The Management of ER-Low, HER2-Negative Breast Cancer in the United Kingdom: A Survey of Current Clinical Practice.

Background PARP inhibitors have proven efficacy in breast cancer patients with germline BRCA1 or BRCA2 mutations (gBRCAmt) but also have potential to be effective in cancers with defects in homologous recombination (HR) DNA repair. Moreover, synergy between PARP inhibition and immune checkpoint blockade is expected based on increased mutation burden, neoantigen expression, and immunogenic cell death. Triple negative breast cancer (TNBC) or low estrogen receptor (ER)-positive breast cancers may have diverse defects in HR repair. Methods This is a window of opportunity, serial biopsy trial of olaparib and durvalumab before standard neoadjuvant chemotherapy for TNBC or low ER+ breast cancer (NCT03594396). Patients had clinical stage II/III TNBC or low ER+ HER2- breast cancers where ER was expressed in 10% or lower in tumor cells. Olaparib 300mg bid was given for 4 weeks without rest. One dose of durvalumab 1500mg was given on day 15. Study tumor biopsy and blood sample were taken before the study treatment, after 2 weeks of olaparib before durvalumab, and 2 weeks after durvalumab at the completion of 4 weeks of olaparib. FDG-PET/MRI was taken at baseline, after 2 weeks, after 4 weeks of study treatment, and computed tomography (CT) scan at baseline and after 4 weeks. After the study treatment, standard neoadjuvant chemotherapy with 4 cycles of doxorubicin+cyclophosphamide followed by 4 cycles of docetaxel was given. Primary endpoint was the changes of tumor biology detected by serial tumor biopsy. Secondary endpoints were pathological complete response (pCR) rate, response rate, prediction of early metabolic response by functional HR status, and safety. Functional HR deficiency was assessed by counting RAD51 foci as a marker for HR repair in the baseline tumor tissues before and after 30Gy irradiation to induce DNA damage. Results Fifty-four female patients were enrolled (median age 40 years, range 24-68). ER was negative (TNBC) in 43 patients and low-positive in 11 patients. Clinical stage was II in 25 patients and III in 29 patients, and axillary lymph node involvement was in 47 patients. gBRCAmt was assessed in 53 patients and 16 (30.1%) harbored pathogenic mutations. Functional HR status as measured by RAD51 foci formation was deficient in 27 (50%) patients and proficient in 27 (50%) patients. Functional HR deficiency was related with early metabolic response by FDG-PET after 2 weeks of olaparib (response in 17/27 HR-deficient tumors [63.0%] vs. 7/27 HR-proficient tumors [25.9%]; p=.006). After 4 weeks of olaparib and durvalumab, HR-deficiency was still related to metabolic response (23/27 vs. 17/27, respectively; p=.062) but HR-proficient tumors also showed metabolic decline. Moreover, HR deficiency was also related with RECIST response measured by CT after 4 weeks (17/27 vs. 9/27; p=.029). As of June 2021, 40 patients completed the neoadjuvant treatment and surgery; among those, 30 achieved pCR (pCR rate 75%). Among 13 patients with gBRCAmt who underwent surgery, 11 achieved pCR (84.6%). Updated results on pCR will be presented. Conclusions Olaparib and durvalumab followed by standard neoadjuvant chemotherapy shows very high pCR rate in TNBC or low ER+ stage II/III breast cancer. Functional HR status as measured by RAD51 foci formation was predictive of early metabolic response to olaparib. Genomic and transcriptomic analyses are underway in the samples before, during, and after olaparib and durvalumab. Citation Format: Seock-Ah Im, Kyung-Hun Lee, Ahrum Min, Daewon Lee, Tae Yong Kim, Han Suk Ryu, Jiwon Koh, Gi-Jeong Cheon, Yoon-Jung Shin, Yujin Kim, Hyeong-Gon Moon, Wonshik Han, Han-Byoel Lee, Morgan Diolaiti, David Quigley, Alan Ashworth, Nariya Cho. Window of opportunity trial of neoadjuvant olaparib and durvalumab for triple negative or low ER-positive breast cancer [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 PD15-08.

TPS629 Background: Neoadjuvant chemoimmunotherapy is recommended for patients with high risk early stage TNBC. The 5 drug KEYNOTE-522 neoadjuvant chemoimmunotherapy regimen involves 5-6 months of treatment and is associated with suboptimal treatment completion due to toxicity. Approaches to deescalate chemoimmunotherapy without compromising outcomes for patients with highly chemosensitive disease are needed. Stromal tumor infiltrating lymphocyte (sTIL) enrichment is positively associated with pathologic complete response (pCR) in TNBC and may be useful to identify patients for whom de-escalation of neoadjuvant chemoimmunotherapy might be acceptable. NeoTRACT trial investigates deescalating neoadjuvant chemoimmunotherapy based on degree of pretreatment sTIL enrichment. We hypothesize that baseline immune upregulation assessed by sTILs can guide neoadjuvant treatment optimization in TNBC patients. Specifically, in patients with immune enriched TNBC (sTILs ≥30%), short anthracycline free taxane–platinum chemoimmunotherapy will yield high pCR rate. Methods: NeoTRACT is an ongoing open label phase II trial for patients with previously untreated TNM stage I (T>1cm)–III TNBC. TNBC is defined as estrogen and progesterone receptor ≤10% and HER2 negative per ASCO/CAP criteria. Patients with T4 or N3 breast cancer are excluded. Patients must have adequate organ function and no contraindication to pembrolizumab. All participants initiate carboplatin (AUC 6) + docetaxel (75mg/m2) + pembrolizumab (200mg) (CbD+P) every 21 days. After registration, sTILs are evaluated centrally on pretreatment H&E core needle biopsy slide using standard criteria. Participants are assigned to three neoadjuvant treatment regimens (A, B, or C) based on sTIL enrichment. Regimen A (sTILs ≥30%) includes four cycles CbD+P. All participants assigned to regimen A undergo breast MRI after four cycles: those with complete MRI response proceed to breast surgery; those with less than complete MRI response receive two additional cycles of CbD+P. Regimen B (sTILs 5-29%) includes six cycles of CbD+P. Regimen C (sTILs <5%) includes four cycles of CbD+P followed by four cycles of doxorubicin (60mg/m2) + cyclophosphamide (600mg/m2) + P (200mg) (AC+P). All patients undergo surgery after completing the assigned neoadjuvant regimen. Breast/axillary surgery, adjuvant systemic therapy, and radiotherapy are recommended per standard of care. pCR is defined as absence of residual invasive disease in breast and axilla. Primary endpoint is pCR rate among participants with ≥30% sTILs. Secondary endpoints include residual cancer burden (RCB) rates in patients with ≥30% sTILs, pCR and RCB rates in patients with 5-29% and <5% sTILs, and event free and overall survival for all patients. As of January 2024, 45 of 139 participants have been enrolled. Clinical trial information: NCT05645380 .

CDK4/6 inhibitors as neoadjuvant treatment in breast cancer—what can we learn?

Background: Overexpression of HER2 is a significant prognostic and predictive factor in early breast cancer. HER2 positive tumors are those scored by immunohistochemistry (IHC) 3+ or 2+ with amplification by in situ hybridization (ISH). These tumors may benefit from HER2-targeted treatment and additionally, in early HER2-positive BC, achieving a complete pathological response after neoadjuvant treatment improves patient survival. In recent years, new anti-HER2 antibody-drug conjugates have proven effective for HER2 low BC (defined as IHC score 1+ or 2+ not amplified) in the metastatic disease setting; however, in HER2-low early BC, studies testing novel anti-HER2 antibody-drug conjugates as neoadjuvant therapy (NAT) are ongoing. Currently, we don´t know exactly whether HER2 expression can influence the pathological response rate after NAT or disease-free survival (DFS) in these patients compared to HER2-zero (IHC 0). The aim of our study is to determine the impact on response rate to NAT and survival outcomes in early HER2-negative BC. Methods: We conducted a retrospective study in two hospitals in Andalucia, Spain. Patients with early HER2 negative BC treated with NAT from January 2015 to June 2022 were included. Patients were divided into HER2 low patients (IHC 1+ or 2+ not amplified) and HER2 0 (IHC 0). We collected clinical and pathological characteristics, pathological response rate using the Residual Cancer Burden (RCB) system where a complete pathological response (pCR) was defined as ypT0/ypTis and ypN0, and survival outcomes. The primary objective of the study was to analyze the pCR rate after NAT according to HER2 score, and secondary objectives were to assess disease-free survival and overall survival (DFS and OS rates). Results: 574 patients were included (100% women). 397 patients had hormone receptors (luminal BC) on these tumors, and 177 did not have them, i.e., triple-negative BC (TNBC). 225 patients were HER2-zero, and 312 patients were HER2-low (253/312 patients had luminal BC and 59/312 patients were TNBC). The pCR in HER2-low patients was 17.3% and 23.1% in HER2-zero patients (p=0.047). For luminal BC patients, the pCR was 16.7% in HER2-low tumors and 13.7% in HER2-zero tumors (p=0.29). Similarly, there was no difference in pCR rates in TNBC patients (45.8% in HER2-low and 53.8% in HER2-zero tumors, respectively, (p=0.958). The overall survival (OS) at 96 months was 88.7% (95% CI 85.6%-92%). Regarding survival outcomes, neither HER2 expression level was associated with higher 8-year DFS: 81.1% in HER2-low patients (95% CI 75.7%-86.8%) and 74.9% in HER2-zero patients (95% CI 62.3%-90.1%) p=0.64. There was no difference between histological subtypes at 8-years regarding DFS rate: 80.5% (95% CI 74.3%-87.2%) in luminal HER2-low patients and 76.3% (95% CI 60.8%-95.7%) in luminal HER2-zero patients, p=0.22; 83.8% in TNBC HER2-low (95% CI 74.5%-94.2%) and 77.5% in TNBC HER2-zero patients (95% CI 69.4%-86.6%) p=0.26. We also didn´t find significant differences in terms of OS. For HER2-low patients, the 8-year OS was 90.9% (95% CI 87%-94.9%) and for HER2-zero patients, it was 86.4% (95% CI 80.8%- 92.5%) p=0.46. There were also no differences in OS for different histological subgroups with an 8-year OS in luminal HER2-low breast cancer patients of 92.5% (95% CI 88%-96.7%) and 87% in HER2-zero (95% CI 78.9%-96.1%) p=0.91. In patients with triple-negative breast cancer phenotype, the OS was 84.2% for HER2-low (95% CI 74.5%-95.2%) and 85.3% for HER2-zero (95% CI 77.9%-93.4%) p=1. Conclusions: We found no difference in survival outcomes and response rate to conventional NAT between HER2-low and HER2-zero expression levels. Therefore, our data do not support the hypothesis of HER2-low as a biologically specific breast cancer subtype. Further research on this approach with HER2 antibody-drug conjugate schemes as an alternative to traditional NAT schemes is warranted. Citation Format: Ana Gil-Torralvo, Yeray Rodriguez, Alejandro Falcon, David Morales, Mónica Cejuela, Isabel Miras, Marta Amérigo, Manuel Ruíz - Borrego, Juan Bayo, Francisco Javier Salvador Bofill. Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative [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 PO1-27-07.

Bevacizumab in neoadjuvant chemotherapy increases the pathological complete response rate in patients with triple‐negative breast cancer

Background: Single-agent platinum compounds have significant clinical activity in the neoadjuvant and metastatic settings for triple-negative breast cancer (TNBC) in BRCA mutation carriers. Limited data exist regarding activity in estrogen receptor (ER)-positive breast cancer among BRCA carriers. The INFORM trial is an investigator-initiated, randomized, multicenter, phase II study comparing pathologic complete response (pCR) rates with neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin/cyclophosphamide (AC) in BRCA carriers with newly-diagnosed Stage I-III HER2-negative breast cancer. Methods: BRCA carriers with cT1-3 (≥1.5 cm), cN0-3 HER2-negative breast cancer were randomized (stratified by site and ER status) 1:1 to preoperative CDDP (75mg/m2 every 3 wks x 4) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 wks x 4) followed by surgery. Prior chemotherapy was not allowed; subsequent adjuvant therapy was selected by treating clinicians. Baseline tumor features and pathologic responses were centrally determined. The primary endpoint was pCR (ypT0/is, N0). Based on a 2-sided α=0.1, a sample size of 170 provided 80% power to detect an improvement in pCR from 30% with AC to 50% with CDDP. Slow accrual led to early trial closure. We used an intent-to-treat approach and log-binomial regression to calculate risk ratios (95% confidence intervals (CI)), adjusting for ER status. Results: We randomized 118 patients; 117 were included in outcome analyses. The mean age was 42 years (range: 24-73); 69% were BRCA1+, 30% BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% of patients had nodal involvement at baseline. Most patients (70%) had TNBC (ER/PR <10%). Histologic type and grade, clinical stage, lymphovascular invasion and tumor infiltrating lymphocytes were similar between treatment arms. Four patients did not complete protocol-assigned therapy and 7 received additional chemotherapy before surgery; all were assessed as not attaining pCR. The pCR rate was 18% in the CDDP arm and 26% in the AC arm, yielding a crude risk ratio of 0.70 (95% CI: 0.35-1.4); results were similar when adjusting for ER status. Table 1 shows pathologic responses. Table 1: Intention-to-treat analysis comparing CDDP to ACCDDP n=60 n (%)AC* n=57 n (%)Crude Risk Ratio (95% CI)Adjusted Risk Ratio§ (95% CI)Pathologic complete responseResidual cancer burden score: 0All participants11 (18)15 (26)0.70 (0.35-1.4)0.67 (0.35-1.3)Triple negative (ER and PR <10%)10 (23)11 (29)0.79 (0.37-1.6)–Hormone receptor positive (ER or PR ≥10%)1 (6)4 (21)0.30 (0.04-2.4)–Residual cancer burden¥Residual cancer burden score: 0 or 120 (33)26 (46)0.73 (0.46-1.2)0.72 (0.46-1.1)*One patient never received treatment, and is not included in the intent-to-treat analysis.§Adjusted for estrogen receptor status using 10% cutoff¥Residual cancer burden score of 0 or 1 could not be determined for 10 participants; they were assumed to have a residual cancer burden score greater than 1 Conclusion: While CDDP has single-agent activity in BRCA carriers with HER2-negative breast cancer, the pCR rate with CDDP is not higher than with standard AC chemotherapy. CDDP activity was notably lower in BRCA carriers with hormone-receptor positive breast cancer, though the sample size was small. Study-collected tumor and blood samples are being analyzed for biomarkers of response. Clinical information: NCT01670500. Funding: Breast Cancer Research Foundation; Susan G. Komen for the Cure; Myriad Genetics, Inc. Citation Format: Nadine Tung, Banu Arun, Erin Hofstatter, Michele R. Hacker, Deborah L. Toppmeyer, Steven J. Isakoff, Virginia Borges, Robert D. Legare, Claudine Isaacs, Antonio C. Wolff, Paul K. Marcom, Erica L. Mayer, Paulina B. Lange, Andrew J. Goss, Ian E. Krop, Eric P. Winer, Stuart J. Schnitt, Judy E. Garber. Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers (BRCA carriers) with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS6-03.

Background: Neoadjuvant association of immune checkpoints inhibitors (ICI) and dose dense chemotherapy is promising for triple negative breast cancers (TNBC). However, response rates vary from one study to another. Timing, best chemotherapy partner and efficacy in less immunogenic breast cancer (BC), like luminal B tumors, should be further investigated. This study evaluates for TNBC and luminal B HER2(-) BC the neoadjuvant treatment with paclitaxel followed by a short combination of an anti-PD-L1 antibody with anthracyclines. Method B-IMMUNE (NCT03356860), a multicentric phase Ib/II prospective trial, included patients with stage I to III luminal B HER2(-) or TNBC treated with paclitaxel 80mg/m2 weekly from week 1 to 12 followed by 4 cycles of epirubicine 90mg/m2 and cyclophosphamide 600 mg/m2 (EC) Q2W in a neoadjuvant setting. Phase Ib evaluated a single infusion of durvalumab (anti-PD-L1) combined with the 3rd cycle of EC. Phase II evaluated infusions of durvalumab with the 1st and 3rd EC cycles. Surgery was planned 3 weeks after the last EC cycle. Primary objectives were safety and pathological complete response (pCR) rate compared to a historical control. Secondary endpoint was the overall response rate (ORR) based on breast MRI. Eleven patients were enrolled in a control arm without durvalumab, exclusively for translational research purposes. Based on a 2-stage Simon design with an α = 0.1 and β = 0.1, 22 TNBC patients were needed in the phase II to test a null hypothesis of 30% pCR rate against a one-side alternative of 60%, and 24 luminal B BC patients to test a null hypothesis of 15% pCR rate against a one-side alternative of 40% (including an additional accrual margin of 10% for eventual dropouts). At least 9 pCRs had to be observed among the first 20 evaluable TNBC patients and 6 among the first 22 evaluable luminal B patients to rule out the null hypothesis. Results This analysis concerns the 50 patients treated with the experimental treatment, 3 from the phase Ib and 47 from the phase II part. Median age was 51 y-old (31 to 72y), tumor subtypes were 24 TNBC, 25 Luminal B and one sarcoma excluded from the efficacy analysis. Seven (14%) patients had a stage I tumor, 17 (34%) a stage IIA, 13 (26%) a stage IIB, 8 (16%) a stage IIIA, 4 (8%) a stage IIIB and 1 (2%) a stage IIIC. Concerning safety, 232 AEs were reported on 39/50 patients and 34 (14,6%) were graded ≥ 3. The 5 most frequent all-grade AEs were fatigue (8,2%), diarrhea (5,6%), neutropenia (5,2%), anemia and nausea (4,3%). Most frequent grade 3 AEs were anemia and neutropenia (14,7%). Among 4 immune-related adverse events, all were thyroid disorders. One patient died 10 months after the end of treatment due to progressive disease in the liver. Forty-six of the 47 phase II patients were evaluable for efficacy. pCR was reported in 12/22 TNBC patients (55%) and 8/24 luminal B HER2(-) patients (33%). Subgroup analyses based on PD-L1 expression and TILs score are planned. Conclusions The B-IMMUNE study met its primary objective showing a significant improvement in pCR versus the historical control in both TNBC and in Luminal B HER2(-) BC cohorts with the addition of only 2 doses of durvalumab to the anthracyclines. The safety profile is comparable to those previously described with reported immune related adverse events limited to thyroid endocrine disorders. Citation Format: Alix Devaux, Gabriela Beniuga, Claire Quaghebeur, Stéphanie Henry, Mieke Van Bockstal, Christine Galant, Paul Delrée, Jean-Luc Canon, Brigitte Honhon, Dominique Korman, Vincent Verschaeve, Christophe Lonchay, Sarah Lefevre, Lionel D’Hondt, Martine Berlière, Sophie Delmarcelle, Jean-Michel Mine, Timour Willems, Gebhard Müller, Nathalie Myant, Isabelle Bar, Sandy Haussy, Pierre G. Coulie, François P. Duhoux, Javier Carrasco. B-IMMUNE final analysis: a phase Ib/II study of durvalumab combined with dose-dense EC in a neoadjuvant setting for patients with locally advanced luminal B HER2(-) or triple negative breast cancers. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-16.

Background: The American Society of Clinical Oncology/College of American Pathologists recommended that the cut-off for negative status of estrogen receptor (ER) should be <1% positively staining cells, although a 10% cut-off has often been used clinically. Prior studies reported that patients with ER ranging from 1% to 9% showed survival outcomes and molecular features similar to those of patients with ER positivity of <1%; however, those studies did not take into account patients' human epidermal growth factor 2 (HER2) status. This means we have yet to clarify the exact clinical definition of triple-negative breast cancer (TNBC) on the basis of response to preoperative chemotherapy. Previous studies reported that hormone receptor–positive tumors were less sensitive to systemic chemotherapies. On the basis of these facts, we hypothesized that in patients with HER2-negative breast cancer ER expression level as a continuous variable has an inverse linear association with pathological complete response (pCR) rate. Our primary objective was to determine whether a quantitative value of ER between 0% and 10% is predictive of pCR rate in HER2-negative patients treated with neoadjuvant chemotherapy. Secondary objective was to find the ideal cut-off value of ER expression. Methods: We included newly diagnosed stage I-III HER2-negative breast cancer patients with available ER (0%≤ER<10%) who were treated with neoadjuvant systemic chemotherapy. ER status was determined by immunohistochemical (IHC) staining; HER2 status was determined by IHC and/or FISH. We used univariate and multivariate logistic regression models to determine the association between baseline variables and pCR. A backward stepwise method was used to select the covariates for the multivariate analysis. Recursive partitioning and regression tree method were used to identify the potential significant cut-off of ER. Results: The analysis included 1155 patients with newly diagnosed HER2-negative invasive breast cancer. The univariate logistic regression analysis showed that ER as a continuous variable was not a statistically significant factor for predicting pCR (ER: OR=0.98, 95%CI: 0.9-1.07, P=0.68). In the multivariate analysis, ER status again was not a significant factor for predicting pCR (OR=0.97, 95%CI 0.9-1.06, P=0.55). ER as a categorical variable, there was no significant difference of the pCR rate between 0<ER<1 and 1≤ER<10 groups (OR=1.27, 95%CI: 0.62-2.62, P=0.52). Among ER> 0 (n=229), the recommended cut-off value of ER was 5.5. However, the odds ratio of pCR rate divided by this value of 5.5 was not significant (ER≤5 vs ER>5; OR 1.94 95%CI 0.54-6.95 P=0.31). Conclusion: Evaluating ER (<10%) as a continuous variable showed no association with pCR rate, and no cut-off of ER was identified with which to stratify patients into groups more or less likely to achieve pCR. A potential meaningful cut-off ER value might exist between 10% and 100% in HER2-negative patients. We will explore whether a meaningful cut-off ER value exists that will change the pCR rate and possibly lead to redefining the clinical definition of TNBC. Citation Format: Fujii T, Kogawa T, Dong W, Moulder S, Litton JK, Tripathy D, Lim B, Shen Y, Ueno NT. Association between quantitative values of estrogen receptor expression level and pathological complete response in human epidermal growth factor 2-negative breast cancer: Should the clinical definition of triple-negative breast cancer be redefined?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-07.

The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome. To determine treatment outcome for BC according to germline variant status. This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018. Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status. In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor-positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02). Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor-positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start. ClinicalTrials.gov Identifier: NCT02125344.

Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer that accounts for approximately 15% of all breast cancer diagnoses and is associated with a poor prognosis. Based on the KEYNOTE-522 (K522) trial, the FDA approved the use of neoadjuvant immunotherapy, Pembrolizumab along with chemotherapy for high-risk early stage TNBC in July 2021. Specifically, the K522 study demonstrated an increased pathological complete response (pCR) rate of 64.8% vs 51.2% and 36-month event-free survival (EFS) of 84.5% vs 76.8% for Pembrolizumab with chemotherapy vs. chemotherapy alone, respectively. The presence of tumor infiltrating lymphocytes (TILs) is a predictive biomarker of pCR and improved survival in patients with TNBC. In this retrospective cohort study, we examine a clinically diverse patient population who received the K522 regimen to determine whether TILs confer a predictive value in response to neoadjuvant pembrolizumab treatment compared to other tumor and clinical factors. Methods: We reviewed electronic medical records of 271 patients with early TNBC who received neoadjuvant chemo immunotherapy with the K522 regimen at a tertiary care university hospital, UT Southwestern (UTSW), and affiliated safety-net hospital, Parkland Memorial (PM) between August 2021 and May 2024. 184 patients completed the neoadjuvant portion of treatment followed by surgery and fit the criteria for our analysis (UTSW: 120, PM: 64). Baseline patient and tumor characteristics were described. Two proportion Z-tests and Chi-squared tests for independence were used to compare pCR rate between patient ethnicities and univariate logistic regression was used to evaluate the association between binary presence of TILs, grade, and residual cancer burden. Results: In total, 57% achieved a pCR; TILs were reported in 52.8% of pathology reports. The presence of TILs was associated with a significantly improved pCR rate of 70% compared to 48% in individuals without TILs (p=0.0027). The median age of our patient population was 51 years. Of which, 34.8% self-identified as Caucasian, 31.0% Hispanic, 25.5% Black, and 8.7% other. There was no statistically significant difference in pCR rate or presence of reported TILs across different ethnicities. Of note, Hispanic patients with TILs had an increased rate of pCR (80.0%) than Hispanic patients without TILs (54.3%) (p=0.0323). No other ethnic group with TILs showed any statistical association with pCR when compared to their non-TIL presenting counterparts. Controlling for tumor grade, patients with TILs were 2.442 times more likely to have a pCR (CI: 1.310—4.553; p=0.0050). Patients with grade 3 TNBC were 2.89 times more likely to have a pCR (CI: 1.275—11.822; p=0.0170). Node positivity in conjunction with TILs also showed statistically significant pCR rates versus all other subgroups (p=0.0051). Conclusions: The K522 trial did not collect racial data as a baseline demographic characteristic, while our study had a significant percentage of Hispanic and Black populations treated with this regimen. This may account for our pCR rate of 57%, which is lower than what was reported on the K522 trial as studies have shown a lower pCR rate in Black population compared to other ethnicities. Our data suggests that TILs can be considered a predictive marker of pCR rate and treatment response in patients with early-stage TNBC. This is particularly relevant in Hispanic patients with TILs achieving a higher rate of pCR than the rest of our population. This may indicate that TILs have potential to guide treatment decisions for certain subgroups. Current College of American Pathologists guidelines do not mandate standardized or uniform reporting of TILs in pathology reports. While TILs could be considered a potential predictive marker in early stage TNBC, more emphasis needs to be placed in standardized reporting of TILs and larger studies are needed for further validation. Citation Format: Riya Albert, Joshua Thomas, Navid Sadeghi, Sangeetha Reddy, Glenda Delgado, Heather McArthur, Samira Syed, Deborah Farr, Nisha Unni. Tumor Infiltrating Lymphocytes (TILs) as a Predictive Marker of Pathological Complete Response (pCR) in a Diverse Patient Population with Early Triple Negative Breast Cancer (TNBC) Treated with the Neoadjuvant KEYNOTE-522 Regimen [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS1-01.

The present study was conducted to evaluate the clinical, pathological response, and prognosis characteristics of human epidermal growth factor receptor 2 (HER2)-low breast cancer in the neoadjuvant chemotherapy setting. Patients with HER2-negative breast cancer who received neoadjuvant chemotherapy from January 2017 to December 2019 were retrospectively analyzed. HER2-negative breast cancer was divided into two groups: HER2-zero (defined as immunohistochemistry [IHC]0) and HER2-low (defined as IHC1+, or IHC2+ and fluorescence in-situ hybridization-negative. Overall, 314 patients with HER2-negative breast cancer were analyzed. The proportion of HER2-low patients with hormone receptor (HR)-positive disease was higher than in triple-negative breast cancer (TNBC; 75.3% vs. 63.2%, p=0.032). In HR-positive breast cancer, HER2-low tumors presented less nodal involvement (p=0.023) and earlier clinical stage (p=0.015) compared with HER2-zero tumors; however, in TNBC, HER2-low patients had a later clinical stage (p=0.028). With the pathological complete response (pCR) defined as ypTis/0ypN0, there was no difference in pCR rates among the entire cohort, HR-positive disease, and TNBC. However, with the pCR defined as ypT0ypN0, the pCR rate in HER2-low breast cancer was significantly lower than HER2-zero breast cancer in the entire cohort (24.3% vs. 36.4%, p=0.032) and the HR-positive subgroup (18.7% vs. 32.1%, p=0.035), but not for TNBC. Multivariate analysis demonstrated that HER2 status (low vs. zero) was an independent predictive factor for pCR (p=0.013) in HR-positive breast cancer. There were no statistically significant differences in 3-year disease-free survival and overall survival between HER2-low and HER2-zero breast cancer among the entire cohort, HR-positive disease, and TNBC. HER2-low breast cancer exhibits specific clinical features and different response to treatment associated with HR status in the neoadjuvant chemotherapy setting.

Background: The association of immune checkpoints inhibitors (ICI) and dose dense chemotherapy is a promising combination in a neoadjuvant setting for triple negative breast cancers (TNBC). However, response rates vary from one study to another and timing, best chemotherapy partner and efficacy in breast cancer subtypes considered as less immunogenic, like luminal B tumors, should be further investigated. The B-immune study evaluates a neoadjuvant treatment with paclitaxel followed by a short combination of an anti-PD-L1 antibody with anthracyclines for TNBC and luminal B breast cancers (BC). Method: B-immune (NCT03356860), a multicentric phase Ib/II prospective trial, includes patients with stage I to III luminal B or TNBC treated with paclitaxel 80mg/m2 weekly from week 1 to 12 followed by 4 cycles of epirubicine 90mg/m2 and cyclophosphamide 600 mg/m2 (EC) Q2W in a neoadjuvant setting. The phase Ib evaluated a single infusion of durvalumab (anti-PD-L1) combined with the 3rd cycle of EC. The phase II, in progress, evaluates 2 infusions of durvalumab with the 1st and 3rd cycle of EC respectively. Surgery is planned 3 weeks after the last preoperative treatment. Primary objectives are safety and efficacy based on pathological complete response (pCR) rate. Considering a 2-stage Simon design, 22 TNBC patients are needed in the phase II to detect a pCR rate increase from 30% to 60% and 24 luminal B BC patients are needed to detect a pCR rate increase from 15% to 40% (α = 0.1 and β = 0.1). At least 3 pCRs must be observed among 8 TNBC patients and 2 among 10 Luminal B patients treated in the 1st stage to move to the 2nd stage. Results: This analysis concerns 3 treated patients from phase Ib and 18 from phase II who received the experimental treatment (median age 55 y-old, 10 TNBC, 11 Luminal B, 14% stage I, 67% stage II, 19% stage III). Overall, 169 AEs were reported and 22 (13%) were graded > 2 on 10/21 patients, including 27% of neutropenia (6/22), 22% of anemia (5/22), 13% of severe asthenia (3/22) and 9% of diarrhea (2/22). Four patients (19%) developed thyroid immune endocrine disorders. Efficacy was evaluated on 18 patients included in the 1st stage of phase II (8 TNBC and 10 luminal B). Five among 8 TNBC patients (62%) and 2 among 10 luminal B patients (20%) had a pCR. Conclusions: The B-immune interim analysis reveals an acceptable global safety profile. Reported immune related adverse events were limited to thyroid endocrine disorders. Observed pCR rate after neoadjuvant paclitaxel followed by 2 durvalumab infusions combined to EC chemotherapy warrants pursuing the trial for the TNBC and luminal B cohorts. Citation Format: Javier Carrasco, Claire Quaghebeur, Stephanie Henry, Christine Galant, Mieke Van Bockstal, Paul Delrée, Brigitte Honhon, Dominique Korman, Vincent Verschaeve, Christophe Lonchay, Sarah Levefre, Lionel D'hondt, Martine Berliere, Sophie Delmarcelle, Jean-Michel Mine, Timour Willems, Gebhard Müller, Nathalie Myant, Isabelle Bar, Manuel Constant, Sandy Haussy, Alix Devaux, Pierre Coulie, Jean-Luc Canon, François Duhoux. B-immune interim analysis: A phase Ib/II study of durvalumab combined with dose-dense EC in a neoadjuvant setting for patients with locally advanced luminal B HER2(-) or triple negative breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-12.

Introduction: Although patients diagnosed with early-stage triple negative breast cancer (TNBC) are commonly diagnosed before age 50, the impact of age on efficacy and toxicity of recent innovations in standard-of-care curative intent therapy are not well-defined. For example, subgroup analyses from KEYNOTE-522, wherein 11% of the population was aged ≥65y, demonstrated an overall benefit with pembrolizumab (pembro) in addition to neoadjuvant chemotherapy (NAC) in patients aged ≥65y and age <65y; however, the older cohort had an inferior pathologic complete response (pCR) rate of 54.3% vs. 66.2% in the younger cohort, with corresponding event-free survival (EFS) hazard ratios of 0.79 and 0.61, respectively. The aim of this analysis is to examine whether differences in management of older patients with early breast cancer exist and to identify appropriate patients who would benefit from neoadjuvant chemo-immunotherapy (IO). Methods: Patients with early-stage TNBC diagnosed between 7/1/2021 and 12/31/2023 for whom treatment with the KEYNOTE-522 regimen was planned standard-of-care therapy were identified from 2 institutional databases. Patients were excluded if they did not receive at least 1 cycle of NAC, at least 1 cycle of neoadjuvant pembro, or did not undergo definitive surgery. Univariate and multivariate analysis was performed using logistic regression to identify factors associated with pCR. Results: Of the 264 patients (263 female/1 male) included in the analysis, the median age was 52.9 (range 20.8-87.7). 51 (19.4%) patients were age ≥65y, and 213 (80.6%) patients were <65y. Hypertension was more common in patients age ≥65y compared to those <65y (66.7% vs. 21.6%), as was hyperlipidemia (64.7% vs. 23.0%) and type 2 diabetes (33.3% vs. 13.6%) [p<0.001]. Although tumor size, nodal status, and grade were similar between the two age groups, patients age ≥65y were more likely to be diagnosed with non-ductal histologies (17.5%) compared to age <65y (5.1%) [p=0.005]. Patients age ≥65y received fewer cycles of NAC compared to age <65y, with a median of 7 cycles (2-8) and 8 cycles (2-8), respectively (p<0.0001). Similarly, patients age ≥65y received less cycles of neoadjuvant pembro compared to age <65y, with a median of 7 cycles (1-11) and 8 cycles (1-11), respectively (p=0.003). The number of carboplatin and taxane cycles were similar between the two age groups (p=0.34 and p=0.60, respectively). Although the median number of anthracycline-cyclophosphamide (AC) cycles was the same in both age groups [4 (0-4)], the distribution of AC cycles varied: 52% of patients age ≥65y vs. 78% of those age <65y completed 4 cycles of AC, while 36% of patients age ≥65y vs. 12% of those age <65y received 0 AC cycles (p=0.0003). Patients age ≥65y had inferior pCR rates compared to patients age <65y: 49.0% vs. 63.4%, respectively (p=0.059). Although the 65y cutoff was not predictive of pCR, we observed a considerable advantage in patients age <50y vs. those age ≥50y, both in the univariate and multivariate setting. Multivariate analysis showed that younger age (<50y vs. ≥50y) (odds ratio (OR) 1.94; 95% confidence interval (CI), 1.11-3.38; p=0.02), the absence of type 2 diabetes (OR 2.08; 95% CI 1.03-4.18; p=0.04), and higher grade (3 vs. ≤2) (OR 2.18; 95% CI 1.07-4.42; p=0.03) were independent predictors of pCR. Conclusion: This study suggests that older patients with early TNBC are less likely to receive the planned course of neoadjuvant chemo-IO which may, in turn, impact pCR rates. Overall, older patients received fewer cycles of both neoadjuvant pembrolizumab and NAC, with AC most frequently discontinued. Further studies to identify the optimal treatment regimen for patients aged ≥65y with TNBC are needed. Citation Format: Alexis LeVee, Bethania Santos, Megan Wong, Nora Ruel, Heather McArthur, Joanne Mortimer. Impact of age on neoadjuvant chemo-immunotherapy (IO) administration and outcomes in patients with early-stage triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-11-23.

BACKGROUND: Patients with stage III inflammatory breast cancer (IBC) are treated with tri-modality therapy consisting of neoadjuvant systemic therapy followed by modified radical mastectomy and post-mastectomy radiation therapy. Triple negative IBC (TN-IBC) is the subtype of IBC associated with the worst survival outcomes. Pathological complete response (pCR) rates after neoadjuvant chemotherapy have been historically low, with reports ranging between 13% and 42%. It is unknown if the addition of immune checkpoint inhibition to chemotherapy leads to improved pCR rate in TN-IBC as these patients were underrepresented in the seminal studies that led to the approval of chemoimmunotherapy for high-risk early-stage triple negative breast cancer (TNBC). METHODS: We conducted a retrospective analysis of patients with stage III TN-IBC who underwent breast surgery after receiving neoadjuvant chemoimmunotherapy. Patients were seen at Dana-Farber Cancer Institute (DFCI) or MD Anderson Cancer Center (MDACC). The analysis population consisted of all patients that were seen at either institution no more than 30 days after starting immunotherapy. The primary objective was the estimation of the pCR rate. An additional cohort of patients with TN-IBC treated with neoadjuvant chemotherapy and pembrolizumab while participating in the multi-institutional PELICAN trial (NCT03515798) will be added to the analysis at the time of the meeting. RESULTS: Thirty-seven patients (16 DFCI, 21 MDACC) were identified as having stage III TN-IBC and having received neoadjuvant chemoimmunotherapy. Twenty-five patients met criteria for inclusion in the analysis population. Patients in the DFCI cohort initiated treatment with chemoimmunotherapy between May 2021 and June 2022, and in the MDACC cohort between June 2021 and October 2022. Most patients were White (N=20, 80%), premenopausal (N=15, 60%) and overweight/obese (N=19, 76%). All patients received pembrolizumab-based therapy (Table 1). Among the 25 patients in the analysis population, 10 (40%) (95% CI: 21% to 61%) achieved a pCR, 6 patients experienced RCB-II and 9 RCB-III. At the time of last follow up, 84% of patients were alive. The results will be updated at the time of the meeting to include an additional cohort of 17 patients from the PELICAN trial. CONCLUSIONS: The addition of immune checkpoint inhibition to neoadjuvant chemotherapy led to a higher pCR rate in TN-IBC than most historical estimates. However this is still lower than what has been reported in TNBC in general. The investigation of novel systemic therapies is warranted in TN-IBC. Table 1. Patient characteristics and treatment received (analysis population) Citation Format: Filipa Lynce, Samuel Niman, Anthony Gonçalves, Megumi Kai, Sean Ryan, Elizabeth Troll, Rachel Layman, Antonio Giordano, Azadeh Nasrazadani, Faina Nakhlis, Jennifer Bellon, Laura Warren, Caroline Block, Susan Schumer, Anthony Lucci, Savitri Krishnamurthy, Florence Lerebours, Florence Dalenc, Christelle Levy, Thierry Petit, Marianne Leheurteur, Thomas Bachelot, Olivier Trédan, Sylvain Ladoire, Leonor Lopez Almeida, Christophe Zemmour, Sara Tolaney, Vicente Valero, François BERTUCCI, Meredith Regan, Wendy Woodward. Pathological complete response with chemotherapy and immune checkpoint inhibition in triple negative inflammatory breast cancer (TN-IBC) [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 PO2-03-06.

Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. Germline BRCA (gBRCA) breast cancer and TNBC share some phenotypic and molecular similarities, with 10%-20% of TNBC patients having gBRCA mutations. Homologous recombination deficient tumours are particularly sensitive to PARP inhibitors such as olaparib (Lynparza). It has been shown that adjuvant olaparib for patients with high-risk, HER2-negative early breast cancer and gBRCA pathogenic or likely pathogenic variants after adjuvant or neoadjuvant chemotherapy significantly improves 3-year invasive and distant disease-free survival compared to placebo (OlympiA). Aim: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR) rate). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) aiming to establish if the addition of new agents (ATR inhibitor and PDL1 inhibitor) can improve response in those patients with evidence of residual disease before surgery. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; clinical stage T1-4 N0-2; performance status 0-1; treatment commenced within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and the TNBC non-gBRCA cohort) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. It is planned to recruit a minimum of 188 gBRCA patients. A maximum of 15 patients will be allocated into each PARTNERING cohort. Present accrual: Recruitment commenced 27 May 2016 and 678 patients from 30 sites have been accrued to date. The IDSMC reviewed the trial after Stages 1 and 2 and recommended to continue the trial without change. Data analysis for Stage 2 revealed no safety concerns and research arm 2 (olaparib on day 3 to day 14) was selected. Stage 3 Phase I recruitment is in progress (recruiting TNBC non-gBRCA and gBRCA patients) and we anticipate moving to Phase II (recruiting gBRCA patients only) by early 2022. Four patients have been accrued to the PARTNERING optional pathway to date. The trial is open and enrolling patients to UK and international sites. Contact information: partner@addenbrookes.nhs.uk Citation Format: Lynsey M Drewett, Karen A Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Jessica Martin, Camila Maida de Pontes, Nicola Johnson, Caron Harvey, Erdem Demir, Kimberley St John Green, James Jones, Gemma Young, Anne-Laure Vallier, Wendi Qian, Andrea Machin, Karen McAdam, Rebecca Roylance, Ellen R Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [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 OT2-24-01.