Search

The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

Background In early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose‐dense (DD) doxorubicin‐cyclophosphamide (AC)–paclitaxel regimen. Patients, Materials, and Methods In this prospective, single‐arm study, patients who completed four cycles of DD‐AC for stage I–III breast cancer received paclitaxel 175 mg/m2 every 2 weeks for four cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine, and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles three and four if there were no HSRs in previous cycles. We estimated the rate of grade 3–4 HSRs. Results Among 127 patients enrolled, 125 received more than one dose of protocol therapy and are included in the analysis. Fourteen (11.2%; 90% confidence interval, 6.9%–20.0%) patients had any‐grade HSRs, for a total of 22 (4.5%; 3.1%–6.4%) HSRs over 486 paclitaxel cycles. Any‐grade HSRs occurred in 1.6% (0.3%–5.0%), 6.5% (3.3%–11.3%), 7.4% (3.9%–12.5%), and 2.6% (0.7%–6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02%–2.0%) (1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any‐grade HSRs occurred in 2.7% (3/111; 0.7%–6.8%) and 0.9% (1/109; 0.05%–4.3%) of patients in cycle 3 and 4, respectively. Conclusion Corticosteroid premedication can be safely omitted in cycles 3 and 4 of dose‐dense paclitaxel if HSRs are not observed during cycles 1 and 2. Implications for Practice Because of the potential for hypersensitivity reactions (HSRs) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. This prospective study, including 125 patients treated with 486 paclitaxel cycles, demonstrates that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard of care., To avoid hypersensitivity reactions, corticosteroids are routinely prescribed before each dose of paclitaxel. This article reports the results of a study that focused on whether corticosteroids could be safely omitted in later cycles of treatment if reactions did not occur during earlier cycles.

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59–1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659., A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates

PURPOSEThe Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.METHODSWe conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non–breast cancer deaths and new nonbreast primary cancers from the invasive disease–free survival end point.RESULTSAmong 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.CONCLUSIONWe recommend an additional end point, invasive breast cancer–free survival, which includes all invasive disease–free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.

We evaluated the efficacy and safety of poly-(adenosine diphosphate-ribose) polymerase (PARP) 1 and 2 inhibitor veliparib and temozolomide in metastatic breast cancer patients with and without germline BRCA1/2 mutations. In this single-arm phase II trial, patients with metastatic breast cancer received veliparib 30 to 40 mg twice daily on days 1 to 7 with concurrent temozolomide 150 mg/m2 on days 1 to 5 of a 28-day cycle. The primary cohort was unselected for BRCA mutation status, and an expansion cohort enrolled only BRCA1/2 carriers. The primary endpoint was objective response rate (ORR) in each cohort. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and evaluation of safety and tolerability. In the primary cohort of 41 unselected patients, which included 9 BRCA mutation carriers, the ORR was 10% and clinical benefit rate at 4 months (CBR) was 27%. In the expansion cohort of 21 BRCA1/2 carriers, the ORR was 14% and CBR was 43%. Among all 30 BRCA1/2 carriers, the ORR was 23% versus 0% among non-carriers. In the subset of BRCA1/2 carriers, the ORR was 32% among platinum-naive patients versus 9% among platinum-exposed patients. The median PFS was 3.3 months among BRCA1/2 carriers compared to 1.8 months among non-carriers (HR: 0.48, p = 0.006). A longer median PFS of 6.2 months was observed among BRCA1/2 carriers who had no prior platinum therapy. The most common grade 3 and 4 toxicities were thrombocytopenia (32%) and neutropenia (21%) that generally improved with dose modifications. Veliparib and temozolomide demonstrated clinical activity in platinum-naive BRCA-associated metastatic breast cancer with manageable toxicity at doses of veliparib well below the single-agent active dose. Although the study did not meet its primary endpoint in unselected nor BRCA-associated breast cancer, this regimen was further evaluated in the BROCADE 2 study. NCT01009788 (ClinicalTrials.gov), November 9, 2009

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

Background Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. Methods Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; distant relapse or death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; > 2 years) or ‘no relapse’ (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. Results Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. Conclusions We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

Male breast cancer is an uncommon disease, and population-based information regarding prognostic factors is limited. Most cases are hormone receptor (HR) positive; however, the association of tumor subtype with overall survival (OS) and breast cancer-specific survival (BCSS) is unclear. Using SEER data, we identified men with invasive breast cancer between 2010 and 2017 with known HR and HER2 status. We examined tumor subtypes by patient characteristics and performed multivariate Cox proportional hazards analyses to determine the associations of each variable with OS and BCSS. We included 2389 men with a median follow-up of 43 months (IQR 19–68). Median age was 66 years. Tumor subtype distribution was 84.1% HR+/HER2−, 12.7% HR+/HER2+ , 0.8% HR−/HER2+, and 2.3% triple-negative (TN). In univariate analysis, OS at 5 years was 76.5% for HR+/HER2−, 65.1% for HR+/HER2+ , 84.2% for HR-/HER2+, and 48.1% for TN (p

We aimed to report the 20-year risk of breast cancer-specific mortality (BCSM), report the risk of BCSM conditional on having survived 5 years, and identify factors associated with late deaths in stage III breast cancer. Using Surveillance, Epidemiology, and End Results data, we included women with stage III breast cancer diagnosed from 1990 to 2005. We excluded women with unknown hormone receptor (HR) status, women who did not undergo resection of the primary tumor or axillary nodes, or unknown cause of death. We estimated risks of BCSM using cumulative incidence function and used Fine and Gray regression to identify factors associated with late deaths. Final sample was 36,500 patients with 14 years of median follow-up. For each stage subgroup, the risk of BCSM at 20 years was significantly higher for HR-negative vs HR-positive tumors (IIIA: 49.8% vs 43.2%, P

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

Purpose: In contrast to recurrence after initial diagnosis of stage I–III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS). Experimental Design: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC. Results: When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2, and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR+/HER2− tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC (P = 0.041). Conclusions: Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.

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

Summary Background Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. Methods PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). Findings Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76–1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. Interpretation At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. Funding Pfizer.

Purpose: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer. Patients and Methods: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. Results: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Conclusions: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients’ insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient’s perspectives, are presented in this consensus article.

The 21-gene Breast Recurrence Score test predicts benefit from adjuvant chemotherapy in estrogen receptor-positive, HER2-negative (ER+/HER2−) breast cancer (BC). We examined whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NCT). We identified patients with stage I–III ER+/HER2− BC treated with NCT from the Young Women’s Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤40 years. The 21-gene assay was performed on tumor specimens removed prior to NCT either as part of clinical care or retrospectively for research. Pathological complete response (pCR) was defined as ypT0/is ypN0. The relationship between Recurrence Score result and pCR was evaluated using logistic regression modeling. 76 women received NCT for ER+/HER2− BC and were eligible for this analysis. Median age at diagnosis was 37 years (range 24–40). Scores ranged between 5 and 77 with 50% >25 and 5% 25 was 21% (8/38) vs. 5% in patients with scores

In 2016, we initiated standardized “reflex” Oncotype DX Recurrence Score (RS) testing for patients ≤ 65 years with pT1-2N0-1 HR+/HER2− breast cancer. Here, we examine RS testing patterns, RS distribution, and factors associated with chemotherapy use in patients with pN1 breast cancer. Patients with stage I–III HR+/HER2− pN1 breast cancer treated with upfront surgery from February 2016 to March 2019 were identified. Clinical characteristics were compared between patients meeting reflex RS testing criteria, those with RS ordered outside of reflex criteria, and those without RS testing. RS was categorized as low (

Background Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. Patients and methods This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). Results Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. Conclusion The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. Clinical Trial Registration NCT01921335.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations—in AKT1, RAS, and AURKA—have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients.Significance:We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079

PURPOSE The use of growth factors adds considerable expense and some toxicity to adjuvant breast cancer chemotherapy. We tested the feasibility and safety of omitting routine peg-filgrastim use during the paclitaxel portion of the dose-dense doxorubicin-cyclophosphamide–paclitaxel regimen. PATIENTS AND METHODS This was a prospective, single-arm study in which patients 18 to 65 years of age who completed 4 cycles of dose-dense doxorubicin-cyclophosphamide for stage I-III breast cancer received paclitaxel 175 mg/m2 every 2 weeks. Peg-filgrastim was administered after paclitaxel only if patients had had febrile neutropenia in a prior cycle or at investigator discretion if patients had infections or treatment delays of > 1 week. Once a patient received peg-filgrastim, it was administered in all future cycles. The primary end point was the rate of paclitaxel completion within 7 weeks from cycle 1 day 1 to cycle 4 day 1. If ≥ 100 out of 125 patients completed 4 cycles of paclitaxel without dose delay, the regimen would be considered feasible. RESULTS The enrollment goal of 125 patients was met. Median age was 46 years (range, 21-65 years), and 112 patients (90% [95% CI, 83% to 94%]) completed dose-dense paclitaxel within 7 weeks. Omission of peg-filgrastim was not causally related to noncompletion of paclitaxel in any patients. The most common reasons for dose reduction or delays were nonhematologic. One patient experienced febrile neutropenia but was able to complete paclitaxel on time. Eight patients (6.4%) received peg-filgrastim during the trial. Overall, peg-filgrastim was administered in only 4.3% of paclitaxel cycles. CONCLUSION Omission of routine peg-filgrastim during dose-dense paclitaxel according to a prespecified algorithm seems to be safe and feasible and was associated with a 95.7% reduction in the use of peg-filgrastim relative to the current standard of care.

PURPOSE Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers ( BRCA carriers). Limited data exist for estrogen receptor (ER)–positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC. PATIENTS AND METHODS BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review. RESULTS A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities. CONCLUSION pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.

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.

BackgroundHigh tumor mutation burden (TMB) has been associated with benefit to immunotherapy in multiple tumor types. However, the prevalence of hypermutated breast cancer is not well described. The aim of this study is to evaluate frequency, mutational patterns, and genomic profile of hypermutated breast cancer.Patients and MethodsWe used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients’ samples that underwent whole exome sequencing or gene panel sequencing. Samples were classified as having high TMB if they had ≥10 mutations per megabase (mut/Mb). An additional 8 patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among patients with high TMB, the mutational patterns, and genomic profile were determined. A subset of patients was treated with regimens containing PD-1 inhibitors.ResultsThe median TMB was 2.63 mut/Mb. Median TMB significantly varied according to tumor subtype (HR-/HER2-> HER2+ > HR+/HER2-,p< 0.05) and sample type (metastatic > primary,p2.2×10−16). Hypermutated tumors were found in 198 patients (5%), with an enrichment in metastatic versus primary tumors (8.4% versus 2.9%, p = 6.5 × 10−14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer—including two with a dominant APOBEC activity signature and one with a dominant MMRd signature—treated with pembrolizumab-based therapies derived an objective and durable response to therapy.ConclusionHypermutation occurs in 5% of all breast cancers, with an enrichment in metastatic tumors. Different mutational signatures are present in this population, with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.Key MessageHigh tumor mutation burden is found in 5% of all breast cancers and is more common in metastatic tumors. While different mutational signatures are present in hypermutated tumors, APOBEC activity is the most common dominant process. Preliminary data suggest that those tumors are more likely to benefit from PD-1 inhibitors.

Background: Recent studies in murine models and humans suggest that modulation of the gut microbiome may enhance response to immune checkpoint blockade in different cancer types. However, little is known about the landscape of gut microbiome in pts with HR+ MBC and its influence on response to chemotherapy and immunotherapy.Methods: A randomized phase 2 trial of E +/- P for pts with HR+ MBC (n= 88) was conducted. The results of this study have been previously presented and found the addition of P did not result in an improvement in progression-free survival (PFS). Fecal samples were prospectively collected (baseline (BL), after 2 cycles of therapy (C2), and end of treatment (EOT)) in a subset of pts (E+P, n = 12; E, n = 11) in order to evaluate if microbiome was associated with response (partial response [PR], stable disease [SD], and progressive disease [PD]), PFS, and overall survival (OS). 16S rRNA gene sequencing was performed to characterize the diversity and composition of fecal microbiome. Results: A total 23 pts provided 23 BL, 22 C2, and 5 EOT fecal specimens for microbiome profiling. 16S(v3-4) rRNA gene data was successfully generated for all samples and the dataset was rarefied to 24,743 reads for analysis. Overall, the variability in the composition and structure of the fecal microbiome was significantly driven by each individual (p Conclusion: The composition and structure of the fecal microbiome identified in this study were found to be associated primarily with the pt rather than with any of the variables studied including type of treatment and outcome. Although the fecal microbiome from all pts randomized were indistinguishable at BL, shifts in the abundance of certain types of bacteria like Faecalibacterium and Akkermansia were observed from BL to C2. These shifts were characteristic of pts receiving E but not of those receiving E+P. Although this study is limited by the small sample size in each arm, these findings warrant further evaluation in a larger population to interrogate if the composition and metabolic potential of the fecal microbiome can be used as a predictor of benefit to treatment. Citation Format: Romualdo Barroso de Sousa, Nadim Ajami, Tanya E Keenan, Chelsea Andrews, Jessica L Pittenger, Gerburg Wulf, Laura Spring, Ian E Krop, Eric P Winer, Elizabeth A Mittendorf, Sara M Tolaney. Fecal microbiome and association with outcomes among patients (pts) receiving eribulin (E) +/- pembrolizumab (P) for hormone receptor positive (HR+) metastatic breast cancer (MBC) [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 P3-09-16.

Introduction: mTNBC progresses rapidly on first-line chemotherapy. For instance, in the TNT trial, median progression-free survival (PFS) was 3 months on first-line carboplatin. Selective inhibition of Wee1, a negative regulator of the G2 cell cycle checkpoint, may enhance the efficacy of DNA-damaging agents by reducing DNA damage repair. We report the results of the first phase II study assessing the efficacy of the Wee1 inhibitor adavosertib (AZD-1775) with cisplatin in mTNBC. Methods: mTNBC patients (pts) with 0-1 prior lines of chemotherapy in the metastatic setting were eligible. Pts received cisplatin 75 mg/m2 IV followed by combination therapy 21 d later with cisplatin plus adavosertib 200 mg oral twice daily x 5 doses over 2.5 d every 21 d. Tumor biopsies were mandatory for patients with safely accessible tumors, and occurred 5-48 h after monotherapy and 5-8 h after the last adavosertib dose in the first combination therapy cycle. The study used a Simon optimal two-stage design that had 90% power to detect the difference between null (20%) and alternative (40%) response rates with a one-sided type I error of 0.1. The primary endpoint was objective response rate (ORR): an ORR > 30% would identify the regimen as worthy of further study. Key secondary endpoints were PFS and overall survival (OS). Exploratory analyses evaluated the association of response, defined as clinical benefit rate (CBR) > 6 months (CR + PR + SD > 6 mos), with transcriptional and immunostaining profiles of on-treatment tumors (n = 16), as well as with targeted panel genomic alterations in archival tissue. Tumor immune cell composition was assessed by CIBERSORT. Results: 34 pts initiated protocol therapy; median age was 56 yrs, 2 (6%) pts had known BRCA2 mutations, and 14 (41%) had 1 prior line of chemotherapy. Median follow-up was 13 mos. ORR was 29% (3 CR + 7 PR), median PFS 4.9 months (95% CI, 2.3-5.8 mos), CBR 35%, and preliminary OS 14.0 mos (95% CI, 11.8-21.8 mos). All-cause AEs occurred in 100% of pts (G3-4, 56%; most commonly diarrhea, 21%), including one death due to sepsis possibly related to study therapy. The primary tumor of the longest responding patient had a possible biallelic loss-of-function alteration (missense mutation and loss of heterozygosity) in the homologous recombination-related gene FANCM. In Hallmark gene set enrichment analyses of 26 on-treatment biopsies across 16 pts, responding tumors (n = 4) demonstrated enriched expression of immune response gene sets (allograft rejection FDR q < 0.001, IL2-STAT5 signaling FDR q = 0.001, inflammatory response FDR q = 0.003), while non-responding tumors (n = 12) showed enrichment of cell cycle gene sets (E2F targets FDR q < 0.001, G2M checkpoint FDR q < 0.001). In the same on-treatment biopsies, responding tumors (n = 4) had higher tumor infiltrating lymphocytes (46% v. 29%, Mann-Whitney p = 0.04) and lower M0 macrophages (3% v. 17%, Mann-Whitney p = 0.04) than non-responding tumors (n =12). Updated data, including OS and tissue immunostaining results, will be presented. Conclusions: Among mTNBC pts, the combination of adavosertib and cisplatin was associated with a 29% ORR, failing to meet the pre-determined ORR of > 30% required to support further investigation. Responses were associated with immune-related gene expression and TILs detected by RNA sequencing. Citation Format: Tanya E. Keenan, Zhenying Tan-Wasielewski, Lorenzo Trippa, Bose Kochupurakkal, Jennifer L. Guerriero, Rie K. Tahara, Grace Winship, Wafa Osmani, Chelsea Andrews, Jake R. Conway, Meng X He, Ricardo Pastorello, Adam Tracy, Robert E. Godin, Beth A. Overmoyer, Eric P. Winer, Elizabeth A. Mittendorf, Geoffrey I Shapiro, Eliezer M Van Allen, Sara M Tolaney. A phase II study of cisplatin and the Wee1 inhibitor adavosertib in metastatic triple-negative breast cancer (mTNBC) [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 P3-10-08.

Background: For patients (pts) with HR+ /HER2- MBC, the optimal regimen following disease progression on the combination of a CDK4/6i plus endocrine therapy (ET) is unknown, and there is a need to evaluate whether continued CDK 4/6 blockade is beneficial in subsequent lines of therapy. Methods: We developed an investigator initiated Phase I/II, open-label trial (NCT02871791) of triplet therapy: palbociclib (PALBO; CDK4/6i) + everolimus (EVE; mTOR inhibitor) + exemestane (EXE; ET) in men or postmenopausal women with measurable HR+ /HER2− MBC who had progressed on prior CDK4/6i and a non-steroidal aromatase inhibitor (NSAI). Pts may have received any number of prior lines of ET, and 0-1 prior line of chemotherapy. Exclusion criteria included prior use of mTORi or EXE. The primary objective was to estimate efficacy of the combination, defined as the clinical benefit rate (CR+PR+SD>6mo). With a one-sided alpha of 0.1, the study had 90% power to detect an improvement in CBR from 40% to 65%. The phase I determined RP2D to be PALBO 100 mg/day (21 of 28 days) + EVE 5mg/day + EXE 25mg/day (previously presented). For pts who entered into the phase IIa part of the study, a research biopsy at baseline and serial research blood collection for circulating tumor DNA (ctDNA) analysis were mandatory. The tumor tissue underwent whole exome sequencing and RNA sequencing and the ctDNA underwent whole exome sequencing. Here we present the first results of the phase 2 study of this triplet regimen. Results: As of June 29, 2019, after a median follow up of 3.8 (2.8-6.2) months, 32 patients were evaluable in the phase II portion of the study. The triplet combination was associated with a clinical benefit rate of 12.5% (n=4), which did not meet the predefined primary endpoint threshold (65%). There were no objective responses achieved. The median PFS was 3.8 (95%CI: 2.0-8.4) months and the 1-year PFS was 16.1% (95%CI: 3.1%-38.0%). The most common AEs were mucositis (all grades, 87.5%; grade 3/4, 15.6%), neutropenia (all grades 84.4%; grade 3/4, 71.9%), and fatigue (all grades 53.1%; grade 3/4, 0%). Data regarding genomic alterations and its association with outcomes will be presented. Conclusions: Among patients with metastatic HR+/HER2- MBC who had previous progression on a NSAI and a CDK 4/6i, there did not appear to be benefit from the addition of PALBO to EXE and EVE, but there were added toxicities. These findings suggest further evaluation of this triplet combination in patients with CDK 4/6i resistance is not warranted. Genomic data from baseline biopsies and circulating tumor DNA will be presented and may help us to explain why patients included in this study were intrinsically resistant to the triplet. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Lorenzo Trippa, Rebecca Rees, Chelsea Andrews, Arlindo R Ferreira, Karla Helvie, Ann H Partridge, Beth Overmoyer, Eric P Winer, Nikhil Wagle, Sara M Tolaney. A phase I/IIb study of palbociclib (PALBO) plus everolimus (EVE) and exemestane (EXE) in hormone-receptor positive (HR+)/HER2- metastatic breast cancer (MBC) after progression on a CDK4/6 inhibitor (CDK4/6i): Results of the phase II study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-04.

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

Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-02.

Background: The Adjuvant Paclitaxel and Trastuzumab (APT) trial was a single-arm trial in patients with small node-negative HER2-positive early breast cancer (EBC). Although the regimen used in the APT trial has been adopted clinically, single-arm trials have limitations, and interest remains if these patients, particularly those with T1c or T2 disease would benefit from more intensive chemotherapy. Methods: Patient-level data from five randomized trials (BCIRG 006, NSABP-B31, HERA, N-9831, and APHINITY) submitted to FDA to support drug approval in adjuvant HER2-positive EBC were pooled (n=19087). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane (ACTH) (n=932), or taxane/carboplatin (TCH) (n=434), were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n=406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT) (n=374) were also matched (1:1) to those treated with TH on the APT trial. Propensity score models included age, tumor size (Tim/T1a, T1b, T1c, T2), grade, and hormone receptor status. Invasive disease-free survival (iDFS) and overall survival (OS) were compared between patients treated with ACTH or TCH and patients treated with TH from the APT trial, and between patients treated with ACT and TH. Results: After matching, 305 patients were included from the APT trial and 305 patients from the trastuzumab containing external control (ACTH or TCH). One hundred and sixty-nine patients from the APT trial were also matched to 169 patients from the ACT external control. The propensity score matching adequately balanced the patients’ baseline age and disease characteristics (Table 1). The iDFS and OS results are shown in Table 2. Similar results were observed when comparing patients who received ACTH versus TH, and comparing patients who received TCH versus TH. Similar results were also seen in trastuzumab-based treatment subgroups based on tumor size. Conclusions: External controls can be useful to contextualize single arm studies. These exploratory analyses further support the use of de-escalated therapy in patients with low-risk HER2-positive EBC. Table 1: Demographics and Disease CharacteristicsAPT (TH) N = 305External Control (ACTH/TCH) N = 305Std. Mean Diff (%)Age (Yrs), Mean (Std)54.6 (10.7)54.7 (9.8)1.1Primary Tumor Size (cm), Mean (Std)1.3 (0.6)1.4 (0.6)19.7Tumor Stage, n (%)T1ami16 (5.3)11 (3.6)-8.0T1b93 (30.5)95 (31.2)1.4T1c162 (53.1)166 (54.4)2.6T234 (11.2)33 (10.8)-1.1Grade, n (%)G119 (6.2)20 (6.6)1.3G2107 (35.1)95 (31.2)-8.4G3179 (58.7)190 (62.3)7.4ER+, n (%)198 (64.9)200 (65.6)1.4PR+, n (%)158 (51.8)157 (51.5)-0.7HR+, n (%)204 (66.9)202 (66.2)-1.4 APT (TH) N = 169External Control (ACT) N = 169Std. Mean Diff (%)Age (Yrs), Mean (Std)51.9 (10)52.5 (8.9)6.7Tumor Size (cm), Mean (Std)1.5 (0.6)1.6 (0.6)24.3Tumor Stage, n (%)T1ami6 (3.6)6 (3.6)0T1b30 (17.8)25 (14.8)-8.0T1c103 (61.0)109 (64.5)7.4T230 (17.8)29 (17.2)-1.6Grade, n (%)G13 (1.8)3 (1.8)0G252 (30.8)52 (30.8)0G3114 (67.5)114 (67.5)0ER+, n (%)100 (59.2)93 (55.0)-8.4PR+, n (%)81 (47.9)79 (46.8)-2.4HR+, n (%)103 (61.0)100 (59.2)-3.6 Table 2: iDFS and OSAPT (TH) (%)External Control (ACTH/TCH) (%)iDFS3 yrs98.6 (96.4, 99.5)96.6% (93.7, 98.1)5 yrs96.5 (93.6, 98.1)92.9% (88.2, 95.8)OS3 yrs99.7 (97.6, 100.0)99.0% (96.9, 99.7)5 yrs99.3 (97.2%, 99.8)97.4 (94.5, 98.7)APT (TH) (%)External Control (ACT) (%)iDFS3 yrs98.8 (95.3, 99.7)91.3 (85.7, 94.7)5 yrs96.1 (91.5, 98.2)83.5 (76.5, 88.6)OS3 yrs100 (NA, NA)97.4 (93.3, 99.0)5 yrs99.3 (95.3, 99.9)94.0 (88.8, 96.8) Citation Format: Laleh Amiri-Kordestani, Diqiong Xie, Erik Bloomquist, Shenghui Tang, Richard Pazdur, Rajeshwari Sridhara, Sara M Tolaney, Eric P Winer, Julia A Beaver. An FDA analysis of survival outcomes comparing adjuvant paclitaxel and trastuzumab trial (APT) to an external control from historical clinical trials [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 PD4-08.

Background: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. Methods: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha Citation Format: Jose P Leone, Lorenzo Trippa, Lindsey Milisits, Chelsea Andrews, Jennifer Ligibel, Heather Parsons, Wenya L Bi, Jean Zhao, Eric P Winer, Nancy U Lin. Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM) [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 OT1-08-05.

Introduction: Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers (BC) and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Few studies have examined the genomic landscape of male BCas, with six male BCas included in The Cancer Genome Atlas (TCGA). Familial studies of male BCas have shown genomic changes similar to female BCa, while a larger targeted sequencing study of 59 male breast cancers identified recurrent mutations affecting PIK3CA and GATA3. To date, there is still limited information regarding the genomic landscape of male BCas; particularly in the context of identifying targeted treatments. To reveal genomic changes that characterize male BCas in the context of known cancer driver genes linked to prognosis and targeted agents, we performed a targeted sequencing study on 248 male BCas from the International Male Breast Cancer Program. Methods: 248 primary M0, ER+ve, HER2-ve male BCas enrolled in the Part 1 (retrospective joint analysis) International Male Breast Cancer Program of 1483 patients diagnosed between 1990-2010 (Cardoso et al. Annals of Oncology, 2018) were processed for nucleic acid extraction from formalin-fixed paraffin embedded (FFPE) tissues. Using the Thermo Fisher Scientific Oncomine Comprehensive Assay v3 (OCAv3), a validated targeted sequencing panel currently used in the NCI-MATCH trial (NCT02465060), we evaluated mutational and copy number variations (CNVs) of genes that are prognostic or predictive to targeted therapies currently in use in the clinic or late-stage clinical trials. The OCAv3 DNA pan-cancer panel assays 115 genes for determining mutational status (48 full coding and 67 hotspot) as well as copy-number assessment in 43 genes. The OCAv3 uses Ampliseq-based technology linked to the Oncomine NGS workflow to identify actionable mutations and CNVs Results: Of the 248 samples assayed, 216 passed strict quality control parameters (87.1%). Using the Oncomine NGS workflow, actionable mutations at ≥5% variant allele frequency (VAF) were most frequently identified in PIK3CA (29.2%), BRCA2 (11.1%), NF1 (11.6%), indels in TP53 (10.6%), ATR (5.6%), ATRX (5.1%), indel BRCA2 (5.1%), TP53 point mutations (4.6%), MET (4.6%), ATM (4.6%), NOTCH2 (4.6%), CHEK1 (4.2%), FANCI (4.2%), PTEN (3.2%) with a number of additional genes identified at lower frequencies. Gene amplifications were most frequently detected in MYC (24.5%), FGFR1 (14.8%), CCND1 (12%), FGF3 (9.7%), FGF19 (9.7%), MDM2 (6.5%), CDK4 (1.4%), FGFR3, MDM4, ERBB2 (0.9% each), and FLT3, AR, MYCL, CDK6, IGF1R, FGFR4, KRAS, AKT3 and ESR1 (0.5% each). Although the results here describe the mutations and copy-number changes deemed to be actionable, further analysis of all non-actionable somatic mutations and CNVs will be presented and compared to female BCas previously assayed using the same panel. Conclusion: In this targeted sequencing study of the largest series of male BCas to our knowledge, we have revealed that PIK3CA continues to be a frequently altered gene in both male and female BCas. However, there is an enrichment of mutations in genes related to DNA repair in male BCs. Interestingly, while MYC is commonly amplified in female BCa, a higher frequency of amplified cases were seen in male BCas, in contrast to female BCas. Together with our previously generated transcriptional profiling data in this data set, we believe that both common and unique biological processes comprising male and female BCas will ultimately improve their clinical management and move towards the goal of precision medicine. This work has been funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Jane Bayani, Coralie Poncet, Cheryl Crozier, Quang M Trinh, Megan Hopkins, Aime Lambert Uwimana, Tammy Piper, Carrie Cunningham, Monika Sobol, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Florentine Hilbers, Ingrid Hedenfalk, Larissa Korde, Barbro Linderholm, John Martens, Lavinia Middleton, Melissa Murray, Catherine Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Aleksandra Peric, Peggy Porter, Carolien Schröder, Isabel T Rubio, Kathryn J Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna Vermeij, Eric Winer, Lincoln D Stein, Sharon H Giordano, Fatima Cardoso, John MS Bartlett. The genomic landscape of male breast cancers using the oncomine comprehensive assay for actionable mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-03.

Background: Immune checkpoint inhibitors (ICI), such as those targeting the PD-1/PD-L1 axis, have shown modest activity as monotherapy in both HR+ MBC and MOC. Strategies to improve ICI for these diseases are under investigation. In mouse models, CDK4/6 inhibitors boost anti-tumor immunity in part by increasing the infiltration and activation of cytotoxic T lymphocytes, and by suppressing regulatory T lymphocyte function, providing rationale for combining CDK4/6 inhibition and ICI. Methods: We conducted an open-label phase 1b dose escalation study with the primary objectives of determining the safety, tolerability, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ribociclib and spartalizumab in patients with HR+ MBC and MOC. Ribociclib was administered on days 1-21 and spartalizumab on day 1 of a 28-day cycle. The study used a 3 + 3 dose escalation design with dose-limiting toxicities (DLTs) formally defined during the first cycle. For the dose escalation there were no restrictions on prior chemotherapy or CDK4/6 inhibitor use but prior PD-1/PD-L1 inhibitor use was not allowed. Once the MTD/RP2D was determined, we conducted a safety run-in for the combination of ribociclib and spartalizumab with fulvestrant in patients with HR+ MBC. Results: During dose escalation, 9 patients with HR+ MBC and 1 patient with MOC were enrolled. Three patients each were enrolled to dose levels 1 and 2 (ribociclib 400 mg and 600 mg PO QD for 21/28 days, respectively, and spartalizumab 400 mg IV q28 days) and no DLTs were observed. Four additional patients were enrolled to dose level 2; one was deemed unevaluable due to drug compliance issues and was replaced. Among the 3 evaluable patients, 1 experienced a DLT of grade 3 atrial fibrillation and flutter, which were possibly related to both ribociclib and spartalizumab. Based on this experience, the MTD/RP2D was declared to be ribociclib 600mg PO QD for 21/28 days in combination with spartalizumab 400mg IV q28 days. For the safety run-in, evaluating the addition of fulvestrant to the combination of ribociclib and spartalizumab, 6 patients with HR+ MBC were enrolled and no additional DLTs were observed. Among all patients with MBC (n=15), the median number of prior hormonal therapies was 2 (range 0-4); 10 patients (67%) had previously received fulvestrant, and all patients had previously received a CDK4/6 inhibitor. For the entire group (n=16), 10 patients (63%) had received 4 or more prior lines of chemotherapy for metastatic disease. The most common grade 3 and 4 toxicities regardless of treatment attribution were neutropenia (n = 8, 50%), increased aspartate aminotransferase (n = 4, 25%), increased alanine aminotransferase (n = 4, 25%). Median follow-up for all patients was 3.5 months (95% CI: 2.8 - 5.1). Among the 16 patients treated, 1 breast cancer patient had a PR (ORR=6.25%, 95% CI: 0-30%) and 1 breast cancer patient had SD for > 24 weeks (6.25%, 95% CI 0-30%); CBR = 12.5% (95% CI: 1.6-38.3%): both of these patients received ribociclib and spartalizumab with fulvestrant. The median PFS for all patients was 3.1 months (95% CI: 1.9 - NR), and the median OS was 6.0 months (95% CI: 6.0 - NR). Conclusion: In this phase 1b study, the combination of ribociclib and spartalizumab was well tolerated with toxicity consistent with that expected from each agent alone and no new toxicities were observed. The RP2D for the combination is ribociclib 600mg PO QD for 21/28 days and spartalizumab 400mg IV q28 days with or without fulvestrant. Clinical benefit was achieved in 2 breast cancer patients who had previously received a CDK4/6 inhibitor combined with hormonal therapy. Dose expansion cohorts are currently enrolling for patients with HR+ MBC and MOC. Citation Format: Christina I Herold, Lorenzo Trippa, Tianyu Li, Khanh Do, Aditya Bardia, Leilani Anderson, Kamaneh Montazeri, Jessica Pittenger, Chelsea Andrews, Elizabeth A Mittendorf, Shom Goel, Eric P Winer, Geoffrey I Shapiro, Sara M Tolaney. A phase 1b study of the CDK4/6 inhibitor ribociclib in combination with the PD-1 inhibitor spartalizumab in patients with hormone receptor-positive metastatic breast cancer (HR+ MBC) and metastatic ovarian cancer (MOC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-03.

Background: The CDK4/6 inhibitors have emerged as standard first- or second-line regimens in combination with an antiestrogen for patients with HR+/HER2- MBC. While these agents convey significant clinical benefit in many patients, intrinsic resistance can occur and, in patients who respond, acquired resistance is unfortunately inevitable. Despite their widespread use, we have limited insight into the molecular mechanisms governing response and resistance to these agents. Methods: Whole exome sequencing (WES) was performed on metastatic tumor biopsies from 58 patients (pts) with HR+/HER2- MBC who received a CDK4/6 inhibitor with or without an antiestrogen at the Dana-Farber Cancer Institute, including 7 pts with pre/post-exposure biopsy pairs. Among these biopsies, 69.5% were characterized as resistant (intrinsic or acquired) and 30.5% were characterized as sensitive. To validate putative resistance mediators identified in patient samples, HR+/HER2- breast cancer cells were modified via CRISPR knockout or lentiviral overexpression. Sensitivity of these cells to antiestrogens and CDK4/6i was interrogated via cell-titer-glo assay. In parallel, HR+/HER2- breast cancer cells were cultured to resistance in the presence of an escalating dose of CDK4/6i. Derivative cell lines were subjected to western blotting in an effort to interrogate the putative resistance mediators identified in pts. Novel dependencies were identified in these derivative cell lines via treatment with targeted therapeutic agents in vitro. Results: WES of tumors with CDK4/6i exposure revealed candidate mechanisms of resistance including biallelic RB1 disruption (n=4, 10%) and activating events in AKT1 (n=5, 12.5%), RAS (n=4, 10%), aurora kinase A (AURKA, n=11, 27.5%), and cyclin E2 (CCNE2, n=6, 15%). Convergent evolution toward biallelic RB1 disruption was identified in a single patient with one pre- and two post-exposure biopsies, while acquisition of AKT1 mutation and amplification was identified in two separate instances. Knockout of RB1 and overexpression of AKT1, KRAS G12D, AURKA, and CCNE2 provoked CDK4/6i and antiestrogen resistance in vitro. Breast cancer cells cultured to resistance in CDK4/6i demonstrated concordant acquisition of RB1 downregulation, RAS/ERK activation, AURKA overexpression, and CCNE2 overexpression. Derivative resistant cell lines with RB1 loss or AURKA gain demonstrated enhanced sensitivity to a novel AURKA inhibitor (LY3295668), while cells with RAS activation were highly sensitive to ERK inhibition (via LY3214996). CCNE2-overexpressing cells were highly sensitive to prexasertib, a CHEK1 inhibitor. Conclusions: The genomic landscape of resistance to CDK4/6i is heterogeneous with multiple potential mediators that play well-established roles in cell division and oncogenic signal transduction. We present novel mechanisms of clinical resistance including activation of AKT1 and RAS family oncogenes as well as amplification of AURKA and CCNE2. These drivers were able to provoke resistance to CDK4/6i in vitro. Finally, in each case, a novel dependency was identified which is readily translatable into the clinic. These results underscore the potential of next-generation sequencing as a critical tool to enable identification of resistance mediators, while also suggesting that the presence of specific genomic alterations may define new therapeutic opportunities in CDK4/6i-resistant HR+ MBC. Citation Format: Seth A. Wander, Ofir Cohen, Xueqian Gong, Gabriela N. Johnson, Jorge Buendia-Buendia, Maxwell Lloyd, Dewey Kim, Flora Luo, Pingping Mao, Karla Helvie, Kailey Kowalski, Utthara Nayar, Stephen Parsons, Ricardo Martinez, Lacey Litchfield, Xiang Ye, Chun Ping Yu, Valerie Jansen, Levi A. Garraway, Eric P. Winer, Sara M. Tolaney, Nancy U. Lin, Sean Buchanan, Nikhil Wagle. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in patients with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC) [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 PD2-09.

Background: Patients (pts) with mTNBC have a poor prognosis, and new therapies are needed. Cabozantinib is a multikinase inhibitor that blocks VEGF receptor 2, reduces myeloid-derived suppressor cells, and increases T cell infiltration, suggesting it may enhance the activity of the anti-PD-1 checkpoint blockade agent nivolumab. Here, we report the safety and efficacy of nivolumab plus cabozantinib in a phase II single-arm study in mTNBC pts. Methods: Eligible pts had metastatic breast cancer that was estrogen and progesterone receptor < 10% and HER2 negative, measurable disease, and received 0-3 prior lines of chemotherapy in the advanced setting. Pts received nivolumab (480 mg intravenously on day 1, every 28 days) plus cabozantinib (40 mg daily by mouth). The primary endpoint was objective response rate (ORR) by RECIST v1.1. Using the Simons “optimal” method, if ≥ 3/18 pts responded during the first stage, 17 more would be enrolled. If ≥ 7/35 responded, the null hypothesis (ORR=10%) would be rejected in favor of a 30% ORR. Predefined secondary endpoints included progression free survival (PFS), clinical benefit rate (CBR), and toxicity. CBR was defined as the fraction of pts with any objective response or stable disease (SD) ≥ 24 weeks. Analyses associating PD-L1 expression, tumor-infiltrating lymphocytes (TIL), and genomic alterations (assessed by next generation sequencing on archival tissue) with outcomes were exploratory. Results: From 12/15/2017 to 01/24/2019, 18 pts were enrolled into the first stage of the trial; one partial response was seen (ORR 5.6%; 95% CI: 0.3-29.4), and the study was closed to further accrual. The median age was 58y, all pts had ECOG PS 0, and 7 (38.9%) had liver metastases. The median number of prior cytotoxic therapies for mTNBC pts was 1 (range 0 to 3). Three pts had SD ≥24 weeks and two had progressive disease best response. The CBR was 22.2%. After a median follow up of 3.7 months, the median PFS was 4.4 months (95% CI: 1.9-12.8), and the median OS was 6.9 months (95% CI: 3.4-NR). All-cause adverse events occurred in 100% of pts (G3-4, 78%) including elevated liver enzymes (any 50%; G3-4 16.7%), hand-foot syndrome (any 38.9%; G3-4 16.7%), fatigue (any 38.9%; G3-4 11.1%), and hypothyroidism (any 33.3%; no G3-4). Of the 9 pts with available genomic data, none had tumor mutational burden ≥ 10 mutations per megabase. Updated data with TIL, PD-L1, whole exome sequencing and RNA-sequencing results will be presented. Conclusions: The combination of nivolumab plus cabozantinib was not associated with any unexpected adverse events, however, with an ORR of 5.6%, the study did not achieve its primary endpoint. Exploratory genomic and immunological correlative studies are ongoing. Clinical trial information: NCT03316586. Citation Format: Romualdo Barroso-Sousa, Lorenzo Trippa, Tianyu Li, Tanya E Keenan, Grace Winship, Chelsea Andrews, Wafa Osmani, Beth Overmoyer, Eric P Winer, Elizabeth A Mittendorf, Dan G Duda, Sara M Tolaney. A phase II study of nivolumab in combination with cabozantinib for metastatic triple-negative breast cancer (mTNBC) [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 P3-09-10.

Background Relative to other metastatic breast cancer subtypes, metastatic triple-negative breast cancer (mTNBC) has a shorter duration of response to therapy and worse overall survival. Among patients with mTNBC, it is hypothesized that inflammatory breast cancer (IBC) and young women have particularly aggressive phenotypes. We investigated clinical and cell-free DNA (cfDNA) characteristics of inflammatory-mTNBC and young-mTNBC. Patients and Methods We evaluated 158 patients with mTNBC who were stratified into 3 groups: (1) IBC; (2) patients aged 45 years or younger at primary diagnosis without IBC (non-IBC young); and (3) patients over age 45 at diagnosis without IBC. We evaluated clinicopathologic characteristics, sites of metastasis, survival outcomes, and the fraction of DNA in circulation derived from tumor (TFx). Results Analysis of metastatic sites revealed that young patients without IBC had the most frequent lung metastases (P = .002). cfDNA analyses of first sample showed that TFx was highest in the non-IBC young group but not elevated in the IBC group (analysis of variance P = .056 for first TFx). Individually, median overall survival from metastatic diagnosis for the IBC group was 15.2 months; for the non-IBC young group, 21.2 months, and for the non-IBC over 45 group, 31.2 months. Patients with IBC and young patients without IBC had worse prognosis relative to patients over 45 without IBC (log-rank P = .023). Conclusions Among patients with mTNBC in this single-institution cohort, patients with IBC and young patients without IBC had significantly worse overall survival compared with patients over 45 without IBC. Young patients without IBC had significantly higher cfDNA TFx, whereas patients with IBC did not have elevated TFx despite a poor prognosis. These findings demonstrate that further analyses of mTNBC subsets are warranted.

Chemotherapy-induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient-reported outcome and (2) propose a dose-adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose-neuropathy model was developed using dosing and patient-reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin-bound paclitaxel or ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose-adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin-bound paclitaxel, and ixabepilone, simulations with the proposed dose-adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient-reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

PURPOSE The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling. PATIENTS AND METHODS Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877 ). Our primary aim was to describe the proportion of patients with a qualifying ERBB2 mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of ERBB2 mutations, and survival. Associations were calculated using Fisher’s exact test. RESULTS We identified a total of 1,045 patients with metastatic breast cancer without ERBB2 amplification who had available genomic testing results. Of these, 42 patients were found to have ERBB2 mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing. CONCLUSION More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.

Background Signaling through the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway can mediate therapeutic resistance in HER2-positive breast cancer. Preclinical studies have demonstrated that CDK4/6 inhibitors can resensitize resistant HER2-positive breast cancer to anti-HER2 therapies. Patients and Methods We conducted a phase 1b/2 study of ribociclib (400 mg per day on a continuous schedule) plus trastuzumab (6 mg/kg every 3 weeks) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. There were no restrictions on the number of prior therapy lines. Primary objective was clinical benefit rate at 24 weeks, and secondary objectives included safety, objective response, rate and progression-free survival. The study was enrolled at ClinicalTrials.gov as NCT02657343 . Results From March 2016 to March 2017, 13 patients were enrolled. One patient was found to have HER2-negative disease and did not receive treatment. Median number of prior lines in the metastatic setting was 5 (range, 0-14); 67% had hormone receptor–positive disease. No dose-limiting toxicities were observed during the safety run-in phase, and ribociclib was thus dosed at 400 mg per day continuously for the expansion cohort. Grade 3 adverse events were observed in 4 patients (33.3%) and included neutropenia (n = 2) as well as fatigue and pain in 1 patient each. No grade 4/5 adverse events or QTc prolongation were observed. One patient (8.3%) experienced stable disease > 24 weeks; no objective responses were observed, and median progression-free survival was 1.33 months (95% confidence interval, 0.92-2.57). Conclusion Continuous low-dose ribociclib (400 mg) plus trastuzumab is safe, with no new safety concerns. The limited activity observed in this study suggests that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pretreated population.

This single-arm phase II study investigated the efficacy and safety of cabozantinib combined with nivolumab in metastatic triple-negative breast cancer (mTNBC). The primary endpoint was objective response rate (ORR) by RECIST 1.1. Biopsies at baseline and after cycle 1 were analyzed for tumor-infiltrating lymphocytes (TILs), PD-L1, and whole-exome and transcriptome sequencing. Only 1/18 patients achieved a partial response (ORR 6%), and the trial was stopped early. Toxicity led to cabozantinib dose reduction in 50% of patients. One patient had a PD-L1-positive tumor, and three patients had TILs > 10%. The responding patient had a PD-L1-negative tumor with low tumor mutational burden but high TILs and enriched immune gene expression. High pretreatment levels of plasma immunosuppressive cytokines, chemokines, and immune checkpoint molecules were associated with rapid progression. Although this study did not meet its primary endpoint, immunostaining, genomic, and proteomic studies indicated a high degree of tumor immunosuppression in this mTNBC cohort.

Introduction: TNBCs show marked heterogeneity in their spectrum of genomic alterations, patterns of gene expression, proteomic profiles, and immune microenvironments. Although TNBC heterogeneity has been characterized at each of these levels individually, how variation at one level is associated with differences at other levels is poorly understood. As new targeted and immune-based therapies are developed for TNBC, there is a critical need to better understand this interplay. In this study, we performed “multi-omic” profiling on a cohort of TNBCs in order to determine how various DNA, RNA, protein, and immunologic parameters are correlated. Methods: A cohort of 95 formalin-fixed, paraffin-embedded tumor specimens from primary and metastatic TNBCs was curated. The following parameters in each tumor specimen were quantified: stromal tumor-infiltrating lymphocytes (sTILs) assessed on hematoxylin and eosin stained sections; expression of programmed death-ligand 1 (PD-L1), androgen receptor (AR) and the retinoblastoma tumor suppressor protein (RB) by immunohistochemistry (IHC); and expression of 776 breast cancer-related transcripts (using the nCounter Breast Cancer 360 panel). Targeted tumor DNA sequencing was performed in a subset of cases and tumor mutational burden (TMB) and DNA mismatch repair (MMR) status were determined. Gene expression patterns were analyzed using customized algorithms and we performed descriptive statistics to evaluate associations between DNA, RNA, and protein variables. Results: All 95 TNBC specimens were analyzed for sTILs; IHC for RB, AR, and PD-L1; and transcriptomic profiling. DNA sequencing was performed on 68 cases. The genomic, transcriptomic, and proteomic classification of the cohort is provided in Table 1. AR+ TNBCs (>1% tumor cells on IHC) were more likely to be non-basal (p RB-positivity (>50% tumor cells on IHC) correlated with higher RB1 transcript levels but not with RB1 deletion/mutation status. RB+ tumors were depleted for expression of genes associated with HRD and BRCAness (p=0.029 and p=0.071). TNBCs showing widespread upregulation of gene expression signatures related to numerous immune processes included those with: (i) higher levels of sTILs, (ii) >1% PD-L1+ stromal mononuclear cells and/or tumor cells, (iii) tumors without RB1 or TP53 alterations. Genomic aberration in the PI3K pathway was associated with increased expression of AR and FOXA1 but not with alterations in immune gene expression. Conclusion: Patterns exist connecting TNBC heterogeneity across the DNA, RNA, and protein levels. Further analyses determining associations between genomic, transcriptomic, and proteomic features in this cohort of TNBC will be presented at the meeting. Genomic, transcriptomic, and proteomic classification of tumors in the entire TNBC cohortTumor site (n=95)Primary64 (67%)Regional nodal4 (4%)Distant nodal or visceral27 (28%)Stromal TILs (n=93)50%13 (14%)RB staining (n=95)Positive (>50% tumor cells)52 (55%)AR staining (n=95)Positive (>1% tumor cells)34 (36%)PD-L1 staining (stromal, n=94)Positive (>1% mononuclear cells)34 (37%)PD-L1 staining (tumor, n=94)>1% tumor cells27 (29%)PAM50 subtype (n=90)Basal72 (80%)HER2-enriched15 (17%)Luminal B3 (3%)TNBC subtype (n=91)Basal-like immune activated (BLIA)76 (80%)Basal-like immunosuppressed (BLIS)7 (7%)Mesenchymal (MES)8 (8%)Luminal androgen receptor (LAR)4 (4%)DNA alterations (n=68)TP53 alterations54 (80%)BRCA1/2 mutations14 (21%)RB1 alterations21 (31%)PI3K pathway alterations31 (46%) Citation Format: Shom Goel, Heather Ann Brauer, Yuqi Ren, Kara Gorman, Wafa Osmani, Jessica Pittenger, Chelsea Andrews, Edward T Richardson III, Elizabeth A Mittendorf, MD PhD, Eric P Winer, Stuart Schnitt, Sara M Tolaney. Using multi-omic profiling to unravel the complexity of triple-negative breast cancer (TNBC) [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 P4-06-01.

Background The 16th St. Gallen International Breast Cancer Conference 2019 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Design Treatments were assessed in light of their intensity, duration and side-effects, estimating the magnitude of clinical benefit according to stage and biology of the disease. The Panel acknowledged that for many patients, the impact of adjuvant therapy or the adherence to specific guidelines may have modest impact on the risk of breast cancer recurrence or overall survival. For that reason, the Panel explicitly encouraged clinicians and patients to routinely discuss the magnitude of benefit for interventions as part of the development of the treatment plan. Results The guidelines focus on common ductal and lobular breast cancer histologies arising in generally healthy women. Special breast cancer histologies may need different considerations, as do individual patients with other substantial health considerations. The panelists' opinions reflect different interpretation of available data and expert opinion where is lack of evidence and sociocultural factors in their environment such as availability of and access to medical service, economic resources and reimbursement issues. Panelists encourage patient participation in well-designed clinical studies whenever available. Conclusions With these caveats in mind, the St. Gallen Consensus Conference seeks to provide guidance to clinicians on appropriate treatments for early-stage breast cancer and guidance for weighing the realistic tradeoffs between treatment and toxicity so that patients and clinical teams can make well-informed decisions on the basis of an honest reckoning of the magnitude of clinical benefit.

Purpose: Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window-of-opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer. Experimental Design: Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind–body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery. Results: Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2 kg/m2, and exercise was 49 minutes/week. Exercise participants significantly increased exercise versus controls (203 vs. 23 minutes/week, P < 0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants versus controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants (q < 0.1). Top-ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3+ cells in exercise versus control participants over the intervention period (P = 0.08). Conclusions: A window-of-opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer. See related commentary by Koelwyn and Jones, p. 5179

Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local–regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan–Meier method. Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4–96.2), and LRR-free survival was 98.6% (95% CI 97.4–99.8). LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.

Summary Background Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. Methods In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov , number NCT01623349 . Findings Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3–4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. Interpretation Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. Funding Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.

PURPOSE Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake values corrected for lean body mass (SULmax) on [18F]fluorodeoxyglucose positron emission tomography/computed tomography would predict pathologic complete response (pCR) to neoadjuvant pertuzumab and trastuzumab (PT). PATIENTS AND METHODS Patients with stage II/III, estrogen receptor–negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. [18F]Fluorodeoxyglucose positron emission tomography/computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percentage of change in SULmax by C1D15 predicting pCR is less than or equal to 0.65, with a one-sided type I error rate of 10%. RESULTS Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 34%. Receiver operating characteristic analysis yielded an area under the curve of 0.76 (90% CI, 0.67 to 0.85), which rejected the null hypothesis. Between patients who obtained pCR versus not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 33.5%; P < .001), an SULmax reduction greater than or equal to 40% was more prevalent (86% v 46%; P < .001; negative predictive value, 88%; positive predictive value, 49%), and a significant difference in median C1D15 SULmax (1.6 v 3.9; P < .001) and higher proportion of C1D15 SULmax less than or equal to 3 (93% v 38%; P < .001; negative predictive value, 94%; positive predictive value, 55%) were observed. CONCLUSION Early changes in SULmax predict response to four cycles of PT in estrogen receptor–negative, HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate a more tailored approach to therapy in this setting.

Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER+ breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25–30% of people treated with aromatase inhibitors1–4, knowledge about clinical resistance mechanisms remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to aromatase inhibitors, tamoxifen or fulvestrant. Examination of treatment-naive primary tumors in five patients showed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. The HER2 mutations and ER mutations were mutually exclusive, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that the HER2 mutations conferred estrogen independence as well as—in contrast to ER mutations—resistance to tamoxifen, fulvestrant and the CDK4 and CDK6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib. Activating HER2 mutations are shown to confer resistance to ER-directed therapies in patients with ER+ metastatic breast cancer. Drug resistance caused by HER2 mutations was overcome by combining ER-directed therapy with a HER2 kinase inhibitor.

Despite the availability of multiple human epidermal growth factor receptor 2–targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1–positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.

Chemotherapy-related amenorrhea (CRA) is a surrogate for ovarian toxicity and associated risk of infertility and premature menopause. Here, we compare CRA rate with paclitaxel (T)-trastuzumab (H) to that with ado-trastuzumab emtansine (T-DM1). Patients with T1N0 HER2 + early-stage breast cancer (eBC) enrolled on the ATEMPT trial and were randomized 3:1 to T-DM1 3.6 mg/kg IV every (q) 3 weeks (w) × 17 vs. T 80 mg/m2 with H IV qw × 12 (4 mg/kg load → 2 mg/kg), followed by H (6 mg/kg IV q3w × 13). Enrollees who self-reported as premenopausal were asked to complete menstrual surveys at baseline and every 6–12 months for 60 months. 18-month CRA (no periods reported during prior 6 months on 18-month survey) was the primary endpoint of this analysis. Of 512 ATEMPT enrollees, 123 who began protocol therapy and answered baseline and at least one follow-up menstrual survey were premenopausal at enrollment. 76 had menstrual data available at 18 months without having received a gonadotropin-releasing hormone agonist or undergone hysterectomy and/or oophorectomy. Median age was 45 (range 23–53) among 18 who had received TH and 46 (range 34–54) among 58 who had received T-DM1. The 18-month rate of CRA was 50% after TH and 24% after T-DM1 (p = 0.045). Amenorrhea at 18 months was less likely in recipients of adjuvant T-DM1 than TH. Future studies are needed to understand how T-DM1 impacts risk of infertility and permanent menopause, and to assess amenorrhea rates when T-DM1 is administered after standard HER2-directed chemotherapy regimens.

Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [1%] vs 14 [5%]), decreased neutrophil count (one [1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (1%) of 601 participants had treatment-related adverse events that led to death (one [1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [1%] due to pancytopenia and sepsis and one [1%] haemothorax).Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.Merck SharpDohme.

Purpose Most reports describing the risk of late relapse in breast cancer (BC) have been based on selected patients enrolled into clinical trials. We examined population-based long-term risks of BC-specific mortality (BCSM), the risks of BCSM conditional on having survived 5 years, and factors associated with late BCSM. Methods Using SEER, we identified women diagnosed with BC (T1-T2, N0-N2, M0) between 1990 and 2005 with known hormone receptor (HR) status. Kaplan–Meier analyses determined cumulative risks of BCSM. We performed Fine and Gray regression stratified by HR status. Results We included 202,080 patients (median follow-up of 14.17 years). Of all BC deaths, the proportion that occurred after 5 years was 65% for HR-positive vs 28% for HR-negative (p Conclusion The risks of BCSM beyond 5 years, although different, remain important for both HR-positive and HR-negative BC. Strategies to prevent early and late recurrences are warranted.