit additional cases. This effort could raise the level of breast cancer care around the world. Ongoing assessment of educational and patient care impacts will be necessary. QuestionNumber answered (n)Number who answered yes (%)Number who answered no (%)Did you learn something new from the PrecisCa discussion of your case scenario?1614 (87.5)2 (12.5)Will anything you learned from the PrecisCa discussion of your case scenario change the management of this or future patients?1615 (93.8)1 (6.2)Are you likely to submit a future challenging case scenario to PrecisCa?1616 (100)0 (0) Citation Format: Naomi Dempsey, Lauren Chiec, Mikala Lodder, Erin Shonkwiler, Kayla Haines, Reshma Mahtani, William Gradishar, Thomas Buchholz, Anne O'Dea, Norman Wolmark, Sara Hurvitz, Joyce O'Shaughnessy, Maxine Jochelson, Reni Butler, Eleftherios Mamounas, Frank Vicini, Mark Pegram, Chirag Shah, Tari King, Ruth O'Regan, Monica Morrow, Mohammad Jahanzeb. Raising the level of cancer care around the world: The feasibility and perceived benefit of a virtual breast tumor board [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-17-03.

The management of estrogen receptor positive (ER+)/HER2- and lymph node (LN) negative breast cancers can be influenced by Oncotype DX recurrence score (RS) in the USA. However, the benefit of RS in T1 tumors (≤ 1 cm) is not clear.We retrieved 199 T1 ER+/HER2-/LN- breast cancer diagnosed between 1993 and 2016 that had undergone RS testing. The median follow-up time was 51 months. We examined the disease-free survival (DFS) and distant metastasis and their association with RS and other clinicopathologic features.Of the 199 cases, 40 were T1a (≤ 0.5 cm) and 159 were T1b ( 0.5 cm to 1 cm) tumors. In the 40 T1a tumors, 11 would benefit from chemotherapy by the TAILORx study results. Of these T1a tumors, 36 were Nottingham grade 1/2, 3 were grade 3, and 1 was microinvasive carcinoma; 2 (5%) had local recurrence and 1 (2.5%) had distant metastasis to the bone. The only patient with T1a tumor (Nottingham grade 3, RS = 42) and distant metastasis to bone had received adjuvant chemotherapy. In the 159 T1b tumors, 25 would benefit chemotherapy by the TAILORx results. Of the T1b tumors, 149 were Nottingham grade 1/2 and 10 were grade 3. Nine (5.7%) had local recurrence and 2 (1.3%) had distant metastasis to bone and mediastinum, respectively. The two T1b tumors with distant metastasis had a RS 20 and Nottingham grade 2, and RS 27 and Nottingham grade 3, respectively. Both patients received adjuvant chemotherapy. In multivariate analysis of the entire cohort (T1a and T1b tumors), Nottingham tumor grade and receiving chemotherapy were significantly associated with DFS. In univariate analysis of the entire cohort, Nottingham tumor grade, receiving adjuvant chemotherapy, and RS were significantly associated with distant metastasis.This study demonstrates that the metastatic rate of T1a and T1b ER+/HER2-/LN- breast cancer is very low. Patients with low grade (1 or 2), T1a ER+/HER2-/LN- breast cancer may not need RS for treatment decision-making; however, in patients with high-grade T1a or T1b ER+/HER2-/LN- breast cancer, RS analysis should be strongly considered.

Purpose The role of neoadjuvant endocrine therapy in the treatment of patients with early-stage, hormone receptor-positive (HR +) breast cancer is not well defined. Tools to better determine which patients may benefit from neoadjuvant endocrine therapy versus chemotherapy or upfront surgery remain an unmet need. Methods We assessed the rate of clinical and pathologic complete response (cCR, pCR) among a pooled cohort of patients with early-stage HR + breast cancer who had been randomized to neoadjuvant endocrine therapy or neoadjuvant chemotherapy in two earlier studies to understand better how outcomes varied by Oncotype DX Breast Recurrence Score® assay. Results We observed that patients with intermediate RS results had no statistically significant differences in pathologic outcomes at the time of surgery based on whether they received neoadjuvant endocrine therapy or neoadjuvant chemotherapy, suggesting that a subgroup of women with a RS 0–25 may omit chemotherapy without compromising outcomes. Conclusion These data suggest that Recurrence Score® (RS) results may serve as a useful tool in treatment decision-making in the neoadjuvant setting.

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for patients with metastatic estrogen receptor-positive breast cancer but its value in earlier-stage patients is unclear. We examined evolutionary trajectories of early-stage breast cancer tumors, using single-cell RNA sequencing of serial biopsies from the FELINE clinical trial of endocrine therapy (letrozole) alone or combined with the CDK inhibitor ribociclib. Despite differences in subclonal diversity evolution across patients and treatments, common resistance phenotypes emerged. Resistant tumors treated with combination therapy showed accelerated loss of estrogen signaling with convergent upregulation of JNK signaling through growth factor receptors. In contrast, cancer cells maintaining estrogen signaling during mono- or combination therapy showed potentiation of CDK4/6 activation and ERK upregulation through ERBB4 signaling. These results indicate that combination therapy in early-stage estrogen receptor-positive breast cancer leads to emergence of resistance through a shift from estrogen to alternative growth signal-mediated proliferation. Bild and colleagues identify convergent clonal evolution mechanisms through single-cell genomic analyses, explaining therapy resistance in patients with early-stage breast cancer treated with endocrine and CDK4/6 therapy in the FELINE trial.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Background: A CDK4/6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET) is standard first-line therapy for advanced, hormone receptor (HR)-positive, HER2-negative breast cancer (BC). However, not all patients respond and responders eventually develop drug resistance and disease progression. Exosomes are small extracellular vesicles that are secreted by both normal and tumor cells as a mechanism for intercellular communication. The protein cargo of exosomes reflects biological processes activated in cancer cells and may serve as predictive biomarkers to select patients most likely to benefit from treatment and to identify mechanisms of resistance. Methods: Whole blood was collected in Streck tubes at baseline and at time points during treatment from patients with advanced, HR+/HER2- BC enrolled in a single arm, phase 2 trial of first line therapy with palbociclib plus tamoxifen that was conducted by The Big Ten Cancer Research Consortium (NCT02668666). Plasma was separated and stored at -80C within 48 hours of collection. Different exosome protein isolation methods were evaluated and optimized to maximize protein recovery. Exosome and plasma proteins were extracted, purified, and digested with trypsin. Tryptic peptides were isotopically labeled with Tandem Mass Tag (TMT) 10plex for protein expression level quantitation. Triplicate samples from each patient were analyzed by LC-MS/MS with QExactive HF Orbitrap mass spectrometer. An unsupervised clustering method was used to classify patients based on exosomal proteomic profiles. Results: We developed a sensitive and efficient exosome extraction method to obtain exosome protein from minimal volumes of patient plasma. The optimized exosome isolation method quantitatively identified 800 proteins from a 100 µl plasma sample. Significant enrichment of exosome-specific markers was observed when comparing patient samples with healthy donor samples. A network model was developed to differentiate responders/stable disease patients from non-responders using exosome proteomics data generated from pretreatment plasma samples. Preliminary data from the first 22 patients analyzed (responders, n= 6; stable disease, n=12, and non-responder, n=4) identified a network of 45 proteins that predicted response/stable disease vs progressive disease with high specificity (95%) and sensitivity (89%). We also noted significant differences in the exosome proteomic profiles of patients with de novo vs. recurrent metastatic disease. A network of 22 proteins differentiated de novo vs recurrent metastatic disease with > 85% sensitivity and 78% specificity, providing molecular evidence differentiating the two disease states. This finding is relevant in light of the higher response rate and improved PFS in patients with de novo metastatic disease in this trial, and confirms that this approach may provide molecular insight into mechanisms of primary resistance to CDK4/6i. Results for the entire trial cohort of 46 patients will be presented, along with analysis of serial samples collected at various time points during treatment. Conclusion: This proof-of-concept study demonstrates that an ultrasensitive exosome proteomics platform combined with deep learning methods is ideally suited for developing predictive protein biomarkers and for exploring molecular mechanisms of drug resistance. If results are confirmed, this novel approach holds great promise for identifying protein biomarkers that could be used to select patients unlikely to respond to ET and CDK4/6i in order to spare them ineffective treatment and for selecting participants for clinical trials of novel agents. Additionally, exosome proteomics data generated from serially collected specimens can be used to identify mechanisms of resistance that emerge during therapy. This approach can be widely applied to other treatment regimens and disease sites. This study was funded by Pfizer. Citation Format: Ziwei Zhang, Xiuyuan Ma, Julia Ekiert, Gayatry Mohapatra, Louis Coleman, Cristina I. Truica, Anne Blaes, Jatin Rana, Tandra Pavankumar, Lauren Green, Menggang Yu, Deborah Toppmeyer, Ruth O’Regan, Kari B. Wisinski, Oana C. Danciu, Kent Hoskins, Yu Gao. Quantitative proteomic analysis of plasma exosomes from patients with advanced hormone receptor-positive/HER2-negative breast cancer receiving palbociclib and tamoxifen [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-47.

Background: Palbociclib is a CDK4/6 inhibitor used to treat metastatic hormone receptor-positive (HR+) breast cancer (MBC) in combination with endocrine therapy. Tamoxifen is an effective treatment for HR+ MBC, with different toxicity profile compared with aromatase inhibitors (AI) and fulvestrant. Preclinical data demonstrated synergy for the combination of tamoxifen and palbociclib, being effective in a model of acquired tamoxifen resistance. Methods: We conducted a non-randomized, open-label, single-arm, multicenter, phase II trial of palbociclib in combination with tamoxifen in patients with HR+/HER2 - advanced BC, with no prior therapy for MBC. Ovarian suppression was recommended for pre-menopausal women. Primary objective was progression free survival, PFS. Secondary objectives: objective response rate, ORR (CR or PR) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease); safety and tolerability (using CTCAE v4); clinical benefit rate, CBR (CR, PR or SD lasting min 24 weeks); 2-year overall survival. Correlative objectives: proteomic analysis of plasma exosomes to identify mechanisms of primary and secondary resistance to tamoxifen/palbociclib. Results: Between 6/30/2016 and 7/02/2019, we enrolled 49 patients (47 evaluable): 23 pts with de-novo metastatic disease and 24 pts with recurrent BC (12 pts were on adjuvant treatment with AI at time of recurrence and 12 pts on surveillance). As of 6/30/2022 data cut-off, 2 pts were still on treatment. This is an updated analysis with median follow-up time of 24 months (range 8-51). Median age was 60 (range 39-82). The median PFS was 19.8 months with 95% CI (8-41) for pts with de-novo MBC and 7 months (2-12) for pts with recurrent BC. The ORR was 30% overall, 39% for pts with de novo MBC, 21% for pts with recurrent BC. CBR was 64% overall, 77% for pts with de novo MBC and 50% for pts with recurrent BC. CBR was 65% for white pts and 55% for AA pts. Best response per RECIST1.1: 14 pts (34%) had PR, 18 pts (44%) had SD, 9 pts (22%) had PD. All 6 pts with bone only disease had SD. The most common drug related grade ≥ 3 AE was neutropenia (51%), transient and manageable by dose modifications, no cases of febrile neutropenia. Four patients (8%) developed thromboembolic events (grades 2, 3, 4) and discontinued treatment. One patient died while on treatment from PD. More than 800 exosome proteins were detected in the samples analyzed so far. Exosomal protein networks in pretreatment samples predicted treatment response with 89% sensitivity and 95% specificity in unsupervised clustering. Data on correlative objectives will be presented in a separate abstract. Conclusions: The combination of palbociclib and tamoxifen showed tolerable, expected safety profile. This may be an alternative approach for selected patients in first line treatment of HR+ MBC, especially those who present with de-novo metastatic disease and are intolerant to AI; although this small study indicates a lower PFS. Table 1: Baseline Demographics Citation Format: Oana C. Danciu, Kent Hoskins, Jennifer Weiss, Cristina I. Truica, Anne Blaes, Deimante Tamkus, Jatin Rana, Tandra Pavankumar, Lauren Green, Yu Gao, Menggang Yu, Qianqian Zhao, Deborah Toppmeyer, Ruth O’Regan, Kari B. Wisinski. A single arm phase II trial of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-38.

Background: The CALGB 40603 and BrighTNess studies found that adding high dose carboplatin every 3 weeks to the standard neoadjuvant DD AC - paclitaxel regimen in TNBC increased the pathologic complete response (pCR) rate to 54-58% but with the cost of increased treatment related toxicities resulting in decreased completion of the full course of treatment. Our hypothesis is by changing the high dose carboplatin every 3 weeks to low dose weekly carboplatin, it will retain the same benefit in pathologic response rate and minimize the treatment related toxicities, which in turn permits the full course of neoadjuvant treatment given to patients. Patients and Methods: This multi-center study was conducted through the WON (NCT03301350). Eligible TNBC patients for neoadjuvant chemotherapy received weekly carboplatin (AUC=2) and paclitaxel 80 mg/m2 for 12 doses, followed by dose dense doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks with granulocyte growth factor support for 4 cycles. A one-week break was added before DD AC after the first 22 patients in order to minimize prolonged cytopenia. Primary end point was pCR. Secondary endpoints were frequency of dose modification and treatment related toxicities. Results: Accrual target was 50 with 80% power to detect a 20% difference using a one-sided binomial test at an alpha significance level of 0.025, but study was terminated earlier. Twenty-nine eligible patients consented for the study from November 2017 to February 2020. Median age was 52 year-old (range, 33-80). Twenty-eight patients received the study regimen. Three were removed due to early study termination and one (3.8%) died from grade 5 neutropenic sepsis after the last cycle of DD AC before surgery. Thus, 24 patients were evaluable for the primary outcome and 26 were evaluable for dose modification and toxicity outcomes. Eight patients (33%) achieved pCR and another 4 patients (17%) had minimal (ypT1aN0) residual disease. Of 26 patients, 24 (92%) were able to receive the full course of treatment +/- dose modification. One patient required the discontinuation of weekly carboplatin/paclitaxel completely due to severe infusion reaction and one did not finish the treatment before the study was terminated. Eight patients (31%) required dose delay with 5 of them during the weekly carboplatin/paclitaxel treatment. Seven patients (27%) also required dose reduction with 5 of them during the weekly carboplatin/paclitaxel treatment. Seventeen patients (65%) experienced severe adverse event (grade 3 or 4) with the majority of events (12/17) relating to grade 3-4 neutropenia or neutropenic fever. Conclusion: Although our study showed a lower pCR rate of 33% in compare to the previous CALGB 40603 (54%) and BrighTNess (58%) studies, we demonstrated that the majority of patients (92%) were able to receive the full course of study treatment. This weekly carboplatin with paclitaxel - AC regimen was used in the recent Keynote 522 study as the backbone chemotherapy to combine with check-point inhibitor immunotherapy in TNBC. However, any dosing schedules of carboplatin, weekly or every 3 weeks, add substantially to grade 3 or 4 toxicity of paclitaxel - AC. Aggressive supportive care management is needed when carboplatin is used. Citation Format: Yee Chung Cheng, Ruth O'Regan, Lubna N Chaudhary, Sailaja Kamaraju, Harvey Einhorn, Emmanuel Sampene, Marialane Pigsley, Mark E Burkard, Christopher R Chitambar, Kari B Wisinski. A phase II study of neoadjuvant weekly carboplatin/paclitaxel followed by dose-dense doxorubicin/cyclophosphamide (DD AC)in patients with triple negative breast cancer (TNBC): Wisconsin oncology network (WON) 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 PS13-51.

Background: Somatic genomic alterations that activate the phosphatidylinositol-3-kinase (PI3K) pathway signaling are found in 30-50% of breast cancers, and the p110a-specific inhibitor alpelisib is approved for use in combination with fulvestrant in PIK3CA mutated hormone receptor-positive (HR+) metastatic breast cancer. However, preclinical and clinical data has demonstrated significant variability in response to alpelisib and other PI3K inhibitors even in the presence of hotspot PIK3CA activating mutations, likely reflecting functional differences between somatic alterations, bypass signaling mechanisms, and intratumor clonal heterogeneity. Thus, there is an ongoing need for novel predictive biomarkers to help guide patient selection for these therapies. Circulating tumor cells (CTCs) represent an accessible source of tumor derived analytes that allow for the interrogation of protein level readouts of PI3K pathway activation, may better reflect the biologic heterogeneity of metastatic disease than single site solid tumor biopsy, and are amenable to longitudinal analysis. Here, we report the development of an assay to evaluate the expression of activated AKT (AKT pS473) in CTCs as a putative biomarker of sensitivity to PI3K inhibitor therapies in metastatic breast cancer. Methods: Peripheral blood for CTC isolation was collected serially from patients with metastatic breast cancer and known somatic PI3K pathway mutation status. Samples were processed using VERSA (Versatile Exclusion-based Rare Sample Analysis), a microfluidic technology that integrates CTC capture and downstream analysis. Following fixation, CTCs were captured immunomagnetically with antibodies for EpCAM and Trop2, permeabilized and stained on chip for pan-AKT plus AKT pS473. Quantitative fluorescent microscopy was used to enumerate CTCs, defined as cytokeratin positive cells with intact nuclei and negative for a group of normal blood cell markers (CD45/CD11b/CD34/CD66b), and to quantify activated AKT protein expression in CTCs and matched peripheral blood mononuclear cells (PBMCs). Results: 100% of patients with somatic PIK3CA mutations in our pilot cohort had CTCs with detectable phospho-AKT expression, and in 50% of patients, the median phospho-AKT/pan AKT ratio was higher in CTCs compared to matched peripheral blood cells, suggestive of increased PI3K pathway activity. All patients demonstrated heterogeneity in phospho-AKT expression and phospho-AKT/pan-AKT ratio among individual CTCs at a single timepoint and across timepoints in longitudinal analysis. Conclusion: We report here the feasibility of quantitative and longitudinal detection of activated AKT in EpCAM/Trop2 captured CTCs from metastatic breast cancer with somatic PIK3CA mutations. Future work will prospectively evaluate multiple clinical applications of this assay in patients receiving alpelisib plus endocrine therapy for PIK3CA mutated HR+ metastatic breast cancer, as well as expanding the assay to include the detection of additional phospho-protein readouts of PI3K pathway activity in CTCs. In addition to the potential to complement solid biopsy PIK3CA mutation status as a predictive biomarker of sensitivity to PI3K therapies, this assay has the unique potential to provide a pharmacodynamic assessment of PI3K inhibitor activity in CTCs while on treatment, which may serve as an early biomarker of clinical response or resistance. Citation Format: Marina N Sharifi, Jamie M Sperger, Cole Gilsdorf, Serena K Wolfe, Amanda Parkes, Kari B Wisinski, Ruth M O'Regan, Joshua M Lang. Detection of PI3K pathway activation in circulating tumor cells in PIK3CA mutated metastatic breast cancer as a putative predictive biomarker for PI3K inhibitor therapies [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 PS5-35.

Purpose: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months). Patients and Methods: Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods. Results: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI. Conclusions: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Purpose To design and implement a chemotherapy stewardship process to optimize the location of chemotherapy administration in an effort to decrease the number of inappropriate inpatient anticancer regimen administrations and decrease institutional costs associated with inpatient administration. Summary As the costs of anticancer agents continue to rise, it is crucial that multidisciplinary efforts are aimed at managing anticancer medication utilization; this is especially important for high-cost medications, medications whose use requires increased monitoring due to safety concerns, and medications that do not exert effects quickly and, as such, can be more appropriately administered in the outpatient setting. It is imperative that pharmacists play a role in managing chemotherapy medication utilization, as pharmacists provide expertise in formulary management, a vast knowledge of financial impact and reimbursement processes, and clinical knowledge that can help predict the expected effectiveness and adverse effects of each anticancer regimen. Our institution sought to develop and implement a multidisciplinary chemotherapy stewardship program targeting the optimization of site of anticancer agent administration with a goal of decreasing both cost and inappropriate utilization of high-cost, high-risk anticancer agents. Conclusion Implementation of a chemotherapy stewardship service may decrease the number of inappropriate inpatient anticancer regimen administrations and decrease inpatient resource use, thereby decreasing costs to institutions. The concept of a chemotherapy stewardship process was well received by multidisciplinary healthcare colleagues, and a collaborative approach should be used to design and implement such processes.

PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

Background Endocrine therapies and CDK4/6 inhibitors have dramatically improved outcomes for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). To help inform treatment decisions among healthcare providers (HCPs) caring for patients with MBC, we have developed and regularly updated an online treatment decision support tool that provides recommendations from multiple breast cancer experts for specifically defined patient scenarios. Here we report data for HR+/HER2- MBC cases entered into the tool since 2016, capturing self-reported practice trends from HCPs compared with matched treatment recommendations from experts. Methods For the most recent MBC treatment tool (published October 2018), 5 breast cancer experts provided treatment consultation for 549 unique MBC case scenarios based on a simplified set of variables: disease phenotype, previous systemic therapy, visceral crisis (yes/no), rate of disease progression, and the presence or absence of germline BRCA1/2 mutations. HCPs used selection menus to enter patient and disease factors based on these variables along with their intended treatment plan. When completed, the experts’ treatment recommendations for that specific patient case were shown to the HCPs at which time they were asked to indicate if the expert recommendations changed their planned treatment. Results From October 2018 through June 2019, 603 HCPs entered 1127 patient case scenarios, including 581 HR+/HER2- MBC cases, in the most recent online tool. A comparison of expert and HCP treatment choices for select HR+/HER2- MBC case scenarios from the October 2016 and October 2018 tool is shown in the Table. In the setting of HR+/HER2- MBC, among those HCPs whose planned treatment differed from the consensus expert recommendation, 55% indicated that they would change their original choice of treatment. Conclusions CDK4/6 inhibitors have had a large impact on expert treatment recommendations for patients with HR+/HER2- MBC. However, data from this online treatment decision support tool suggest ongoing differences in practice between experts and community HCPs in this setting. For many cases entered into the tool, the practice of the majority of HCPs differed from expert consensus (Table). Consensus expert recommendations in this online tool changed the intended treatment plan of many using it and, therefore, can help optimize the care of patients with MBC. A detailed analysis of overall community practice trends for HR+/HER2- MBC along with a comparison of expert and HCP practice for different case scenarios will be presented. HR+/HER2- MBC Case Scenarios (no visceral crisis)Expert Consensus Recommendation (%)Expert Consensus Recommendation (%)HCP Practice Matched Expert Consensus Recommendation, % (n)HCP Practice Matched Expert Consensus Recommendation, % (n)2016201820162018de novoCDK4/6i + AI (100)CDK4/6i + AI (100)23 (111)32 (188)Previous (neo)adjuvant AICDK4/6i + FULV (92)CDK4/6i + FULV (90)22 (54)17 (77)Previous CDK4/6i + AIFULV (82)FULV ± EVE (92)0 (14)18 (40)Previous AI and CDK4/6i + FulvEVE + EXE (87)EVE + EXE (73)63 (19)28 (18) Citation Format: Timothy Quill, Sara Hurvitz, Kathy D. Miller, Ruth O'Regan, Tiffany A. Traina, Rachael Andrie, Kevin L. Obholz, Mohammad Jahanzeb. Treatment patterns for metastatic hormone receptor-positive breast cancer: Comparing expert and community practice [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 P4-14-07.

Background: TTC-352 is a selective human ER partial agonist (ShERPA) developed for treatment of ER+ breast cancer (BC). ShERPAs mimic the effects of estradiol (E2) in hormone-independent, endocrine-resistant BC cells, but since it has only partial agonist activity in ER+ cells, it could have an improved side effect profile. Thus, TTC-352 could be a promising option for endocrine-resistant BC. Methods: This is an open-label, accelerated dose escalation study with primary endpoint of maximum tolerated dose (MTD) that is evaluating up to five dose levels of TTC-352 in patients with ER+ endocrine-resistant metastatic BC (NCT03201913). The MTD of TTC-352 is determined using initial single-patient cohort escalations until grade 2 toxicity, then expansion to a modified-Fibonacci dose-escalation 3+3 design. The secondary objectives are: best response (BR), progression-free survival, overall survival, treatment tolerability, and pharmacokinetics (PK) of TTC-352. Patient population: patients with metastatic ER+ BC who received and progressed on at least two lines of endocrine therapy, with one that included a CDK4/CDK6 inhibitor, and with adequate hepatic, renal, and bone marrow function at screening. Results: This study completed enrollment of a total of 15 patients on June 5, 2019. Dose LevelTTC-352 Dose Level (mg)Number of SubjectsTwice-Daily (BID) DoseTotal Daily Dose115302230601360120141202401518036010 No dose limiting toxicity has been seen to date with any of the tested dose levels. There was one treatment-related grade 3 event of asymptomatic pulmonary embolism (30mg BID). The number and percentage (n, %) of patients with treatment-related grade 1 and grade 2 adverse events reported in two or more patients across all dose levels were diarrhea (9, 60), hot flush (4, 26), headache (3, 20), nausea (3, 20), abdominal pain (3, 20), rash (3, 20), blurred vision (2, 13) vomiting (2, 13), dizziness (2, 13), peripheral neuropathy (2, 13), breast pain (2, 13), uterine/vaginal hemorrhage (2, 13) and vaginal discharge (2, 13). BR in the 7 evaluable patients (patients with at least two 28-day cycles of treatment) showed that 3 patients had stable disease (SD) for 4, and 10 months, respectively; 1 patient continues study treatment with SD after 9 months; and 4 patients had progressive disease (PD) after completing two cycles of treatment. All 5 non-evaluable patients had PD prior to completing two cycles of treatment. PK: The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞., Half-life was 7.6-14.3 hrs. Trough TTC-352 plasma concentrations at steady-state (SS) remained well above the plasma concentrations associated with efficacy in animal models. PKC alpha expression in tumor tissue did not correlate with length of disease control with TTC-352 therapy, though the numbers are small and not all of the available specimens were metastatic. Conclusions: TTC 352 demonstrates manageable safety and early clinical evidence of antitumor activity in patients with BC progressing on endocrine therapy. Based upon SS TTC-352 plasma concentrations and tolerability, the 180mg BID dose is recommended for further testing. Citation Format: Ruth O'Regan, Randolph Hurley, Jasgit Sachdev, Jonathan Bleeker, Debra Tonetti, Gregory Thatcher, Robert Venuti, Arkadiusz Dudek. Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine therapy [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 P5-11-06.

Background HER2-targeted neoadjuvant therapy has high efficacy in treating HER2-positive breast cancer. Response to neoadjuvant therapy helps clinicians make treatment decisions and make estimates about prognosis. This study examined clinicopathologic features to determine which may be most predictive of response to neoadjuvant therapy in HER2+ breast cancer. Patients and Methods Patients with HER2+ breast cancer (n = 173) who had an initial biopsy performed between 2010 and 2016 were identified at our institution. Tumor response was evaluated on excisional specimens using the MD Anderson residual cancer burden (RCB) classification. Tumors with pathologic complete response (defined as no residual invasive carcinoma in the breast and lymph nodes) and RCB-I were classified as having response and tumors with RCB-II and -III as having no response. Patient age, tumor size, nuclear grade (1/2 vs. 3), mitosis, Nottingham grade, HER2 immunohistochemistry (1/2+ vs. 3+), HER2/CEP17 (chromosome enumeration probe 17) ratio, HER2 copy number, estrogen receptor, progesterone receptor, Ki-67, and tumor-infiltrating lymphocytes (TIL) were evaluated and correlated with response. TILs were evaluated for an average and also for the hot spot/total tumor stromal ratio. Results Small tumor size, low estrogen receptor and progesterone receptor expression, HER2 immunohistochemistry 3+, high Ki-67, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with response (all P Conclusion Clinicopathologic features may help predict HER2+ breast cancer response to neoadjuvant therapy. Larger studies would be useful to confirm these associations, which may have relevance to clinical practice.

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+) breast cancer patients but its value in earlier stage patients is unclear. We examined evolutionary trajectories of early-stage breast cancer tumors, using single cell RNA sequencing (scRNAseq) of serial biopsies from the FELINE clinical trial (#NCT02712723) of endocrine therapy (letrozole) alone or combined with the CDK inhibitor ribociclib. Despite differences in subclonal diversity evolution across patients and treatments, common resistance phenotypes emerged. Resistant tumors treated with combination therapy showed accelerated loss of estrogen signaling with convergent up-regulation of JNK signaling through growth factor receptors. In contrast, cancer cells maintaining estrogen signaling during mono- or combination therapy showed potentiation of CDK4/6 activation and ERK upregulation through ERBB4 signaling. These results indicate that combination therapy in early-stage ER+ breast cancer leads to emergence of resistance through a shift from estrogen to alternative growth signal-mediated proliferation.

Paclitaxel (Taxol) is a cornerstone of cancer treatment. However, its mechanism of cytotoxicity is incompletely understood and not all patients benefit from treatment. We show that patients with breast cancer did not accumulate sufficient intratumoral paclitaxel to induce mitotic arrest in tumor cells. Instead, clinically relevant concentrations induced multipolar mitotic spindle formation. However, the extent of early multipolarity did not predict patient response. Whereas multipolar divisions frequently led to cell death, multipolar spindles focused into bipolar spindles before division at variable frequency, and maintaining multipolarity throughout mitosis was critical to induce the high rates of chromosomal instability necessary for paclitaxel to elicit cell death. Increasing multipolar divisions in paclitaxel resulted in improved cytotoxicity. Conversely, decreasing paclitaxel-induced multipolar divisions reduced paclitaxel efficacy. Moreover, we found that preexisting chromosomal instability sensitized breast cancer cells to paclitaxel. Both genetic and pharmacological methods of inducing chromosomal instability were sufficient to increase paclitaxel efficacy. In patients, the amount of pretreatment chromosomal instability directly correlated with taxane response in metastatic breast cancer such that patients with a higher rate of preexisting chromosomal instability showed improved response to taxanes. Together, these results support the use of baseline rates of chromosomal instability as a predictive biomarker for paclitaxel response. Furthermore, they suggest that agents that increase chromosomal instability or maintain multipolar spindles throughout mitosis will improve the clinical utility of paclitaxel.

Background: The HER2 receptor is a cancer driver which is overexpressed on 15-20% of breast cancers. Though historically survival is poor with this disease subtype, HER2+ targeted therapy has improved survival in both early and advanced disease. In spite of this, most patients in the metastatic setting will eventually experience disease progression and death. Therefore, new therapeutic options and innovative treatments are needed for patients with recurrent or refractory disease. ARX788 is a next-generation antibody–drug conjugates (ADC) using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specific, high homogenous, and stable covalent conjugation in ARX788 leads to slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity, increased targeted delivery of payload to tumor cells, and lower effective dose compared to other HER2 ADCs.Methods: ACE-Breast-03 (NCT04829604) is a global, single arm, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability and lack of steroid dependence. Approximately 200 subjects with advanced HER2-positive breast cancer will be enrolled. ARX788 will be administered as an intravenous (IV) infusion at 1.5 mg/kg as the initial dose on Day 1 of the first 4-week cycle and followed by 1.3 mg/kg at every subsequent 4-week cycle. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 via imaging every 8 weeks (±7 days) on study and endpoints include objective response rate (ORR), duration of response (DOR), time to response (TTR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The safety and tolerability profile will be assessed. Blood samples will be collected at specified time points to determine serum concentrations of ARX788 (intact ADC), total antibody, and metabolite pAF-AS269. Biomarkers (e.g., cell-free DNA, serum HER2 extracellular domain, and circulating tumor cells) at baseline and on-treatment will be analyzed for exploratory research. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Citation Format: Janice Lu, Kevin M Kalinsky, Debu Tripathy, George W Sledge, William Gradishar, Ruth O’Regan, Joyce O’Shaughnessy, Shanu Modi, Joshua Drago, Haeseong Park, Amelia McCartney, Sophia Frentzas, Catherine Shannon, Katharine Cuff, Richard Eek, Miguel Idzwan Martin, Giuseppe Curigliano, Guy Jerusalem, Chiun-Sheng Huang, Michael Press, Matt Li, Dong Xu, Cynthia Song, Richard Huhn, Jinchun Yan, Sara Hurvitz. A global, phase 2 study of ARX788 in patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-02.

Background Human epidermal growth factor receptor 2–positive (HER2+) breast cancer is generally treated with HER2-targeted therapy combined with chemotherapy. Patients with HER2+ and estrogen receptor–positive (ER+) cancer are additionally treated with long-term hormone therapy. This study examined the metastatic pattern and prognosis of both ER+/HER2+ and ER−/HER2+ breast cancer. Patients and Methods A total of 54,147 patients with HER2+ breast cancer from the National Cancer Data Base (NCDB, 2010-2013) and 31,946 patients with HER2+ breast cancer from the Surveillance, Epidemiology, and End Results Program (SEER, 2010-2014) were examined. Sites of metastasis and overall survival (OS) were examined in the NCDB, while OS and breast cancer–specific survival were examined in the SEER database. Results Compared to ER−/HER2+ breast cancer, ER+/HER2+ breast cancer was more likely to metastasize to bone but less likely to brain, liver, and lung and less likely to result in multiple metastases. In univariate analysis based on the NCDB, patients with ER−/HER2+ breast cancer had worse OS in all metastasis subsets, including patients who received HER2-targeted therapy. This poor survival for ER−/HER2+ persisted in patients with metastasis to bone and lung, and multiple metastases. In multivariate analysis adjusting for age, tumor grade, surgery, chemotherapy, HER2-targeted therapy, and hormone therapy, ER−/HER2+ patients with bone metastasis still had worse OS. In the SEER, ER−/HER2+ patients had both worse OS and breast cancer–specific survival in univariate analysis. Conclusion This large study showed patients with ER+/HER2+ and ER−/HER2+ breast cancers had different metastatic patterns. Patients with ER−/HER2+ breast cancer may require more aggressive treatment.

Background Increased signaling through growth factor receptor pathways, including HER2, plays a role in resistance to endocrine therapy (ET) in patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). Inhibition of mechanistic target of rapamycin improves outcomes when used in addition to ET in patients with HR-positive MBC, who previously received ET. We hypothesized that the additional use of trastuzumab (T) or everolimus (E) could restore sensitivity to ET in patients with endocrine-resistant, HR-positive, HER2-negative MBC. Patients and Methods Patients with endocrine-resistant HR-positive, HER2-negative MBC continued the ET during which they had experienced disease progression, and were randomized to receive T or E. At disease progression, patients could continue the therapy they were receiving and have E or T used in addition. Results Fifty-four patients were randomized to the additional use of E (n = 30) or T (n = 24) with existing ET. Progression-free survival (PFS) was 5.7 months, and 2.2 months, respectively, and clinical benefit rate at 24 weeks was 48% and 11% for patients receiving E or T, respectively. PFS was 4.5 months and 3.1 months for patients in whom E (n = 16) or T (n = 12) was used post progression, respectively. There were no new safety signals apart from 2 patients who had a decreased ejection fraction while receiving E with ET. Conclusion These results suggest that E, but not T, can potentially reverse resistance to ET in patients with endocrine-resistant HR-positive, HER2-negative MBC. Further, the additional use of E with an ET to which the cancer has already been exposed might offer the possibility of delaying time to use of chemotherapy.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

TPS1112 Background: The overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. This HER2 subtype confers aggressive tumor behavior and the HER2 receptor remains a valuable target for antibodies, bi-specifics, and antibody drug conjugates (ADC). With advances in targeted therapy, patients with HER2-positive breast cancer (HER2+ BC) may experience an improved prognosis, including survival. Novel HER2-targeted therapies are being investigated to overcome drug resistance and to help mitigate adverse events (e.g., cardiotoxicity). ARX788 is a next-generation ADC using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to its slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Clinical activity has been seen in Phase I HER2 breast and pan-tumor studies. Methods: Trial Design: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function. Any brain metastases must be radiographically stable without steroid dependence. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by imaging every 6 weeks on study. Endpoints include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), best overall response (BOR), duration of response (DOR), and time to response (TTR). The safety and tolerability profile will be evaluated. Blood samples will be collected at specified time points to determine serum concentrations of ARX788, total antibody, and metabolite pAF-AS269. Potential predictive and/or prognostic biomarkers at baseline and on-treatment will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Clinical trial information: NCT04829604.

Breast cancer is the most common tumor type observed in women in the United States. The majority of patients are diagnosed at an early stage, but the disease often recurs after initial treatment. Human epidermal growth factor receptor 2 (HER2) gene amplification is present in approximately 20% to 25% of breast tumors and is associated with invasive disease and an aggressive phenotype. The addition of anti-HER2 therapy to chemotherapy has significantly improved the prognosis for patients with these aggressive tumors. However, despite the dramatic advances in survival achieved by targeting HER2, patients with these tumors are still at risk for recurrence after initial treatment. In an effort to address the risk for recurrence, recent clinical trials have evaluated the efficacy and safety of anti-HER2 antibodies and HER2 tyrosine kinase inhibitors as adjuvant or extended adjuvant therapy. Meaningful reductions have been observed in the risk for invasive and distant recurrence, particularly in certain HER2-positive breast cancer subpopulations. To optimize adjuvant treatment, therapies should be prescribed for patient subpopulations based on factors such as underlying risk profile, response to initial therapy, and patient preference. Neratinib is a small-molecule, irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4 that penetrates the blood-brain barrier. This monograph examines neratinib in the setting of early-stage/extended adjuvant breast cancer, with a focus on clinical trial data, the mechanism of action, and ways to optimize clinical use.

Taxanes remain one of the most effective medical treatments for breast cancer. Clinical trials have coupled taxanes with immune checkpoint inhibitors in patients with triple-negative breast cancer (TNBC) with promising results. However, the mechanism linking taxanes to immune activation is unclear. To determine if paclitaxel could elicit an antitumoral immune response, we sampled tumor tissues from patients with TNBC receiving weekly paclitaxel (80 mg/m2) and found increased stromal tumor-infiltrating lymphocytes and micronucleation over baseline in three of six samples. At clinically relevant concentrations, paclitaxel can induce chromosome missegregation on multipolar spindles during mitosis. Consequently, post-mitotic cells are multinucleated and contain micronuclei, which often activate cyclic GMP-AMP synthase (cGAS) and may induce a type I IFN response reliant on the stimulator of IFN genes (STING) pathway. Other microtubule-targeting agents, eribulin and vinorelbine, recapitulate this cGAS/STING response and increased the expression of immune checkpoint molecule, PD-L1, in TNBC cell lines. To test the possibility that microtubule-targeting agents sensitize tumors that express cGAS to immune checkpoint inhibitors, we identified 10 patients with TNBC treated with PD-L1 or PD-1, seven of whom also received microtubule-targeting agents. Elevated baseline cGAS expression significantly correlated with treatment response in patients receiving microtubule-targeting agents in combination with immune checkpoint inhibitors. Our study identifies a mechanism by which microtubule-targeting agents can potentiate an immune response in TNBC. Further, baseline cGAS expression may predict patient treatment response to therapies combining microtubule-targeting agents and immune checkpoint inhibitors.

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionary trajectories of early stage breast cancer tumors using serial tumor biopsies from a clinical trial of preoperative endocrine therapy (letrozole) alone or in combination with the cell cycle inhibitor ribociclib. Applying hierarchical regression and Gaussian process mathematical modelling, we classified each tumor by whether it shrinks or persists with therapy and determined cancer phenotypes related to evolution of resistance and cell cycle transcriptional rewiring. We found that all patients’ tumors undergo subclonal evolution during therapy, irrespective of the clinical response. However, tumors subjected to endocrine therapy alone showed reduced diversity over time, while those facing combination therapy exhibited increased diversity. Despite different subclonal diversity, single nuclei RNA sequencing uncovered common phenotypic changes in tumor cells that persist following treatment. In these tumors, cancer cells with accelerated loss of estrogen signaling have convergent up-regulation of the JNK pathway, while cells that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. These convergent phenotypes were associated with growing tumors resistant to combination therapy. Cell cycle reconstruction identified that these tumors can rebound during combination therapy treatment, indicating stronger selection and promotion of a proliferative state. These results indicate that combination therapy in early stage ER+ breast cancers with ER and CDK inhibition drives rapid evolution of resistance via a shift from estrogen signaling to alternative growth factor receptor mediated proliferation and JNK signaling activation, concordant with a bypass in the G1 checkpoint.

BackgroundAccurately determining changes in tumor size during therapy is essential to evaluating response or progression. However, individual imaging methodologies often poorly reflect pathologic response and long-term treatment efficacy in patients with estrogen receptor positive (ER+) early-stage breast cancer. Mathematical models that measure tumor progression over time by integrating diverse imaging and tumor measurement modalities are not currently used but could increase accuracy in measuring response and provide biological insights into cancer evolution.MethodsFor ER+ breast cancer patients enrolled on a neoadjuvant clinical trial, we reconstructed their tumor size trajectories during therapy by combining all available information on tumor size, including different imaging modalities, physical examinations and pathological assessment data. Tumor trajectories during six months of treatment were generated, using a Gaussian process and the most probable trajectories were evaluated, based on clinical data, using measurement models that account for biases and differences in precision between tumor measurement methods, such as MRI, ultrasound and mammograms.ResultsReconstruction of tumor trajectories during treatment identified five distinct patterns of tumor size changes, including rebound growth not evident from any single modality. These results increase specificity to distinguish innate or acquired resistance compared to using any single measurement alone. The speed of therapeutic response and extent of subsequent rebound tumor growth quantify sensitivity or resistance in this patient population.ConclusionsTumor trajectory reconstruction integrating multiple modalities of tumor measurement accurately describes tumor progression on therapy and reveals various patterns of patient responses. Mathematical models can integrate diverse response assessments and account for biases in tumor measurement, thereby providing insights into the timing and rate at which resistance emerges.

Purpose: As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings. Patients and Methods: In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination. Results: The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)]. Conclusions: Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

The role of clinical researchers is vital to cancer progress. The teaching, research, and leadership roles that academic oncologists hold need to be accounted for and appropriately compensated. National metrics are currently inexistent, but are necessary to move the oncology research field forward. Clinical research and routine clinical care must be harmoniously integrated without competing. This article reviews the national landscape of clinical cancer research and proposes a call for action.

Hormone receptor (HR) positive breast cancer has a high propensity for late recurrences that might be prevented with longer durations of endocrine therapy (ET). However, trials evaluating extended adjuvant ET have produced somewhat conflicting results. Additionally, ET is associated with not only day to day side effects that can impact quality of life, but more detrimental effects that can cause significant morbidity. Although patients with higher stage disease are at greater risk of late recurrences, even patients with stage 1 disease have a significant risk of recurrence after 5 years. Current guidelines recommend extending therapy for patients with node-positive disease, but recommendations for patients with node-negative disease are less clear. This has led to the development of various genomic tests to aid oncologists in further individualizing their approach when it comes to deciding which subpopulation of patients with HR-positive breast cancer may benefit from extending their endocrine therapy beyond 5 years. There are several assays that are prognostic of recurrences years 6 to 10 following diagnosis. Additionally, the breast cancer index has been shown to be predictive of extended ET in patients who have completed 5 years of tamoxifen. None of the available assays are, to date, predictive of recurrence after 10 years. Genomic testing is not appropriate for all patients, especially if the results will not predict the choice of further treatment. Ultimately, genomic testing should help facilitate shared decision making between the patient and oncologist.

TTC-352 is a selective human estrogen receptor (ER) partial agonist developed for treatment of hormone-refractory ER + breast cancer. This was an accelerated dose escalation study with the primary endpoint of maximum tolerated dose that evaluated five dose levels of TTC-352 in breast cancer progressing after at least two lines of hormonal therapy including one in combination with a CDK4/6 inhibitor. The secondary objectives were to determine treatment tolerability, pharmacokinetics of TTC-352, best response, progression-free survival (PFS), and PKCα expression in tumors. The study enrolled 15 patients. No dose-limiting toxicity was observed. Patients experienced the following grade 3 toxicities: asymptomatic pulmonary embolism, diarrhea, aspartate transaminase elevation, and myalgia, and one grade 4 toxicity of gamma glutamyltransferase elevation. Pharmacokinetic half-life was 7.6–14.3 h. The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞. Median PFS was 58 days (95% CI = 28,112). Higher PKCα expression in tumor stroma was associated with a trend toward longer PFS. TTC-352 demonstrates safety and early clinical evidence of antitumor activity against heavily pretreated hormone-refractory breast cancer. Based upon TTC-352 plasma concentrations and tolerability, the 180 mg twice a day is recommended for further testing. (ClinicalTrials.gov Identifier: NCT03201913)

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guerin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

The tumor immune microenvironment plays a critical role in the prognosis and outcome of breast cancers. This study examined the role of tumor-infiltrating lymphocytes (TILs), CD8+, FOXP3+ lymphocytes, PD-L1 expression, and other clinicopathological parameters in HER2+ breast cancer and correlate with tumor response to neoadjuvant therapy. We included 173 HER2+ patients treated with neoadjuvant HER2-targeted chemotherapy regimens from 2010 to 2016. 67 cases had biopsy blocks to evaluate TIL, CD8, FOXP3, and PD-L1 immunohistochemistry staining. Tumors were classified as pCR vs non-pCR group. Clinicopathological parameters, TIL, CD8+ and FOXP3+ cell count, and PD-L1 expression were correlated with pCR rate. Univariate analyses showed that pCR rate was significantly correlated with low PR, low ER, high Ki-67, high FOXP3, HER2 IHC3+ , high HER2 ratio and copy number. By multivariate analysis, Ki-67 was the only variable significantly correlated with pCR. PD-L1 expression was detected in 9.2% cases. TIL hotspot has a non-significant correlation with pCR rate (p = 0.096). High Ki-67 is a strong predictor for pCR in HER2+ breast cancer. TIL and FOXP3 T cells may play a role in tumor response in HER2+ cancer. PD-L1 is expressed in a subset of HER2+ breast cancer, supporting a role of immunotherapy in treating a subset of HER2+ breast cancers. The role of PD-L1, TIL, and other markers of immunogenicity as predictors of response to neoadjuvant chemotherapy in HER2+ breast cancer should be further evaluated.