Translational Breast Cancer Research Research Articles

Abstract PS03-07: Morphometric signature identifies ductal carcinoma in situ of the breast with low risk of progression to invasive breast cancer

Abstract Background. Ductal carcinoma in situ (DCIS) is a frequently found precursor of invasive breast cancer (IBC). However, the majority of DCIS will never progress to IBC. As we cannot distinguish yet which DCIS will remain indolent (‘harmless’) from those that might progress in the future to IBC, almost all women with DCIS are intensively treated by surgery, often followed by radiotherapy. This brings an urgent clinical need to learn distinguishing harmless from potentially progressive DCIS to save many women with indolent DCIS the burden of unnecessary overtreatment. Aim. We aimed to investigate if the geometry and spatial configuration of DCIS ducts in Hematoxylin-Eosin (H&E) stained tissue sections are related to the risk of progression of DCIS to ipsilateral IBC (iIBC). Methods. We obtained data from a population-based cohort of women diagnosed with primary DCIS between 1989 and 2004 in the Netherlands, treated with breast conserving surgery (BCS) only and a median follow-up time of 12 years. A nested case-control study (n=689) was designed in which patients diagnosed with iIBC recurrences during follow-up were considered as “cases” (n= 226) and those with no subsequent iIBC as “controls” (n=463). The DCIS and stroma regions were digitally annotated on H&E-stained whole slide images (WSIs) by a pathologist as ground truth for the deep learning neural network of HALO AI module (IndicaLabs). We developed a computational pipeline to automatically detect and measure stroma areas, DCIS ducts, and the nucleus of their cells. We validated the accuracy of DCIS detection in H&Es WSIs from an external study, in which DCIS regions were digitally annotated by an independent pathologist (Translational Breast Cancer Research Consortium, TBCRC). We classified cases and controls according to morphological measurements using logistic ridge regression with double-loop cross-validation, followed by hierarchical clustering. The risk of subsequent iIBC after primary DCIS diagnosis was evaluated by multivariate Cox proportional hazards models. Results. The accuracy of DCIS detection performed by the computational pipeline was compared with pathologist annotations in 20 slides from the TBCRC study. Results showed a satisfactory DCIS overlap area agreement of 0.76 (0.68 – 0.83). We applied the DCIS computational pipeline on the case-control series. We obtained 15 morphological measurements for each DCIS duct, such as duct area, cell density, distance between ducts, average nucleus area, etc. We calculated 8 distribution parameters from each measurement in each WSI, including median and range. After leaving out redundant variables, 55 unique morphometric variables were obtained, representing the heterogeneity of DCIS ducts per WSI. The c lassifier revealed a median area-under the curve (AUC) of 0.66 (0.55-0.77) to predict 5-years free of iIBC, 0.59 (0.50-0.67) to predict 10-years and 0.60 (0.52-0.68) to predict 15-years. The 30 variables with the highest association with outcome were used to build four morphometric signatures. Signature number 1, which is characterized by lesions with small-sized ducts, a lower number of cells and a lower DCIS/stroma area ratio, showed a significant lower risk of developing iIBC compared to the other three signatures in a multivariate Cox regression model including grade, ER, COX-2 and HER2 expression: HR = 0.56 (0.28-0.78 95%CI). Conclusion. We developed a computational pipeline able to detect and measure DCIS ducts in H&E WSIs with high accuracy and reproducibility. DCIS lesions presenting the morphometric signature of small-sized DCIS ducts have a very low chance to progress to invasive breast cancer. After successful validation, our morphometric method will serve as a robust and easy to implement biomarker for de-escalation strategies in DCIS, and as such, could limit unnecessary overtreatment in the near future. Citation Format: Marcelo Sobral-Leite, Simon Castillo, Shiva Vonk, Xenia Melillo, Noomie Lam, Brandi de Bruijn, Yeman Hagos, Joyce Sanders, Mathilde Almekinders, Lindy Visser, Emilie Groen, Carolien Van der Borden, Petra Kristel, Ercan Caner, Leyla Azarang, Yinyin Yuan, Renee Menezes, Esther Lips, Jelle Wesseling, Grand Challenge PRECISION Consortium. Morphometric signature identifies ductal carcinoma in situ of the breast with low risk of progression to invasive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS03-07.

Abstract PO5-26-11: The Breast Cancer Research Foundation Drug Research Collaborative – A unique and innovative model for industry-funded, academically driven research to advance the field of breast cancer

Abstract The Breast Cancer Research Foundation (BCRF) is committed to preventing and curing breast cancer through groundbreaking research. In pursuit of this mission, the BCRF launched the Drug Research Collaborative (DRC) in 2016—a pioneering program designed to bridge the gap between academic investigators and access to investigational therapies, thereby fostering greater academic-driven research in breast cancer. The DRC's primary objective is to fund independent, innovative, and high-quality investigator-initiated trials (IITs) and pre-clinical/translational research projects. In conventional drug development, industry-sponsored registration trials play a crucial role, leaving limited resources and scope for exploratory and translational IITs that fall outside the industry's drug approval strategy. Additionally, industry-funded IIT research faces challenges such as reputational risks, perceived influence during internal review processes, intellectual property (IP) concerns, and logistics/program management burdens. The BCRF-DRC program addresses these challenges by issuing requests for proposals to generate creative and unbiased ideas, which are then vetted through an academic review process involving leading breast cancer experts. The most promising research projects are selected for further advancement. The BCRF-DRC program is facilitated by the BCRF research staff, providing project management, while the Translational Breast Cancer Research Consortium (TBCRC), founded by the BCRF and also supported by Susan G. Komen, supports the clinical trial aspects of the program. Since its inception, the BCRF-DRC has expanded from one to three industry partners, securing a total funding of $25 million for 15 projects, including seven clinical trials and eight pre-clinical projects. This abstract reports on the ongoing progress and outcomes achieved by these three programs. The BCRF-DRC represents a revolutionary paradigm in research funding and collaboration by harnessing the collective power of industry partners, philanthropic organizations, and academic institutions. Through this collaborative effort, the BCRF-DRC provides a unique platform for researchers to accelerate the translation of scientific discoveries into effective clinical interventions, thus making significant strides in the field of breast cancer in the coming decades. By empowering academic investigators, fostering unbiased research, and addressing the limitations of industry-funded IITs, the BCRF-DRC is revolutionizing breast cancer research and driving the development of novel interventions. This abstract highlights the transformative potential of the BCRF-DRC program and its contribution to advancing breast cancer treatments and ultimately improving patient outcomes. The success of this collaborative model serves as a testament to the power of multi-sector partnerships and the pivotal role they play in shaping the future of breast cancer research. Citation Format: Unnati Jariwala, Dorraya El-Ashry, Judy Garber, Larry Norton. The Breast Cancer Research Foundation Drug Research Collaborative – A unique and innovative model for industry-funded, academically driven research to advance the field of breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-26-11.

Abstract PO2-20-01: The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062)

Abstract BACKGROUND: Anti-HER2 therapies have transformed the trajectory for patients with HER2-positive (HER2+) MBC. A subset of patients with HER2+ MBC do exceptionally well and remain on maintenance anti-HER2 therapy for many years. However, current therapy is non-curative and patients are treated indefinitely. While these therapies often are well-tolerated, they may cause significant toxicities, are expensive, and typically require frequent infusion and provider visits. Case reports and retrospective series demonstrate that some patients may do well after stopping anti-HER2 treatment. We currently lack prospective data on the likelihood of clinical impact of successful treatment discontinuation, outcomes among patients who progress and restart HER2-directed therapy, and tools to predict who may safely stop therapy. In this study, we will enroll pts with an exceptional response to anti-HER2 therapy. Pts may elect to either continue or stop anti-HER2 therapy and will be followed clinically and radiographically on a protocol-specified schedule. Considering the central role of patients in choosing the study intervention arm, and the unique nature of stopping therapy as a treatment intervention, patient advocates have been deeply involved in the study design to ensure patient concerns are being heard and addressed. We will retrospectively assess minimal residual disease (MRD), measured in plasma, as a biomarker of ongoing response, in a step toward shifting the treatment paradigm for pts with HER2+ MBC. METHODS: STOP-HER2 is a prospective, non-randomized, phase II, multicenter study of either continuation (cohort 1) or cessation (cohort 2) of anti-HER2 therapy in exceptional responders with HER2+ MBC. Eligible patients must have biopsy-proven HER2+ MBC by ASCO/CAP guidelines and must have been receiving first-line anti-HER2 therapy for MBC for at least 3 years without evidence of progressive disease (PD) as determined by the treating investigator. Patients with prior brain-only PD or oligo-PD outside the brain are eligible at least 2 years after local treatment to the central nervous system (CNS) and in absence of subsequent PD. Up to fifty-two participants will be enrolled into cohort 2, and an additional thirty participants enrolled into the cohort 1, at 10 US sites within the Translational Breast Cancer Research Consortium. Co-primary endpoints are the 1-year progression-free survival (PFS) in cohorts 2 and 1, separately. Secondary endpoints include the clinical benefit rate upon re-initiation of anti-HER2 therapy for patients in cohort 2 experiencing PD after treatment discontinuation; and 3-year overall survival in both cohorts. Correlative endpoints include MRD status at baseline and the correlation between MRD dynamics and outcomes. Patient-reported outcomes will be collected and analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, and decision regret. The study will use a two-stage design to assess the primary objective of estimating the rate of participants who are free of progression at one year after discontinuing anti-HER2 therapy. If 50% or less are free of progression at one year, stopping HER2 therapy would not be considered a viable treatment plan (null hypothesis). The study is designed to have 80% power to reject the null hypothesis at the 10% type I error rate when 68% of exceptional responders are free of progression at one year after stopping HER2 therapy. STOP-HER2 began enrollment in Q2 2023 (NCT05721248). Citation Format: Heather Parsons, Kathryn Ruddy, Stefania Morganti, Karen Smith, Victoria Attaya, Eliza Kallfelz, Michelle DeMeo, Jamie LaScala, Shirley Mertz, Teri Pollastro, Patricia Spears, Adam Brufsky, Chau Dang, Susan Dent, Ahmed Elkhanany, WIlliam Gwin, Ciara O'Sullivan, Kathy Miller, Sara Nunnery, Elaine Walsh, Anna Maria Storniolo, Sara Tolaney, Nabihah Tayob, Antonio Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy Lin. The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-01.

Cracking the Genomic Code of CDK4/6 Inhibitor Resistance.

The therapeutic approach to metastatic hormone-receptor positive, human epidermal growth factor-2 negative metastatic breast cancer (HR+/HER2- MBC) has evolved rapidly over recent years. The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become first-line targeted agents of choice, in combination with an anti-estrogen. Simultaneously, the clinical landscape of therapeutic options has been rapidly shifting, with novel anti-estrogens, signal transduction inhibitors, and next-generation CDK inhibitors in various staging of development. Given these dynamic changes, understanding the genomic and molecular landscape of resistance to currently available anti-estrogen therapy and CDK4/6 inhibitors represents a major focus of translational breast cancer research globally.

Predisposing and Overall Effects of Reproductive Hormones on Breast Cancer: A Review.

Cancer, the second leading cause of mortality worldwide, has been the subject of extensive and quickly changing scientific study and practice. Cancer remains a mystery despite the enormous effort put into understanding the genesis of cancerous cells, the development of malignant tissues, and the process by which they propagate and recur. Cells from humans that have been recruited by cancer and, to some extent, changed into pathogenic organisms or the foundation of tumors serve as agents of destruction. Understanding cancers leads to challenging philosophical issues since they undermine and use multicellular organization processes. Cancer metastasizing cells adopt new phenotypes while discarding previous behaviors. The absence of comprehensive knowledge of this has hampered the development of therapeutics for metastatic illness. For systems-level experimental and computational metastasis modeling, integrating these complex and interconnected features continues to be a problem because metastasis has typically been studied in separate physiological compartments. Lung, breast, and prostate cancers accounted for the bulk of the 18 million new cases of cancer that were diagnosed in 2018. The most frequent cancer in women is breast cancer. Animal experimentation plays a significant role in primary and translational breast cancer research. In theory, such breast cancer models should be comparable to breast cancer in humans in terms of tumor etiology, biological behavior, pathology, and treatment response.

Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer

Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown. To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC. This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022. Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2). Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%. All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]). This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable. ClinicalTrials.gov Identifier: NCT02860000.

Abstract P3-08-08: Establishment of a Breast Cancer Rat Model of Chemotherapy-Induced Cardiotoxicity

Abstract Establishment of a Breast Cancer Rat Model of Chemotherapy-Induced Cardiotoxicity Katherine Wallis, Marjan Boerma, Antiño Allen, Joseph Su, Sam Makhoul, Ping-Ching Hsu Background. Doxorubicin (DOX) is a highly effective chemotherapy agent that is commonly used in combination with precision medicine to treat a wide range of cancers, including 32% of breast cancer (BC) cases. Although the treatment has greatly increased the number of long-term cancer survivors, it has also increased the number of patients experiencing DOX-induced cardiotoxicity (DIC). Animal models have played a vital role in the development of basic and translational breast cancer research in humans, and rat is a preferred animal to study breast cancer for the similarity to human neoplasms and metabolism. However, most studies were established using mouse models, male rats and commonly non-cancer bearing animals. Currently no single universal cancer-bearing female rat model is utilized for DOX-induced chronic cardiotoxicity. The number of cancer cells to be injected to mimic human experience is not known. Large numbers of injected cancer cells grow quickly and kill the animal before the investigators have the time to assess for cardiac toxicity. Here we aimed to identify the minimal number of cancer cell injections to mimic tumor growth of BC patients and to achieve chemotherapy-induced toxicities. Methods. Various numbers (5 × 104 – 1 × 106) of MAT B III adenocarcinoma cancer cells derived from Fischer 344 (F344) rats were injected in the mammary fat pad of female F344 rats, followed by six intraperitoneal (IP) injections of either DOX (1.25mg/kg per dose) or saline post tumor cell injection. The treatments were administered on day 4 from cell injection, and every third day after for a total of six injections. Echocardiography (Vevo 3100, VisualSonics) was conducted before and after the end of chemotherapy. Results. Tumor burden reduced significantly among rats treated with DOX compared with the saline group. In the Kaplan-Meier survival curve, an injection of 5 × 104 cancer cells was associated with tumor growth but the tumor burden was low enough to allow long-term follow-up of both DOX and saline treated rats and assess signs of cardiotoxicity. At 4 days after the final DOX administration, increased left ventricular ejection fraction and fractional shortening in the absence of increased stroke volume were an indication of adverse cardiac effects in the DOX animals but not the saline-treated rats. Plasma was collected from the animals to be subjected to metabolomics testing so that a preliminary assessment of metabolites associated with DIC could be gathered. Conclusion. We have established a breast cancer rat model in which DIC can be studied. Research in this model can aid in identifying mechanisms of DIC and testing novel interventions. Citation Format: Katherine Wallis, Marjan Boerma, Antino Allen, Joseph Su, Sam Makhoul, Ping-Ching Hsu. Establishment of a Breast Cancer Rat Model of Chemotherapy-Induced Cardiotoxicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-08.

Abstract OT2-21-01: Assessing Response to neoadjuvant Taxotere and TrAstuzumab in Nigerian women with HER2-positive breast cancer (ARETTA)

Abstract Background: Populations of African ancestry are underrepresented in global oncology clinical trials resulting in paucity of data on safety and efficacy of cancer medicines in vulnerable Black populations. The ARETTA clinical trial was initiated by the Nigerian Breast Cancer Study Team in partnership with the University of Chicago Comprehensive Cancer Center to build local capacity for biomarker informed clinical trials and translational breast cancer research. ARETTA is a pragmatic single-arm, phase II clinical trial to optimize therapy and determine the safety and efficacy of neoadjuvant taxotere and trastuzumab in women with HER2-positive breast cancer. The study sought to 1) determine the pathological complete response (pCR) rate of patients with early stage breast cancer to neoadjuvant docetaxel and subcutaneous trastusumab 2) develop the capacity of investigators in Nigeria to improve quality of care through participation in oncology clinical trials using upgraded facilities and trained personnel and 3) determine accrual rate and retention of participants. Methods: Inclusion criteria include treatment naïve women aged 18 years to 70 years with HER-2 positive breast cancer stages II-IIIC (AJCC). Eligible participants receive four cycles of docetaxel 75mg/m2 and trastuzumab every 3 weeks. Those with incomplete clinical response by breast ultrasound volume measurements receive 3 additional cycles of chemotherapy; cyclophosphamide 600mg/m2, epirubicin 90mg/m2 and 5-fluorouracil 600mg/m2 every 3 weeks before re-evaluation for surgery. All participants receive a fixed dose of sub-cutaneous Herceptin (600mg) every 3 weeks (total of 18 doses). The primary endpoint is pCR rate. Secondary objectives are to evaluate invasive disease-free survival (iDFS), the pattern of response and mechanisms of resistance to treatment based on genomic markers, the pharmacokinetics of Herceptin SC, quality of life, and adverse event rates, including cardiac toxicity. Planned enrollment is 47 evaluable patients, which will provide 90% power to test the null hypothesis that the pCR rate is 20% versus a 40% alternative (one-sided alpha=0.05). More protocol details can be found at ClinicalTRial.gov NCT03879577 and JCO Glob Oncol2020 doi: 10.1200/GO.20.00043 Progress: The study has met its primary endpoint and will be closed to accrual by the time of the meeting. Results will be submitting as Late Breaking before the meeting Citation Format: Atara Ntekim, Adenike Adeniji-Sofoluwe, Abiola Ibraheem, Anthonia Sowunmi, Ayorinde Folasire, Thomas Olajide, Olalekan Olasehinde, Akinwunmi Komolafe, AbdulRazzak Lawal, Foluso Omodele, Ayodele Sanni, Mustapha Ajani, Olayinka Kotila, Sharifat Folorunsho, Tonyin Aniagwu, Adewumi Alabi, Abiodun Popoola, Chioma Asuzu, Adetola Daramola, Chinedum Babalola, Theodore Karrison, Fatimah Abdulkareem, Olufunmilayo I. Olopade. Assessing Response to neoadjuvant Taxotere and TrAstuzumab in Nigerian women with HER2-positive breast cancer (ARETTA) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-21-01.

Abstract PD7-03: Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM)

Abstract PURPOSE: Treatment options for patients (pts) with HER2+ BCBM remain limited. We previously reported that neratinib monotherapy is associated with a volumetric central nervous system objective response rate (CNS ORR) of 8%, whereas the combination of neratinib and capecitabine resulted in a volumetric CNS ORR of 49% (in lapatinib-naïve pts). Preclinical data suggest that neratinib may overcome resistance to trastuzumab-emtansine (T-DM1) and that the combination has potential CNS efficacy. Here, we report results of neratinib plus T-DM1 in pts with HER2+ BCBM. PATIENTS AND METHODS: In this prospective, multicenter, phase II study, pts with measurable HER2+ BCBM received neratinib 160 mg orally once daily plus T-DM1 3.6 mg/kg IV every 21 days in three parallel-enrolling cohorts. Cohort 4A enrolled pts with previously untreated brain metastases. Cohort 4B enrolled pts with BCBM progressing after prior local CNS-directed therapy without prior exposure to T-DM1. Cohort 4C enrolled pts with BCBM progressing after prior local CNS-directed therapy who had previous exposure to T-DM1. Diarrhea prophylaxis with colestipol and loperamide was required during cycle 1. Cohorts 4A and 4B were single-stage with a planned enrollment of 20 patients; cohort 4C had a two-stage design, with a requirement for at least 1 of the first 9 pts to achieve a response in order to enroll a total of 24 patients. The primary endpoint was Response Assessment in Neuro-Oncology-Brain Metastases (RANO BM) in each cohort separately. Correlative studies included patient-reported outcomes (PROs) for gastrointestinal toxicity. RESULTS: We enrolled 6, 17, and 21 patients to cohorts 4A, 4B, and 4C, during 11/07/2018 – 11/01/2021. Enrollment was stopped prematurely due to slow accrual. Across Cohorts 4A-4C, the median number of prior lines of chemotherapy prior to enrollment was 2 (range 1-10); 25% received prior lapatinib and no patients received prior tucatinib. In cohorts 4B and 4C (prior CNS-treated cohorts), 33% had prior CNS surgery and &amp;gt;94% had prior CNS radiation. Among evaluable patients, CNS ORR in cohorts 4A (n=6), 4B (n=16), and 4C (n=21) was 50.0% (95% CI 18.8- 81.2%), 25.0% (95% CI 8.3-52.6%), and 38.1% (95% CI 19.0-61.3%), respectively. Median (range) number of cycles completed for 4A, 4B, and 4C was 4.5 (1-15), 4 (range 0-49+), and 6 (0-23); three patients on Cohort 4B remain on protocol therapy (cycles 14, 45, and 49). The overall survival at 12-months for cohorts 4A, 4B, and 4C was 83.3% (95% CI, 58.3-100%), 86.2% (95% CI 70-100%), and 83.3% (95% CI 67.6-100%). Diarrhea was the most common grade 3 toxicity (19.0–33.3% across cohorts); one grade 4 liver function event occurred in cohort 4B. Updated efficacy results will be reported at the meeting; PRO analyses are ongoing. CONCLUSION: Intracranial activity was observed for the combination of neratinib plus T-DM1 across all three enrolled cohorts, including those with prior T-DM1 exposure, suggesting synergistic effects of this treatment combination. Our data provide additional evidence for consideration of neratinib-based combinations in pts with HER2+ BCBM. Citation Format: Rachel Freedman, Siyang Ren, Nabihah Tayob, Rebecca Gelman, Karen L. Smith, Raechel Davis, Alyssa Pereslete, Victoria Attaya, Christine Cotter, Wendy Y. Chen, Cesar Augusto Santa-Maria, Catherine Van Poznak, Beverly Moy, Adam M. Brufsky, Michelle Melisko, Ciara C. O’Sullivan, Nadia Ashai, Yasmeen Rauf, Julie Nangia, Dario Trapani, Jennifer Savoie, Robyn Burns, Antonio C. Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy U. Lin. Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-03.

Abstract P1-07-02: Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS

Abstract PURPOSE To examine incremental values of estrogen receptor (ER) status, body mass index (BMI), menopausal status, and a previously reported multi-gene classifier over commonly used clinical factors (i.e. age, tumor grade, comedonecrosis, surgical margins, and treatment) in predicting risk of any ipsilateral recurrence (IR) event within five years after DCIS diagnosis. METHODS A derivation cohort consisted of participants in the Translational Breast Cancer Research Consortium (TBCRC) 038, a retrospective multicenter cohort study in women undergoing surgical resection for DCIS between 01/01/1998 and 02/29/2016 (n=216). The validation cohort, the Repository of Archival Human Breast Tissue (RAHBT) at Washington University School of Medicine, provided cases meeting the same eligibility criteria as TBCRC038 (n=97). Participants in both cohorts had RNA-seq data and either developed IR 1-5y after initial DCIS diagnosis or were free from subsequent breast events for at least five years. The previously reported 812-gene classifier had been developed from a subset of the TBCRC038 samples using a negative-binomial regression model to identify differentially expressed genes in the primary tumor associated with subsequent recurrence events. This classifier has been shown to be highly correlated with 5-year invasive, DCIS, and all breast cancer events, and validated in the RAHBT cohort. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of IR in the TBCRC038 cohort (76 with IR). The clinical score was developed using clinical predictors (aforementioned clinical factors and ER) and their regression coefficients from the model with the maximum predictive accuracy (e.g. c-index) and the minimum number of predictors; the summary score integrated the clinical score and multi-gene classifier. Predictive performance of both clinical and summary scores was validated in the RAHBT cohort (20 with IR). RESULTS In the TBCRC cohort derivation set, we used a multivariable model based on clinical factors alone (clinical score) and found that ER status, but not BMI or menopausal status, was independently associated with a higher IR risk (HR=2.06, 95% CI 1.18-3.58). Adding the multi-gene classifier to the clinical factors-based model (summary score) in the TBCRC038 test set increased predictive accuracy (c-index 0.68 to 0.70), with the genomic classifier-adjusted HR of 14.96 (95% CI 8.64-25.91). The summary score had higher predictive performance for IR risk than clinical score alone (c-index 0.82 vs. 0.70). In the RAHBT validation samples, model performance was similarly improved using summary scores clinical factors-based model plus multigene classifier as compared to clinical scores along (c-index 0.74 vs. 0.58). CONCLUSION Combining clinical factors and a multigene classifier provided more accurate risk estimates of IR within five years after excision of DCIS than clinical factors alone. Figure 1. Observed and predicted recurrence-free survival in the first five years after initial DCIS diagnosis in the RAHBT validation cohort, by risk groups defined by clinical scores (left) and clinical score plus multigene classifier (right). Citation Format: Ying Liu, Siri H. Strand, Lorraine King, Bryan Harmon, Fergus J. Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F. McAuliffe, Jeffrey Marks, Carlo Maley, Robert West, E Shelley Hwang, Graham A. Colditz. Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-07-02.

Abstract P6-08-07: Reasons for Reduced Willingness to Participate in Clinical Trials During the COVID-19 Pandemic: The Translational Breast Cancer Research Consortium (TBCRC) 057 Survey

Abstract Background: Historically, less than 10% of adult patients with cancer enroll in clinical trials, however, enrollment dropped further at the onset of the COVID-19 pandemic. Barriers to trial participation during the pandemic have not been reported. As part of the TBCRC 057 survey on the impact of the pandemic on willingness to participate in breast cancer trials, we assessed reasons for reluctance to participate in trials during the pandemic. Methods: US residents who self-reported a breast cancer diagnosis were eligible to complete the online survey 8/6/21-9/30/21. Respondents indicated whether they were current trial participants and, if not, their willingness to consider participating in a trial during the pandemic using a 5-point scale (0-not at all willing to 4-definitely willing). Respondents who were not current trial participants and who were not “definitely willing” to consider participation during the pandemic were characterized as “reluctant” and asked to select reasons for their reluctance from a checklist. Pandemic-related anxiety was assessed on an 11-point scale (0-no anxiety to 10-worst anxiety possible). Respondents indicated how the option to conduct trial activities online would affect their decision to participate in a trial (much less likely, somewhat less likely, would not affect my decision, somewhat more likely, or much more likely). In exploratory analyses, we evaluated whether pandemic-related anxiety and favorable reactions towards opportunities to conduct trial activities online were associated with reluctance to consider trial participation during the pandemic due to fear of SARS-CoV-2 exposure. Means were compared with two sample t-tests and proportions with Fisher’s exact tests. Results: Of 385 survey respondents, 185 (48%) were characterized as reluctant to consider trial participation during the pandemic. Among these 185, median age was 55 (range 25-80), 85.7% were non-Hispanic White, 48.1% had metastatic disease and 44.2% received care at academic centers. Reasons for reluctance to consider trial participation during the pandemic cited by ≥15% of the 185 reluctant respondents are shown in the Table. Respondents who selected fear of exposure to SARS-CoV-2 as a reason for their reluctance to consider participating in a trial during the pandemic had higher mean pandemic-related anxiety (7.0 vs 5.2, p&amp;lt; 0.001). These respondents were more likely to indicate telemedicine doctor visits (p=0.01), virtual consents (p=0.001) and online study questionnaires (p=0.001) would make them somewhat or much more likely to participate in trials than respondents who did not select fear of exposure to SARS-CoV-2 as a reason for their reluctance. Conclusions: Reasons for reluctance of patients with breast cancer to consider participation in clinical trials during the pandemic are multifactorial. Although concerns about safety and efficacy remain prominent, fear of exposure to SARS-CoV-2 drives unwillingness to participate in &amp;gt;25% of reluctant patients. Trial accrual may benefit from incorporation of electronic activities when possible. Table Citation Format: Karen L. Smith, Carolyn Mead-Harvey, Gina L. Mazza, Albert E. Holler, Eileen Shinn, Elizabeth Frank, Michelle Melisko, Cyd Eaton, Jeannine M. Salamone, Teri Pollastro, Patricia Spears, Antonio C. Wolff, Gabrielle B. Rocque. Reasons for Reduced Willingness to Participate in Clinical Trials During the COVID-19 Pandemic: The Translational Breast Cancer Research Consortium (TBCRC) 057 Survey [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-07.

Cohort profile: The Clinical and Multi-omic (CAMO) cohort, part of the Norwegian Women and Cancer (NOWAC) study.

Breast cancer is the most common cancer worldwide and the leading cause of cancer related deaths among women. The high incidence and mortality of breast cancer calls for improved prevention, diagnostics, and treatment, including identification of new prognostic and predictive biomarkers for use in precision medicine. With the aim of compiling a cohort amenable to integrative study designs, we collected detailed epidemiological and clinical data, blood samples, and tumor tissue from a subset of participants from the prospective, population-based Norwegian Women and Cancer (NOWAC) study. These study participants were diagnosed with invasive breast cancer in North Norway before 2013 according to the Cancer Registry of Norway and constitute the Clinical and Multi-omic (CAMO) cohort. Prospectively collected questionnaire data on lifestyle and reproductive factors and blood samples were extracted from the NOWAC study, clinical and histopathological data were manually curated from medical records, and archived tumor tissue collected. The lifestyle and reproductive characteristics of the study participants in the CAMO cohort (n = 388) were largely similar to those of the breast cancer patients in NOWAC (n = 10 356). The majority of the cancers in the CAMO cohort were tumor grade 2 and of the luminal A subtype. Approx. 80% were estrogen receptor positive, 13% were HER2 positive, and 12% were triple negative breast cancers. Lymph node metastases were present in 31% at diagnosis. The epidemiological dataset in the CAMO cohort is complemented by mRNA, miRNA, and metabolomics analyses in plasma, as well as miRNA profiling in tumor tissue. Additionally, histological analyses at the level of proteins and miRNAs in tumor tissue are currently ongoing. The CAMO cohort provides data suitable for epidemiological, clinical, molecular, and multi-omics investigations, thereby enabling a systems epidemiology approach to translational breast cancer research.

Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts.

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

SY30-1 Topics on basic and translational breast cancer research of early phase clinical trial

In recent years, development of cancer therapies has been accelerated more than ever before. Within the traditional phase 1, 2 and 3 clinical trials, safety and efficacy are simultaneously assessed in phase 1 trials, and expansion cohorts are being conducted to assess the efficacy of treatments for each cancer type and to determine optimal biomarkers. It is important to be able to select patients with stable general health and to conduct paired biopsy (pre-treatment/after treatment/at tumor progress timing) in early phase trials to enable earlier cancer selection for drug development and biomarker development.

Abstract OT1-18-08: Randomized phase II trial of pembrolizumab/carboplatin vs. carboplatin alone for breast cancer with chest wall recurrence: TBCRC044

Abstract Background: A significant number of patients with breast cancer may develop chest wall recurrence, which can be difficult to treat, and is associated with a poor prognosis. Given the inflammatory nature of chest wall disease, and the association of chest wall disease with lymphovascular invasion, we hypothesized that immunotherapy may be beneficial in this setting. Furthermore, combining immunotherapy and chemotherapy may have a synergistic effect; indeed, the combination of the anti-programmed cell death 1 (PD-1) antibody, pembrolizumab, with chemotherapy has been approved for metastatic triple negative breast cancer (TNBC). Consequently, in this study, we are evaluating the combination of pembrolizumab/carboplatin vs. carboplatin alone for chest wall recurrence. Trial design: This is a phase II study of patients with chest wall disease from breast cancer. Patients are randomized in a 2:1 manner to pembrolizumab/carboplatin x 6 cycles (Arm A) with the option to continue pembrolizumab +/- carboplatin after 6 cycles (Arm Ax) vs. carboplatin alone (Arm B) with the option to cross-over to pembrolizumab +/- carboplatin on progression (Arm Bx). Carboplatin is dosed at AUC 5 IV every 3 weeks, and pembrolizumab at 200 mg IV every 3 weeks. Trastuzumab may be continued with study treatment in patients with HER2 positive disease. Imaging scans (CT chest, abdomen, and pelvis, and bone scan) occur at baseline and every 3 cycles. Chest wall biopsies and peripheral blood is collected at baseline and after completing 2 cycles of treatment for correlative studies. Eligibility criteria: Patients must have chest wall disease from breast cancer. Distant metastases are allowed. TNBC, hormone receptor positive/HER2 negative disease (after 2 prior hormone therapies), and HER2 positive disease (progressed on standard HER2 directed treatment) are eligible. Any number of prior lines of chemotherapy are acceptable, including a prior platinum chemotherapy in the absence of disease progression on the platinum. Specific Aims: Primary aim is to determine disease control rate in the chest wall and other distant sites at 18 weeks of treatment with RECIST 1.1. Secondary aims including determining toxicity, progression-free survival, response based on irRECIST, and response based on tumor PD-L1 expression. Exploratory aims include studying changes in: 1) immune composition of tumor and peripheral blood, 2) peripheral blood cell-free DNA and circulating tumor cells, 3) soluble PD-L1 expression, and 4) association of MYC with PD-1 and immune markers, based on preclinical data demonstrating that MYC upregulates these markers. Statistical Methods: 84 patients (Arm A: 56, Arm B: 28) are being enrolled at 7 sites in the Translational Breast Cancer Research Consortium. The study is powered to identify a 20% difference in disease control rates between Arms A and B (HR 0.52, α= 0.10, ß=0.20). A futility analysis will occur for Arm B after 18 patients are enrolled to allow for early closure if lack of efficacy. Accrual: Present accrual is 57 patients (Arm A: 39, Arm B: 18). (NCT03095352). This trial is partly funded by grants from Merck and University of California San Francisco. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Rita Nanda, Kathy Miller, Leisha Emens, Vandana Abramson, Ben Park, Minetta C. Liu, Andrei Goga, Hope Rugo. Randomized phase II trial of pembrolizumab/carboplatin vs. carboplatin alone for breast cancer with chest wall recurrence: TBCRC044 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-08.

Abstract GS4-07: The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts

Abstract Background. DCIS consists of a molecularly heterogeneous group of premalignant lesions, with variable risk of invasive progression. Understanding biomarkers for invasive progression could help individualize treatment recommendations based upon tumor biology. As part of the NCI Human Tumor Atlas Network (HTAN), we conducted comprehensive genomic analyses on two large DCIS case-control cohorts. Methods. We performed smart3-seq and low-pass whole genome sequencing on two independent, retrospective, longitudinally sampled DCIS case-control cohorts. TBCRC 038 was a multicenter cohort diagnosed with DCIS between 1998 and 2016 at one of the Translational Breast Cancer Research sites; the RAHBT (Resource of Archival Human Breast Tissue) cohort included women identified through the St. Louis Breast Tissue Repository, and the Women’s Health Repository diagnosed between 1997 and 2001. We studied the spectrum of molecular changes present and sought genomic predictors of subsequent ipsilateral breast events (iBEs: DCIS recurrence or invasive progression) in both DCIS epithelium and stroma in formalin fixed paraffin embedded tissue. We generated de novo tumor and stroma-centric subtypes for DCIS that represents fundamental transcriptomic organization. Copy number analysis was performed using low-pass DNA sequencing. Non-negative matrix factorization (NMF) was applied to the RNA expression of all coding genes to identify clusters. A negative-binomial regression model was used to identify differentially expressed genes. Results. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up. In TBCRC samples, we identified three clusters via NMF in TBCRC referred to as ER low, quiescent, and ER high. The ER-low cluster had significantly higher levels of ERBB2 and lower levels of ESR1 compared to quiescent and ER-high clusters. Quiescent cluster lesions were less proliferative and less metabolically active than ER high and ER low subtypes. These findings were replicated in the RAHBT cohort. Focusing on the stromal component of DCIS from laser capture microdissection in RAHBT samples, we identified four distinct DCIS-associated stromal clusters. A “normal-like” stromal cluster with ECM organization and PI3K-AKT signaling; a “collagen-rich” stromal cluster; a “desmoplastic” stromal cluster with high fibroblast and total myeloid abundance, mostly associated with macrophages and myeloid dendritic cells (mDC); and an “immune-dense” stromal cluster. Further, we compared differentially expressed genes in patients with or without subsequent iBEs within 5 years of diagnosis. Hypothesizing that the resulting 812 DE genes (DESeq2) represent multiple routes to subsequent iBEs, we leveraged NMF to identify paths to progression. In both TBCRC and RAHBT cohorts, poor outcome groups exhibited increased ER, MYC signaling, and oxidative phosphorylation, supporting that these pathways are important for DCIS recurrence and progression. Conclusion. Comprehensive genomic profiling in two independent DCIS cohorts with longitudinal outcomes shows distinct DCIS stromal expression patterns and immune cell composition. RNA expression profiles reveal underlying tumor biology that is associated with later iBEs in both cohorts. These studies provide new insight into DCIS biology and will guide the design of diagnostic strategies to prevent invasive progression. Citation Format: Siri H Strand, Belén Rivero-Gutiérrez, Kathleen E Houlahan, Jose A Seoane, Lorraine M King, Tyler Risom, Lunden Simpson, Sujay Vennam, Aziz Khan, Timothy Hardman, Bryan E Harmon, Fergus J Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F McAuliffe, Julie Nangia, Joanna Lee, Jennifer Tseng, Anna Maria Storniolo, Alastair Thompson, Gaorav Gupta, Robyn Burns, Deborah J Veis, Katherine DeSchryver, Chunfang Zhu, Magdalena Matusiak, Jason Wang, Shirley X Zhu, Jen Tappenden, Daisy Yi Ding, Dadong Zhang, Jingqin Luo, Shu Jiang, Sushama Varma, Cody Straub, Sucheta Srivastava, Christina Curtis, Rob Tibshirani, Robert Michael Angelo, Allison Hall, Kouros Owzar, Kornelia Polyak, Carlo Maley, Jeffrey R Marks, Graham A Colditz, E Shelley Hwang, Robert B West. The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-07.

Local Therapy Outcomes and Toxicity From the ATEMPT Trial (TBCRC 033): A Phase II Randomized Trial of Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab in Women With Stage I HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2)-directed therapy improves local control among women with HER2-positive breast cancer. This retrospective analysis evaluates the safety and efficacy of radiation therapy (RT) among patients receiving adjuvant trastuzumab emtansine (T-DM1) or paclitaxel (T) plus trastuzumab (H) in the ATEMPT (Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab) trial; Translational Breast Cancer Research Consortium (TBCRC) 033. Patients with stage I HER2-positive breast cancer were randomized 3:1 to receive adjuvant T-DM1 or TH after mastectomy or breast-conserving surgery (BCS). Breast RT was required after BCS and permitted after mastectomy. Patients receiving T-DM1 began RT after 12 weeks of therapy and received RT concurrently with T-DM1. Patients receiving TH began RT after paclitaxel, but concurrent with trastuzumab. RT records were retrospectively reviewed to determine details of radiation delivery and acute RT-related toxicity. Protocol therapy was initiated by 497 patients. Among the 299 BCS patients, 289 received whole breast RT (WBRT) and 10 partial breast. Among WBRT patients, 40.2% in the T-DM1 arm and 41.5% of TH patients received hypofractionated (≥2.5 Gy/fraction) RT. Eight mastectomy patients received RT, all conventional fractionation. Skin toxicity (grade ≥2) was seen in 33.9% of patients in the T-DM1 arm and 23.2% in the TH arm (P = .11). In conventionally fractionated WBRT patients, 44.7% had a grade ≥2 skin toxicity compared with 17.9% of patients receiving hypofractionation (P < .001). Five patients experienced pneumonitis after RT (T-DM1: n = 4, 1.0%; TH: n = 1, 0.9%). Three-year invasive disease-free survival was 97.8% for T-DM1 (95% confidence interval, 96.3-99.3) and 93.4% for TH (95% confidence interval, 88.7-98.2). Among the 18 invasive disease-free survival events, 7 were isolated locoregional recurrences (2, T-DM1; 5, TH). RT was well-tolerated when given concurrently with either T-DM1 or TH. Among BCS patients, hypofractionation resulted in lower grade ≥2 acute skin toxicity even with concurrent anti-HER2 therapy. Although follow-up was short, local recurrences were uncommon, attesting to the efficacy of HER2-directed therapy combined with RT.

Implementing open science in a daily routine: Team contribution from the Laboratory for Translational Breast Cancer Research

In order to ensure a comprehensive open science approach, the Laboratory for Translational Breast Cancer Research (LTBCR) is developing tools and a working environment that guarantee research integrity, reproducibility, and open access, while respecting GDPR.

Multi-center randomized study of pembrolizumab/carboplatin versus carboplatin alone in patients with chest wall disease from breast cancer: TBCRC 044.

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 .

Trial in progress: A phase 1b/2 study of the PARP inhibitor niraparib in combination with trastuzumab in patients with metastatic HER2+ breast cancer (TBCRC 050).

TPS1098 Background: Approximately 20% of breast cancers (BC) express the human epidermal growth factor receptor 2 (HER2). Although HER2-directed therapies result in improved patient outcome, resistance ultimately occurs. Poly (ADP-Ribose) polymerase (PARP) inhibitors are currently indicated in cancers that express germline mutations in the DNA repair proteins BRCA1/2 due to their synthetic lethality against the homologous recombination repair (HR) pathway. In addition to its role in DNA damage repair, PARP1 has also been implicated in other cellular functions, including co-activation of genes such as NF-κB, which regulate tumor proliferation and HER2 drug resistance. Our group identified that HER2+ BC overexpress the PARP1 and phospho-p65 protein. In HER2+ BC cells and animal models, PARP inhibitors initiated apoptosis independent of a DNA repair deficiency, via inhibition of NF-kB signaling. Key proteins (p65, IKK-α) of the NF-κB-mediated growth pathways were reduced and IκBα was increased in the presence of PARPi, implicating another oncologic pathway in which HER2+ BC cells may be dependent. Methods: The study is a phase 1b/2, multicenter, single arm clinical trial evaluating the safety and efficacy of niraparib 200 mg orally days 1-21 with trastuzumab 6 mg/kg (cycle 1 loading dose of 8 mg/kg) intravenously on day 1 of a 21-day cycle for patients with unresectable or metastatic HER2+ BC. Eligible patients include metastatic HER2+ BC, progression on at least 1 prior HER2-targeted therapy, measurable disease, ECOG PS 0-1, and LVEF ≥ 50%. Stable/treated CNS disease allowed. Prior PARPi and known germline BRCA 1/2 excluded. Forty patients will be enrolled at 7 US sites within the Translational Breast Cancer Research Consortium. The primary objectives are determining the dose-limiting toxicity (DLT) of the combination and assessing the objective response rate. The phase 1b cohort has been completed (N=6). Enrollment in phase 2 began February 2021 with a total accrual goal of 40. Gehan’s two-stage design will be used assuming the response rate is at least 24% and the response rate will be estimated with Clopper-Pearson exact method. Correlative aims include assessing blood and tissue biomarkers (e.g. PARP1, p65, phosphor-p65, let-7a miRNA, NF-kB, ctDNA, etc.) for association with clinical benefit and to predict response to therapy. Clinical trial information: NCT03368729 .