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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.

PURPOSE To update the American Society of Clinical Oncology endorsement of the Cancer Care Ontario recommendations on the Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer. METHODS Two phase III trials—the Trial Assigning Individualized Options for Treatment (TAILORx) in women with hormone receptor–positive, node-negative tumors and the Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) trial—provided the evidence for this update. UPDATED RECOMMENDATIONS Shared decision making between clinicians and patients is appropriate for adjuvant systemic therapy for breast cancer. For patients older than age 50 years and whose tumors have Onco type DX recurrence scores less than 26, and for patients age 50 years or younger whose tumors have Onco type DX recurrence scores less than 16, there is little to no benefit from chemotherapy. Clinicians may offer endocrine therapy alone for these patients. For patients age 50 years or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the Panel recommends that oncologists may offer chemoendocrine therapy to patients with Onco type DX scores of 26 to 30. The MammaPrint assay could be used to guide decisions on withholding adjuvant systemic chemotherapy in patients with hormone receptor–positive lymph node–negative breast cancer and in select patients with lymph node–positive cancers. In both patients with node-positive and node-negative disease, evidence of clinical utility of the MammaPrint assay was only apparent in those determined to be at high clinical risk; the Panel thus did not recommend use of MammaPrint assay in patients determined to be at low clinical risk. Remaining recommendations from the 2016 ASCO guideline endorsement are unchanged. Additional information is available at www.asco.org/breast-cancer-guidelines .

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.

525 Background: Homologous recombination deficiency (HRD) status can be used to identify patients who are eligible for treatment with DNA damaging agents. Using a 3-biomarker Genomic Instability Score (GIS) threshold of ≥42, studies have previously examined the association between HRD status and outcomes in patients with triple negative breast cancer (TNBC). However, evidence suggests that a GIS threshold of ≥33 may be more appropriate. Here, we conducted an exploratory analysis evaluating the ability of ≥33 and ≥42 GIS thresholds to predict response to platinum-based treatment in patients with TNBC. Methods: Patients across 5 cohorts (TBCRC0301, TBCRC0082, NCT013725793, PrECOG 01054, combined cisplatin cohort4) were included in this analysis if they had a primary TNBC diagnosis, received neoadjuvant platinum-based treatment, had a valid GIS, and had known pathologic complete response (pCR) status. GIS was determined by a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions.4,5 BRCA mutation status was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated by comparing binary threshold status and binary pCR status. Results: A total of 204 tumors (158 BRCAwt; 33 BRCAm; 13 unknown) were included; pCR to platinum-based treatment occurred in 55 cases (39 BRCAwt; 14 BRCAm; 2 unknown). Sensitivity, specificity, PPV, and NPV were comparable between the ≥33 and ≥42 GIS thresholds, with the ≥33 threshold producing higher sensitivity values. This was true when thresholds were applied to all samples and to BRCAwt samples only (Table). Among patients who achieved pCR in response to platinum-based treatment, 5.5% of patients in the full cohort and 7.7% of those in the BRCAwt cohort had a GIS between 33-41. Conclusions: To ensure that the majority of patients likely to benefit from treatment are identified, a GIS of ≥33 may be the most appropriate threshold to predict response to platinum-based treatment in patients with TNBC; however, a prospective trial will be needed to confirm these findings. Additional studies will be important to determine whether this threshold may be appropriate to determine eligibility for other DNA-damaging agents such as PARP inhibitors. 1. Ann Oncol. 2020;31(11):1518-25 2. J Nucl Med. 2015;56(1):31-7. 3. Breast Cancer Res Treat. 2015;151(3):629-38. 4. Clin Cancer Res. 2016;22(15):3764-73. 5. Breast Cancer Res Treat. 2014;16(6):1-9. [Table: see text]

1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m2, D2, 9) plus cisplatin 75mg/m2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m2 D2,9 + cisplatin 75mg/m2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]

TPS1111 Background: Chest wall recurrence is a subtype of breast cancer that is challenging to treat, and associated with a short duration of response to treatment and an increased risk of development of distant metastases. Given the inflammatory nature of this disease and the association of chest wall disease with lymphovascular invasion, which is correlated with higher programmed cell death 1 (PD-1) expression, we hypothesized that immunotherapy may be beneficial as treatment. Combinations of immunotherapy and chemotherapy have a synergistic effect and demonstrated efficacy in the treatment of metastatic triple negative breast cancer (TNBC). This study is evaluating the efficacy of pembrolizumab, an anti-PD-1 antibody, in combination with carboplatin, in patients with chest wall infiltration from breast cancer. This drug combination has shown efficacy in advanced lung cancer. Methods: This is a multicenter, 2:1 randomized phase II study of pembrolizumab/carboplatin (Arm A, 56 patients) vs. carboplatin (Arm B, 28 patients) in 84 patients with chest wall disease from breast cancer, with or without distant metastases. Patients may have TNBC, hormone receptor positive/HER2 negative (following receipt of 2 prior hormone therapies), or HER2 positive breast cancer (with option to continue trastuzumab on study). Pembrolizumab is administered as 200 mg IV every 3 weeks, and carboplatin as AUC 5 IV every 3 weeks. Patients on Arm A may continue pembrolizumab +/- carboplatin (Arm Ax) after completion of 6 cycles of treatment, while patients in Arm B can cross-over to pembrolizumab (+/- carboplatin) on progression (Arm Bx). Patients must have adequate organ function, performance status ≤ 2, and may have received any number of lines of prior chemotherapy. Patients undergo serial chest wall photography and imaging (CT chest, abdomen, and pelvis, and bone scan) at baseline and every 6 weeks, as well as blood collection for correlative studies and chest wall biopsies at baseline and after 2 cycles of treatment. The primary endpoint is disease control rate (RECIST 1.1) at 18 weeks of treatment, and the study is powered to determine a 20% difference in disease control rates between arms (HR 0.52, a = 0.10, ß = 0.20). An interim analysis will occur for Arm B after 18 patients are enrolled, with a stopping rule for futility. Secondary endpoints include progression-free survival, toxicity (NCI CTCAE), and response based on irRECIST and tumor programmed death ligand 1 (PD-L1) expression. Exploratory objectives include evaluating changes in soluble PD-L1, tumor and peripheral blood immune composition, circulating tumor cells and cell-free DNA, and MYC oncogene expression. This study (NCT03095352) is open at 7 sites in the Translational Breast Cancer Research Consortium (TBCRC). 52 patients are enrolled. Grant funding is provided by Merck and UCSF. Clinical trial information: NCT03095352 .

Purpose An American Society of Clinical Oncology (ASCO) panel considered the Cancer Care Ontario (CCO) recommendations on the role of patient and disease factors in selecting adjuvant therapy for women with early-stage breast cancer for endorsement. Methods ASCO staff reviewed the CCO guideline for methodologic rigor, and an ASCO panel of content experts reviewed the content of the recommendations. CCO Recommendations For making decisions regarding adjuvant therapy, nodal status, tumor size, estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) status, tumor grade, and lymphovascular invasion are relevant; Oncotype DX score and Adjuvant! Online may be used as risk stratification tools; and age, menopausal status, and medical comorbidities should be considered. Chemotherapy should be considered for patients with positive lymph nodes, ER-negative disease, HER2-positive disease, Adjuvant! Online mortality greater than 10%, grade 3 lymph node–negative tumors (T > 5 mm), triple-negative (ER-negative, PgR-negative, HER2-negative) tumors, lymphovascular invasion positivity, or estimated distant relapse risk of greater than 15% at 10 years based on Oncotype DX recurrence score (RS). Chemotherapy may not be beneficial or required for small node-negative tumors (T < 5 mm) without high-risk features or for patients with HER2-negative, strongly ER-positive, and PgR-positive cancer with micrometastatic nodal disease, T less than 5 mm, or Oncotype DX RS with an estimated distant relapse risk of less than 15% at 10 years. ASCO Panel Conclusion The ASCO panel endorses the recommendations with minor suggested revisions and highlights three areas that warrant further consideration: tumor histology and adjuvant therapy recommendations, risk stratification tools and proposed Oncotype DX RS thresholds to guide decisions about chemotherapy, and patient factors in decision making.

TPS1102 Background: While immunostimulatory therapies have shown great success, a major challenge remains identification of mechanisms to effectively treat the majority of patients with so-called "non-inflamed" tumors lacking marked lymphocyte infiltration and PD-L1 expression. The DNA repair proficiency of a tumor may impact its potential for immune recognition and sensitivity to immune checkpoint blockade. Preclinically, PARP inhibition in HDR-deficient tumors has been shown to trigger antitumor immunity through a STING-dependent antitumor immune response. Effects of PARP inhibitors were augmented when combined with PD-1 blockade. We hypothesize that enhanced DNA damage and cell death induced by PARP inhibition in tumors with homology directed repair (HDR) deficiency will enhance adaptive anti-tumor immune responses and increase sensitivity to PD-1 axis blockers. Methods: This is a randomized, open-label phase II clinical trial exploring the PARP inhibitor olaparib either alone or in combination with the anti-PD-L1 human monoclonal antibody atezolizumab in BRCA1/2 mutated locally advanced or metastatic non-HER2-positive breast cancer. HDR deficiency is defined as the presence of deleterious BRCA 1/2 mutations. Randomization occurs in a 1:1 fashion to two arms: (1) olaparib 300 mg PO bid continuously in 21-day cycles or (2) olaparib 300 mg PO bid continuously in combination with atezolizumab 1200 IV every 3 weeks in 21-day cycles. Patients undergo baseline evaluations and pre-treatment biopsy within 2 weeks of starting therapy. Repeat biopsies are required at the time of first tumor assessment scan (6 weeks from the start of treatment) and in the event of disease progression. Correlative studies, including detailed analysis of the genomic profile and tumor immune contexture, will be performed at each biopsy time point. The primary objective is to compare progression free survival between the study arms. If progression occurs on the olaparib monotherapy arm, cross-over to the combination arm is allowed. This study began enrolling in August 2018; 47 of the planned 72 patients have been registered. Clinical trial information: NCT02849496 .

TPS1112 Background: Patients with metastatic triple negative breast cancer (mTNBC) have limited treatment options. Recent studies with a PD-L1 inhibitor and taxane based chemotherapy have demonstrated an increase in median progression free survival (PFS) in mTNBC. While taxanes target microtubules, platinum agents directly alkylate DNA and may generate additional neoantigens to enhance anti-tumor immunity via immune checkpoint inhibition. In this study, we are evaluating the combination of carboplatin with and without atezolizumab in patients with mTNBC. Serial biopsies are poised to help elucidate biological differences in responders and nonresponders. As optimal timing of adding checkpoint inhibition to chemotherapy is debatable, the randomized, crossover design will give insight into whether priming mTNBCs with DNA damaging chemotherapy results in cellular and immune changes that lead to a greater likelihood of response. Methods: This is a randomized phase II multicenter study at seven sites within the Translational Breast Cancer Research Consortium (TBCRC). Patients with mTNBC, ECOG 0-1, and 0-1 prior regimens for mTNBC are eligible. 106 patients will be randomized 1:1 to receive atezolizumab 1200 mg plus carboplatin AUC 6 (n = 53; Arm A) or carboplatin AUC 6 alone (n = 53; Arm B) every 3 weeks until intolerable toxicity or disease progression occurs. Patients receiving carboplatin alone have the option to cross over to atezolizumab upon progression (Arm Bx). Patients will undergo clinical assessment every cycle, and tumor assessment every 3 cycles with CT scan of the chest, abdomen, and pelvis and bone scan. Core biopsies of a metastatic lesion are performed at baseline and at progression. The primary endpoint is median progression free survival (PFS) with 95% confidence intervals based on RECIST 1.1. The sample size of 106 with 1:1 randomization is powered to detect a 1.5-month difference in PFS between arms (α = 0.10, β = 0.20). Secondary endpoints include overall response rate (ORR), duration of response (DOR), clinical benefit rate, and overall survival. The PFS, ORR, and DOR will also be measured by irRECIST to account for delayed effects of atezolizumab on tumor burden. The quantification of tumor infiltrating lymphocytes (TILs) will study the prognostic effects of TILs on PFS in patients receiving atezolizumab. Biopsy-derived PD-L1 expression by IHC and RNA-seq will assess treatment-induced changes, define triple-negative subtypes, and evaluate for resistance mechanisms. To date, 89 of 106 patients are enrolled. Clinical trial information: NCT03206203 .

TPS1114 Background: Immunotherapy combined with chemotherapy is being studied in metastatic breast cancer, and may have durable outcomes. Chest wall recurrence represents a difficult to treat subtype of breast cancer with a poor prognosis, with lymphovascular invasion in the primary tumor a significant risk factor. Given the inflammatory nature of this disease and the association of programmed cell death 1 (PD-1) expression with lymphovascular invasion, we hypothesized that the combination of pembrolizumab, an anti-PD-1 antibody, with carboplatin may be effective as treatment for breast cancer chest wall recurrences. Methods: This randomized phase II study is enrolling 84 patients with breast cancer involving the chest wall, who may also have distant metastases. Patients receive treatment with pembrolizumab 200 mg and carboplatin AUC 5 every 3 weeks for 6 cycles (Arm A, n = 56) followed by maintenance pembrolizumab +/- carboplatin (Arm Ax), or carboplatin AUC 5 every 3 weeks for 6 cycles (Arm B, n = 28) with an option to cross-over to pembrolizumab +/- carboplatin on progression (Arm Bx). Patients with all disease subtypes, triple-negative, hormone receptor positive/HER2- after 2 prior lines of hormone therapy, and HER2+ disease (with the option to continue trastuzumab) are eligible, with no limit on the number of prior therapies. Prior platinum chemotherapy is allowed in the absence of overt disease progression. Patients undergo clinical assessment with every cycle of treatment including chest wall photography, scans (CT chest, abdomen, and pelvis) every 2 cycles, and have peripheral blood and chest wall biopsies collected at baseline and the start of cycle 3 for correlative studies. The primary endpoint is the disease control rate in the chest wall and distant sites at 18 weeks of treatment based on RECIST 1.1. The study is powered to determine a 20% difference in disease control between arms (hazard ratio 0.52, α = 0.10, β = 0.20). Additional endpoints include response by tumor programmed death ligand 1 (PD-L1) status and irRECIST, progression-free survival, and toxicity. Chest wall tumor samples will be analyzed for changes in tumor immune composition, and PD-L1 and MYC oncogene expression, based on preclinical data to suggest that PD-L1 may be upregulated by MYC. Peripheral blood samples will be evaluated for changes in PD-L1 expression, cell-free DNA, and circulating tumor cells with treatment. The study is enrolling patients at 7 sites within the Translational Breast Cancer Research Consortium (TBCRC), with current enrollment of 38/84 patients. Clinical trial information: NCT03095352 .

502 Background: HER2 targeted therapy without chemotherapy may be insufficient to completely eradicate a HER2+ cancer in cases of significant intratumor HER2 heterogeneity (ITH-HER2). Methods: We conducted a single-arm phase II study enrolling centrally confirmed HER2+ breast cancer. Pts received 6 cycles of T-DM1 plus Pertuzumab before surgery. Central ITH-HER2 was assessed on baseline ultrasound-guided core biopsies from 2 distinct areas of each tumor (3 cores/site). ITH-HER2 was defined as at least one of the six areas demonstrating either 1) HER2 positivity by FISH in > 5% and < 50% of tumor cells (i.e., CAP guideline) or 2) an area of tumor that tested HER2 negative. The primary objective is the association between pathologic complete response (pCR) and ITH, stratified by ER status. pCR defined as residual cancer burden (RCB) 0. Results: 164 pts with centrally confirmed HER2+ tumors were enrolled from 1/2015 to 1/2018. 2 pts withdrew consent. Median tumor size by imaging was 2.8 cm (IQR 2.1-3.8cm); 111 (69%) were ER+ and 51 (32%) ER-. 8 pts discontinued tx (6 due to disease progression, 2 due to toxicity). 49% of pts had a pCR (RCB-0), 14% RCB-I, 26% RCB-II and 11% RCB-III. Higher rates of RCB-0 were seen in ER- (65%) versus ER+ (42%). ITH-HER2 was detected in 10% (16/157) of evaluable cases. No pCR was observed among cases classified as heterogeneous (RCB-I 25%, RCB-II 25%, RCB-III 50%). The study met its primary endpoint by demonstrating a significant association between ITH-HER2 and pCR stratified by ER status (p < .0001). Secondary analysis also demonstrated a significant association between ITH-HER2 and pathologic response defined as RCB 0 or I (OR = 5.6, p = 0.004). Exploratory analysis revealed higher rates of RCB-0 among tumors centrally classified as HER2 3+ (56% [66/118]) versus HER2 2+ (27% [10/37]), (OR = 3.4, p = 0.002). The association of ITH-HER2 and pCR was maintained when stratifying by ER status and HER2 IHC (2+ vs. 3+), (p = 0.002). Conclusions: ITH-HER2 assessed by routine pathology evaluation is a strong predictor of pCR to a dual-HER2 targeted therapy regimen. If validated, ITH-HER2 may need to be considered in selection of pts for HER2-targeted regimens without chemotherapy in the curative setting. Clinical trial information: NCT02326974.

507 Background: Cisplatin (C) and paclitaxel (T) have activity in TNBC, however predictive biomarkers are lacking. The HRD assay detects impaired dsDNA break repair and may identify BRCA1/2-proficient tumors for treatment with DNA targeting therapies. TBCRC 030 was designed to determine the association between HRD and response to preoperative chemotherapy (CT) in TNBC. Methods: This phase II study randomized patients (pts) with BRCA1/2-proficient/unknown stage I-III TNBC to 12 weeks (wks) of preoperative C or T, followed by surgery. HRD was performed on baseline tissue, with positive scores > 33. Non-responders at 12 wks could crossover to alternative CT. The co-primary objectives were to detect a positive association of HRD with pathologic response (RCB 0-1) vs not (RCB 2-3) to C and a negative association to T. Target accrual of 160 pts was planned to yield 140 evaluable specimens for HRD, providing 90% power for the primary objectives. Analyses used logistic models and likelihood ratio tests with one-sided Type I errors of alpha = 0.05. Results: 140 pts initiated treatment, (72 Arm C, 68 Arm T; 81% T1-2, 62% node negative); 138 were evaluable for response at 12 wks. Post-enrollment testing showed 8 pts (5.8%) with germline DNA-repair pathway mutations. HRD results were available for 95 pts (68.8%, 23 inadequate tissue, 22 pending); 68 (71.6%) were HRD positive: 38 in Arm C, 30 in Arm T. In response-evaluable pts, 87 (63.0%) had surgery at 12 wks, and 51 (37.0%) crossed over. Response outcomes are shown in the Table. No association was seen between HRD score and RCB response to either neoadjuvant C (OR 2.78, [CI 0.61, 17.74]) or T (OR 0.98, CI [0.20, 5.06]). There was no evidence of an interaction between HRD and CT arms. Similarly, no association was observed between HRD score and pCR to either C (OR 1.47, CI [0.40, 5.59]) or T (OR 0.61, CI [0.14, 2.52]). There were no new safety signals. Conclusions: In this mostly BRCA1/2 proficient TNBC cohort, 12 wks of preoperative C or T led to a similar response rate of about 40%; baseline HRD was not predictive of response to preoperative CT, defined either by RCB 0-1 or pCR. Further data will be presented. Correlative analyses of research tissues for markers predictive of response to specific CT in TNBC is ongoing. Clinical trial information: NCT01982448. [Table: see text]

e12632Background: Human epidermal growth factor receptor gene 2 (HER2) amplification status in breast cancers provides prognostic information and predicts response to HER2 targeted therapies. Breas...

511Background: Predictive biomarkers to identify patients with HER2-positive breast cancer (BC) that may be treated with targeted therapy alone are of great interest. We hypothesized that early cha...

TPS1113Background: Chest wall disease from breast cancer has limited treatments. Given the inflammatory nature of this disease and the increased expression of PD-1 seen with lymphocytic infiltratio...

3053Background: Immune checkpoint inhibitors (ICI) are standard of care for many cancer patients (pts). There have been conflicting reports on the effect of the influenza (flu) vaccines (flu-V) on ...

1004Background: Sacituzumab govitecan is a novel antibody-drug conjugate consisting of SN-38, the active metabolite of irinotecan, conjugated to a humanized mAb targeting Trop-2 (trophoblastic anti...

1018Background: Activation of Phosphatidylinositol-3-kinase (PI3K) pathway may confer resistance to taxanes and in preclinical models concomitant inhibition of the PI3K pathway enhances efficacy of...

1011 Background: HER2+ BC is an aggressive subset of BC with high rates of BM and poor survival. Two-thirds of BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy (Rx). This phase II study evaluated everolimus (E), a brain permeable mTOR inhibitor, added to trastuzumab (T) and vinorelbine (V) in patients (pts) with HER2+ BCBM. Methods: Eligible pts had progressing HER2+ BCBM. Pts received E (5mg PO QD), T (2mg/kg IV weekly) and V (25mg/m2 IV d1, 8 of 21d cycle). The primary endpoint was intracranial response rate (RR [CR+PR], modified RECIST); secondary objectives (CNS clinical benefit rate [CBR, CR+PR+SD], extracranial RR, time to progression (TTP), overall survival (OS), and correlative studies). Targeted DNA sequencing of 20 tissues from 18 pts was performed. We used a two-stage design to distinguish ORR of 5% vs 20%. Results: 32 pts were evaluable for toxicity; 26 for efficacy. Median age was 53 (28–70 yrs). 31/32 pts had prior radiation: 13 (42%) WBRT, 8 (26%) radiosurgery, 9 (29%) both. Median prior lines of metastatic Rx was 2 (0–7). 30 (94%) received anti-HER2 Rx: 91% T, 69% lapatinib, 38% pertuzumab, 25% TDM1. Intracranial RR was 4% (1 PR, 6 SD > 6 mos, 10 SD > 3 mos, 9 PD). CNS CBR (6 mos) was 27%; CNS CBR (3 mos) was 65%. Extracranial RR was 46%. Median TTP was 4 mos (95% CI, 2.2 –5). OS was 12.2 mos (95% CI, 0.6 – 20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). DNA sequencing showed heterogeneous HER2 copy number amplification (CN amp): only 11/20 show HER2 CN amp (median 40X v 0.7X; 5/11 BC, 4/4 BCBM, 1/2 liver mets, 1/3 LN). BCBM exhibited high-level HER2 CN amp (median 49X) vs other sites (16X). While 11/20 show both HER2 CN amp and PI3K pathway mutation, this was not associated TTP; RAD21 CN amp was associated with TTP < 3 mos. Lack of HER2 CN amp plus a HER2 Tyr-kinase domain mutation was seen in a pt with nonresponse and short OS. Conclusions: While intracranial RR to ETV was low in pts with HER2+ BCBM, a substantial proportion had CNS CBR; OS was 1 year for this pt population. No new toxicity signals were observed. Further evaluation of DNA heterogeneity, including degree of HER2 CN amp in HER2+ BCBM, and association with outcome is warranted. Clinical trial information: NCT01305941.

LBA509 Notice of Retraction: “Therapy of relapsed/refractory metastatic triple-negative breast cancer (mTNBC) with an anti-Trop-2-SN-38 antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): Phase II results.” ASCO's Confidentiality Policy requires that abstracts be considered confidential and embargoed from the time of submission until the findings have been publicly released in conjunction with the ASCO Annual Meeting. Abstract LBA509, published in the 2016 ASCO Annual Meeting Proceedings Part II, violated this policy and was retracted from publication and presentation at the 2016 ASCO Annual Meeting.

TPS1148 Background: We recently reported six distinct molecular subtypes of TNBC, including two basal-like subtypes with cell cycle and DNA damage response (DDR) gene expression (GE) signatures (BL1 and BL2) and a luminal androgen receptor (LAR) subtype which expresses AR by immunohistochemistry. BL1 and BL2 cell lines respond to DNA damaging agents, including cisplatin. Consistent with the frequent alterations in DDR and PI3K pathways in TNBC, the combination of cisplatin and the pan-PI3K inhibitor GDC0941 was very active against AR-negative TNBC cell lines in preclinical studies. This trial will evaluate the benefit of the addition of GDC-0941 to cisplatin in patients with metastatic AR-TNBC. Methods: This is an open-label phase Ib/II multiple institution trial in which patients with metastatic AR-TNBC will be randomized to: a) cisplatin 25 mg/m2 on days 1, 8, and 15 of a 28 day cycle, or b) cisplatin with GDC-0941. Biopsy of a metastatic lesion at baseline, at day 5-10, and at progression is required. ...

TPS1145 Background: Both platinum and taxane chemotherapy have activity in TNBC, however biomarkers predictive for activity of either agent are lacking. The HRD assay detects impaired double strand...

9644 Background: Anthracyclines (ANTH) are widely used as cancer therapies but carry a significant risk of heart failure (HF) and left ventricular dysfunction (LVD). Improved cardiovascular (CV) ri...

8 Background: Mutations in PIK3CA are the most common somatic alterations in breast cancer and represent a potentially useful therapeutic target. As more PI3K pathway inhibitors enter the clinical arena, it is important to understand the characteristics of patients harboring mutations. This study seeks to identify the clinico/pathological characteristics of PI3K mutant breast cancers in patients evaluated at Vanderbilt University Medical Center. Methods: Molecular profiling (SNaPShot) was used to detect mutations in three genes in the PI3K pathway (PIK3CA, PTEN, AKT1). Electronic medical records of breast cancer patients whose tumors underwent testing from June 2010 to January 2013 were reviewed. PI3K mutation rates, histological tumor grade, receptor status (ER/PR/HER2), and recurrence-free survival were tabulated. Results: Three hundred evaluable tests were identified, with PI3K mutations detected in 83/300 (28%). Patients with PI3K mutations were more likely to be ER/PR positive (73% vs. 48%; p

515 Background: Nearly half of women with advanced TNBC develop CNS mets. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that penetrates the blood brain barrier (BBB), and the topoisomerase I inhibitor, irinotecan, in patients (pts) with TNBC CNS mets. Methods: Eligible pts had TNBC with new or progressive CNS mets with at least 1 measurable (> 5mm) lesion. Pts received irinotecan 125mg/m2 IV days (d) 1, 8 and iniparib (initial dose 5.6mg/kg, later changed to 8mg/kg) IV d 1, 4, 8, 11 every 21d. Tumor response rate (RR) was assessed by brain MRI and body CT every 9 weeks. The Kaplan Meier method estimated the primary endpoint of time to progression (TTP, intracranial [modified RECIST] or extracranial [RECIST 1.1]). Secondary endpoints were RR, PFS, OS, quality of life (QOL) and correlative endpoints. Results: Of 37 pts who began treatment, 34 were evaluable for efficacy. Mean age was 48 yrs (34 – 80 yrs). BRCA status was known for 16 patients of whom 5 had a mutation (4 BRCA1, 1 BRCA2). 88% received prior (neo)adjuvant and 68% prior metastatic chemotherapy (median 2 [1–14] lines). While 15% were CNS radiation (RT) naïve, 32% had received whole brain RT, 21% stereotactic RT, and 32% both. The most common grade (gr) 3/4 adverse events were neutropenia (14%), fatigue (5%), leukopenia (5%), hypokalemia (5%). Diarrhea was common (54%), but gr 3/4 was rare (3%). Median TTP (CNS and non-CNS) was 2.1 months (mos) (95% CI 1.7–4.3) and OS was 7.6 mos (95% CI 5.1-10.2). First progression site was CNS in 39%, non-CNS in 29% or both in 32%. CNS best RR was (12%; 0 CRs, 4 PRs); CNS clinical benefit rate (CBR, CR + PR + SD ≥ 6 mos) was 30%. Non-CNS RR was 5% (0 CRs, 1 PR) and CBR was 11%. Conclusions: Iniparib and irinotecan was well-tolerated among pts with TNBC CNS mets. While TTP was shorter than expected and contribution of iniparib to irinotecan remains uncertain, 30% of pts demonstrated CNS clinical benefit raising the question of whether predictive biomarkers could be identified. QOL, volumetric analysis of CNS lesions and translational studies evaluating molecular subtype, germline BRCA1/2, and DNA repair gene expression/methylation are ongoing. Clinical trial information: NCT01173497.

1052 Background: TIG, an agonistic anti-DR5 monoclonal antibody, triggers apoptosis in DR5+ human tumor cells without the aid of crosslinking. TIG has shown strong in vitro and in vivo activity against basal-like breast cancer cells that is enhanced by chemotherapy like paclitaxel. Methods: Randomized 2:1 phase II trial of nab-PAC with/without TIG in TNBC patients. Patients stratified by prior exposure to chemotherapy in the metastatic setting. Patients received nab-PAC weekly x 3 and TIG every other week, every 28 days. Primary endpoint was overall response rate (ORR). Secondary objectives were safety, progression free survival (PFS), TIG immunogenicity, and PK. Biopsies and circulating tumor cells were collected. The trial was not powered to compare arms but allowed early stopping for futility and was sized to estimate ORR with 95% CI. Results: 64 patients enrolled, 60 treated; 39 in the combination arm and 21 in the nab-PAC arm. Of the 39 in the combination arm, there were 2 CR, 9 PR (1 near CR, 96% tumor reduction), 11 SD and 17 PD; ORR 28% (95% CI 14%-42%). Of the 21 in the single agent arm, there were no CR, 8 PR, 4 SD and 9 PD; ORR 38% (95% CI 17%-59%). Higher ORRs were seen in the chemotherapy naïve patients (58% vs. 15% combination and 42% vs. 35% single agent). 2 patients with CR, 1 near CR, and 1 PR in the combination arm are still on therapy (602+, 531+, 466+, 460+ days). PFS was similar in both groups (3.6 months); higher in chemotherapy naïve patients. Combination was well tolerated (most toxicities grade 1/2); the most common AEs were fatigue, alopecia, peripheral sensory neuropathy, anemia, neutropenia, nausea, thrombocytopenia, anorexia, diarrhea, and vomiting. No grade 4 or 5 toxicity. No apparent added toxicity with TIG was seen. Conclusions: Combination therapy with nab-PAC + TIG was well tolerated, without apparent improvement in ORR relative to nab-PAC alone; however, 4 subjects treated as first-line had prolonged clinical benefit with the combination, and correlative studies will investigate markers that might predict clinical outcome (Next-Gen genomic analysis). Clinical trial information: F101004001.

1034 Background: Triple-negative breast cancers (TNBC) comprise 15% of breast cancers and lack ER, PR, and HER2 expression. TNBC is biologically aggressive with high rates of recurrence, but little is known about the prognosis of small (≤1cm) TNBCs compared to similarly sized breast cancers with other receptor profiles. The role of adjuvant chemotherapy for TNBC that is ≤1cm remains unclear. Methods: Electronic medical records of all women aged ≥ 18 years with ≤1 cm, node negative, invasive breast cancer from 1997-2007 diagnosed or treated at Vanderbilt or Wake Forest were reviewed. Tumor grade, receptor status, treatment details, and follow up and recurrence information were tabulated. Rates of local and distant recurrence among three different receptor subtype categories, ER+ or PR+, HER2 negative; ER-/PR-, HER2 negative; or any ER/PR, HER2 positive were compared using chi-square tests. Results: 437 women with ≤1cm breast tumors were identified. Women with TNBC not given chemotherapy were more likely to have distant recurrence at 9% compared to 2% for ER+ or PR+, HER2 negative and 4% for any ER/PR, HER2 positive. There were no recurrences among the 14 women with ≤1cm TNBC who received chemotherapy. Conclusions: Based on our two institution review, women with ≤1 cm TNBC are at an increased risk for distant recurrence compared to other subtypes when not treated with adjuvant chemotherapy. Further studies to determine the benefit of adjuvant chemotherapy in this population are needed. [Table: see text]

11 Background: Aromatase inhibitors (AIs) are standard of care for adjuvant endocrine therapy (AET) to prevent recurrence of early stage breast cancer in postmenopausal women. Previous AET adherence research has focused on the 25-96% adherence observed with, but more information is needed about AI adherence, especially regarding the role of arthralgia (joint pain or stiffness) in AET changes. Our objective was to understand AET changes within a year of AI initiation. Methods: We examined AET switching (either to another AI or to tamoxifen), overall changes in AET (including switching and temporary or permanent discontinuation), and physician- and patient-reported arthralgia, using data abstracted from medical records and self-administered surveys among 93 patients initiating AI. We conducted Chi-square and Wilcoxon univariate analyses. Results: Anastrazole was initially prescribed to 64 patients (69%), letrozole to 28 patients (30%), and exemestane to 1 patient. A year after AI initiation, 64 patients (69%) had no change in AET. Among the 29 patients (31%) who had an AET change, 14 switched to at least one other AI, 11 switched to tamoxifen, 9 temporarily discontinued AET, and 7 entirely discontinued AET (categories not mutually exclusive). Average time to first AET switch was 182.7 days. Average number of AET switches was 1.4. Arthralgia was the most common reason for AET changes, noted in the records of 19 patients (66% of those who changed AET). Patients who changed AET reported more severe arthralgia (median pain from 0-10 among 8 joint groups =1.4, interquartile range [IQR]=0.3-2.6) at week 12 than those who did not (median=0.3, IQR=0-1.1), p=0.03. A higher proportion (46%) of the 28 patients who initiated with letrozole changed AET due to arthralgia, compared with 20% of the 64 patients who initiated with anastrazole (p=0.01). Conclusions: A substantial proportion of women initiating AI change AET over one year. Arthralgia appears to play a key role in AET changes, particularly for letrozole as compared with anastrazole. More longitudinal patient-reported arthralgia data are needed to guide clinical decision making about AI initiation and AET changes.

510 Background: Mutations in PIK3CA, the gene encoding the p110a subunit of PI3K, have been associated with antiestrogen resistance in ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol. This suggests that treatment of ER+/PI3K mutant BC should include PI3K inhibitors plus antiestrogens. Methods: We conducted a phase Ib trial of letrozole (2.5 mg/d) with the pan-PI3K inhibitor BKM120 in post-menopausal patients (pts) with ER+/HER2 MBC. BKM120 (100 mg/d) was given continuously (Arm A) or intermittently (5 on/2 off days; Arm B). Upon toxicity, BKM120 was reduced to 80 and 60 mg/d. Treatment continued until unacceptable toxicity or disease progression. Disease was assessed every 2 months. FDG-PET was done at baseline and at 2 weeks in all pts in Arm A. Results: Fifty-one pts were accrued; 49 had progressed on an AI previously. Median age was 56 years (range 34-77); 95% had bone and 70% visceral metastases. Toxicities and outcomes are summarized in the table. The only DLT* in Arm A and B were transaminitis and depression, respectively; both at 100 mg. Over 50% of Arm A pts had >25% reduction in their peak SUV at the 2-week FDG-PET. Pts who did not exhibit a metabolic response by FDG-PET progressed rapidly on therapy. Three pts in Arm A had a PI3K mutation; one of them has had stable disease on treatment for >12 months. Conclusions: The combination of letrozole/ BKM120 is safe in pts with AI-refractory ER+/HER2 MBC. Arm B is ongoing and will be updated at the meeting. All tumor biopsies will be analyzed for PI3K pathway alterations. FDG-PET at 2 weeks appears to be a useful pharmacodynamic biomarker of PI3K pathway inhibition in most patients. Its value in predicting treatment response remains to be determined. [Table: see text] [Table: see text]

TPS127 Background: TNBC is an aggressive subset of BC with high rates of BM and poor survival. Iniparib, an anticancer agent with poly (ADP-ribose) polymerase (PARP) inhibitory activity, in combina...

TPS119 Background: In a fraction of TN BC, p63 is coordinately expressed with p73, and may be antagonizing p73 transcriptional and tumor suppressive activity. Based on findings that mTOR inhibitors...