Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Importance:Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective:To evaluate the combination of anti-programmed cell death 1 protein (PD-1) cemiplimab and anti-lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2-negative early-stage, high-risk breast cancer. Design, Setting, and Participants:The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2-negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions:Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures:Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results:A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2, 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2-negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance:In this randomized clinical trial, the combination of PD-1 and anti-LAG-3 inhibition with standard NAC was effective in early-stage ERBB2-negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration:ClinicalTrials.gov Identifier: NCT01042379.

We evaluated the feasibility, safety, and efficacy of adjuvant bevacizumab, alone or in combination with chemotherapy, in early-stage breast cancer patients with residual invasive disease after neoadjuvant chemotherapy. Feasibility was demonstrated only for bevacizumab with flat-dosed capecitabine. The 36-month recurrence-free survival (RFS) ranged from 58.0% with bevacizumab monotherapy to 75.0% with bevacizumab plus body surface area-dosed capecitabine. Background: Breast cancer patients with residual disease after neoadjuvant therapy have increased risk of recurrence. Novel therapies to decrease this risk are urgently needed. Methods: Two clinical trials (05-055 and 09-134) offered adjuvant bevacizumab-based therapy to stage I-III breast cancer patients with residual disease after neoadjuvant chemotherapy. Study 05-055 evaluated four treatment regimens: bevacizumab (cohort A); bevacizumab with metronomic cyclophosphamide and methotrexate (CM) (cohort B); and bevacizumab with body surface area-dosed capecitabine (cohorts C); or flat-dosed capecitabine (cohort D). The primary endpoint was feasibility and tolerability. In 09-134, patients were randomized to bevacizumab with or without CM; the primary endpoint was recurrence-free survival (RFS). Study 09-134 closed prematurely for lack of accrual. A pooled survival analysis with participants from 05-055 and 09-134 was conducted. Results: Among 213 total patients (05-055, n = 163; 09-134, n = 50), the most common adverse events (AEs) of any grade were headache (49.3%) and fatigue (57.3%). Grade 3-4 AEs were highest in cohorts C (71.4%) and D (72.5%). The 36-month RFS was 58.0% with bevacizumab monotherapy, 62.3% with bevacizumab plus CM, and 72.7%-75.0% with bevacizumab plus capecitabine (depending on schedule). Treatment with capecitabine was independently associated with improved RFS in triple-negative breast cancer (TNBC) (HR: 0.47; 95% CI, 0.23-0.96). Conclusion: This pooled analysis demonstrates that postneoadjuvant bevacizumab plus capecitabine may be associated with improved RFS, especially in TNBC. Each regimen carries moderate toxicity, and despite these treatments, patients with residual disease after neoadjuvant therapy still experience high rates of recurrence, indicating that new strategies are warranted. Clinical Trial Registration: clinicaltrials.gov, NCT00121134 (DFCI Protocol Number: 05-055); NCT00925652 (DFCI Protocol Number: 09-134).

PURPOSE:Pelareorep (Pel) is a type 3 oncolytic reovirus that upregulates PD-L1 expression. We determined the objective response rate (ORR) with paclitaxel (Pac), Pac + Pel, or Pac + Pel + avelumab (Ave). PATIENTS AND METHODS:Patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had progressed on at least one line of endocrine therapy with a cyclin-dependent kinase 4/6 inhibitor and had not received chemotherapy for metastatic breast cancer were eligible. Patients were randomized 1:1:1 to Pac, Pac/Pel, or Pac/Pel/Ave after a three-patient run-in confirmed safety of the triplet regimen. Response was assessed every 8 weeks until week 16 and then every 12 weeks using RECIST v1.1. The primary endpoint was 16-week ORR. Statistical comparison across arms was not planned. RESULTS:Forty-eight patients were enrolled, with 45 randomized. The 16-week ORR was 20%, 31%, and 14% in the Pac, Pac/Pel, and Pac/Pel/Ave arms, respectively. The median progression-free survival was 6.4, 12.1, and 5.8 months in the Pac, Pac/Pel, and Pac/Pel/Ave arms, respectively. There were more adverse events, particularly infusion reactions, in the combination arms than the Pac arm. Expansion of peripheral T-cell clones was observed by cycle 4 in Pac/Pel but not the Pac or Pac/Pel/Ave arms. CONCLUSIONS:The addition of Pel to Pac was associated with increased toxicity, expanded peripheral T-cell clones, and numerically increased the ORR and progression-free survival compared with Pac; Pac/Pel/Ave further increased toxicity and blunted T-cell responses without obvious increase in efficacy. Investigation of the Pac/Pel combination warrants consideration with careful attention to acute toxicity.

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab-deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2-Immune-DNA repair deficiency- subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379. In the I-SPY2.2 trial, patients with high-risk stage 2/3 breast cancer received neoadjuvant datopotamab-deruxtecan, followed by sequential chemotherapy with or without targeted therapy, with the option of early surgical resection after each block of therapy. In a subgroup of patients, the sequential treatment strategy was superior to standard of care.

Background. Breast cancer has an unacceptably high recurrence rate when any residual disease is found following neoadjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open-label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods. A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2-negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3 mg to 5 mg and capecitabine 800 mg/m2 to 1000 mg/m2. Results. Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar-plantar dysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a prespecified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase, due to drug supply limitations. Conclusion. The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer. This study’s clinical investigation of entinostat in breast cancer was halted, but drug development of this agent continues outside the US. There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.

Breast cancer is the most common cancer among women worldwide, and estrogen receptor-positive (ER+) breast cancer accounts for a significant proportion of cases. While various treatments are available, endocrine therapies are often the first-line treatment for this type of breast cancer. However, the development of drug resistance poses a significant challenge in managing this disease. ESR1 mutations have been identified as a common mechanism of endocrine therapy resistance in ER+ breast cancer. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has shown some activity against ESR1 mutant tumors. However, due to its poor bioavailability and need for intramuscular injection, it may not be the optimal therapy for patients. Second-generation SERDs were developed to overcome these limitations. These newer drugs have improved oral bioavailability and pharmacokinetics, making them more convenient and effective for patients. Several oral SERDs are now in phase III trials for early and advanced ER+ breast cancer. This review summarizes the background of oral SERD development, the current status, and future perspectives.

Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab is an anti-PD-1 inhibitor approved for the treatment of NSCLC and cutaneous basal and squamous cell CA. Lymphocyte activation gene 3 (LAG-3) binds MHC class II leading to inhibition of T-cell proliferation and activation and is often co-expressed with PD-1. REGN3767 is a fully humanized mAb that binds to LAG-3 and blocks inhibitory T-cell signaling. Concurrent blockade of LAG-3 with an anti-PD-1 may enhance efficacy of an anti-PD-1. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included Paclitaxel 80 mg/m2 IV weekly x 12 and Cemiplimab 350 mg and REGN3767 1600 mg both given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. Cemiplimab/REGN3767 was eligible to graduate in 3 of 10 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. The statistical methods for evaluating I-SPY 2 agents has been previously described. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemiplimab/REGN3767 being superior to the dynamic control. Response predictive subtypes (Immune+ vs Immune-) were assessed using pre-treatment gene expression data and the ImPrint signature. Results: 73 HER2- patients (40 HR+ and 33 HR-) received Cemiplimab/REGN3767 treatment. The control group included [357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemiplimab/REGN3767 graduated in both HR-/HER2- and HR+/HER2- groups; estimated pCR rates (as of June 2022) are summarized in the table. Safety events of note for Cemiplimab/REGN3767 include hypothyroidism 30.8%, adrenal insufficiency (AI) 19.2%, hyperthyroidism 14.1%, pneumonitis 1.3%, and hepatitis 3.8%. All were G1/2 except for 6 (7.7%) G3 AI and 3 (3.8%) G3 colitis. Rash occurred in 62.8%, 9% G3 and 2 pts (2.6%) had pulmonary embolism. X% of adrenal insufficiency cases required replacement therapy. 40 patients (11 HR+ and 29 HR-) in Cemiplimab/REGN3767 were predicted Immune+; 32 (29 HR+ and 3 HR-) were predicted Immune-. In the HR+ group pCR was achieved in 10/11 (91%) patients with Immune+ subtype compared with 8/29 (28%) with Immune- subtype. Additional biomarker analyses are ongoing and will be presented at the meeting. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Dual immune blockade with a LAG-3 inhibitor and anti-PD1 therapy resulted in a high predicted pCR rate both in HR-/HER2- (60%) and HR+/HER2- (37%) disease. The novel Imprint signature identified a group of HR+ patients most likely to benefit from this active regimen. Table 1: Estimated pCR rates Citation Format: Claudine Isaacs, Rita Nanda, Jo Chien, Meghna S. Trivedi, Erica Stringer-Reasor, Christos Vaklavas, Judy C. Boughey, Amy Sanford, Anne Wallace, Amy S. Clark, Alexandra Thomas, Kathy S. Albain, Laura C. Kennedy, Tara B. Sanft, Kevin Kalinsky, Hyo S. Han, Nicole Williams, Mili Arora, Anthony Elias, Carla Falkson, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. Evaluation of anti-PD-1 Cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-03.

Supplementary Data from Genetic Polymorphisms and Correlation with Treatment-Induced Cardiotoxicity and Prognosis in Patients with Breast Cancer

PDF file - 507K, Supplemental Table 1A: PCR and Sanger Sequencing Primers Supplemental Table 1B: PCR and Sequenom Genotyping Primers Supplemental Figure 1. Kaplan-Meier estimates of disease free survival for BCIRG 006 study, entire population, third planned analysis. (N=3222) Supplemental Table 2. Patient Characteristics: Genotyped vs. Non-genotyped Supplemental Figure 2. Kaplan-Meier estimates of disease free survival in subset of patients enrolled in BCIRG006 (third planned analysis) who were genotyped for this study (N=1,286) Supplemental Figure 3. Kaplan-Meier estimates of disease free survival in subset of patients enrolled in BCIRG006 (third planned analysis) who were genotyped for this study with stratification for major prognostic factors Supplemental Table 3. Patients Characteristics by Genotype (Advanced Disease Cohort) Supplemental Table 4. Genotype and Allele Frequencies of the FCGR2A and FCGR3A Polymorphisms Supplemental Figure 4. Kaplan-Meier estimates of disease free survival in trastuzumab treated patients within the adjuvant cohort according to FcGammaR polymorphisms, broken down by treatment arm Supplemental Figure 5. Kaplan-Meier estimates of disease free survival in patients treated with chemotherapy alone (no trastuzumab) in the adjuvant cohort according to FcGammaR polymorphisms, broken down by treatment arm. Supplemental Figure 6. Kaplan-Meier estimates of overall survival (OS) in trastuzumab treated patients within the adjuvant cohort according to FcGammaR polymorphisms. Supplemental Figure 7. Kaplan-Meier estimates of progression free survival (PFS) in trastuzumab treated patients within the advanced disease cohort according to FcGammaR polymorphisms.

Purpose A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2 -deficient estrogen receptor–positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2- deficient ovarian cancer. Methods Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. Results A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2 -deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. Conclusions This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.

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

Inflammatory breast cancer (IBC) is a rare variety of breast cancer accounting for two percent of breast cancer diagnoses in the United States. It is characterized by peau d'orange, breast edema and erythema on physical examination and dermal lymphatic invasion by tumor emboli on histological examination. Micrometastases to lymphatics and bone marrow at the time of diagnosis and angiogenic properties of IBC explain the high propensity of this cancer to relapse and metastasize, its aggressiveness and poor prognosis. Preoperative sequential anthracycline and taxane (plus trastuzumab and pertuzumab if HER2-positive) based chemotherapy is the current standard of care for IBC. We herein report a case of stage IIIC triple-negative IBC treated with pembrolizumab plus chemotherapy based neoadjuvant therapy with a complete clinical and complete pathological response. This is the first case of triple-negative IBC treated with this regimen reported in the literature, thereby providing clinical data on the tolerability and efficacy of pembrolizumab plus chemotherapy based neoadjuvant regimen for the treatment of IBC.

Introduction: The COVID-19 pandemic has caused an extraordinary challenge for global health. New guidelines were implemented, including postponing non-essential surgical procedures to conserve resources. In response, the COVID19 Pandemic Breast Cancer Consortium expert opinion suggested the use of core biopsies for genomic testing to help triage patients for surgical vs. systemic treatment. To better understand how expedited genomic results could impact peri-operative care, we performed a pre-operative quality project to assess testing Mammaprint (MP), a 70-gene risk of recurrence assay, and Blueprint (BP), an 80-gene molecular subtyping assay, on core biopsies. Here we report our experience with MP and BP testing on core biopsies, and the correlation between test results and response to neoadjuvant therapy.Design: From April to December 2020, all core biopsies with a breast carcinoma diagnosis from our clinic (300 patients) were routinely sent for MP and BP testing as part of a rapid result program that was initiated to see whether test results could be obtained in time and whether they would lead to more informed pre-operative treatment decisions. Unstained slides were sent for genomic and receptor testing concurrently. When genomic results differed from IHC/FISH results or suggested a different treatment plan vs. clinical factors alone, we referred to this as “reclassification.” For those patients who completed their neoadjuvant chemotherapy, we grouped them by their genomic results and by their conventional IHC/FISH/Clinical classification, and compared the outcome.Results: MP and BP results from core biopsy were available for 96.6% of patients (n=290/300). The average time from biopsy to test results was 10 days, and the average lab turnaround time was 5 days. Results were available for tumor conference discussions 100% of the time. MP and BP re-classified 84 of 300 patients (28%) from conventional IHC/FISH subtyping, and reclassified 42 of 195 patients (22%) of patients from their risk category based on traditional clinical factors (Table-1). Of the 38 patients with available post-neoadjuvant therapy outcome, 13 patients (34%) achieved pathologic complete response (pCR). 16 patients were classified as Her-2 enriched by IHC/FISH of which 9 (56%) achieved pCR. MP/BP aligned with the IHC/FISH Her-2 enriched classification in 11/16 patients, while 5 patients were reclassified to Luminal B by MP/BP. Of the 11 patients with concordant IHC/FISH and MP/BP results, 8 achieved pCR (73%), while one of the 5 cases reclassified to Luminal B achieved pCR (20%). Of the patients who were classified Luminal by IHC (9 patients), one patient achieved pCR (11%), and of the patients classified luminal (A or B) by MP/BP (12 patients) two achieved pCR (16%). Of the IHC-triple negative patients and genomic basal patients, three patients achieved pCR in each group (23% and 20%, respectively).Conclusion: Performing MP/BP tests on core needle biopsies hold a high success rate. Incorporating test results into peri-operative discussions may result in better-informed decisions about treatment planning and timing of surgery versus systemic therapy. A higher rate of pCR was seen in the MP/BP Her-2 enriched group compared to the IHC/FISH Her-2 enriched group. Although this workflow was designed to triage patients during the COVID pandemic, this approach has great potential beyond the pandemic. Table-1: Reclassification Rate vs. path IHC/FISH or Clinical FactorsIHC/FISH/Clinical ◊ Genomic# of reclassified patients/total patients in the corresponding traditional category% of patientsLuminal A ◊ Luminal B25/16116%Luminal A ◊ Her-21/1610.6%Luminal B ◊ Luminal A35/7249%Luminal B ◊ Basal4/726%Her-2 ◊ Luminal A1/313%Her-2 ◊ Luminal B10/3132%Her-2 ◊ Basal1/313%Triple negative ◊ Luminal A4/3611%Triple negative ◊ Luminal B3/368%Clinical high risk ◊ Genomic low risk21/8425%Clinical low risk ◊ Genomic high risk21/11119% Citation Format: Hani Katerji, Huina Zhang, Xi Wang, Linda Schiffhauer, Ajay Dhakal, Alissa Huston, Carla Falkson, David Hicks, Bradley Turner. The utility of using genomic testing on needle core biopsies during the COVID-19 pandemic: Molecular characterization, risk stratification, neoadjuvant outcome, and future implications [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-19.

PURPOSE:Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC).PATIENTS AND METHODS:From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes.RESULTS:One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy.CONCLUSION:Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.

AbstractPurpose: Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. HER2 codon 655 and SLC28A3 gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported. Experimental Design: Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in HER2 codon 655 and SLC28A3. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes. Results: Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in HER2 (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the SLC28A3 gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non–trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy. Conclusions: In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.