Evaluating the Efficacy and Safety of NEOadjuvant CHEmoimmunotherapy in Early ER-Low/HER2-Negative Breast Cancer (NEOCHEER): A Systematic Review and Meta-Analysis.

With the increasing delivery of neoadjuvant chemotherapy (NACT) for patients with breast cancer in the US, it is important to know whether there is differential response to NACT by race and ethnicity and the potential long-term outcomes. To examine whether there were any racial and ethnic differences in pathologic complete response (pCR) rate following NACT and, if so, whether they varied by molecular subtype and were associated with survival. A retrospective cohort study was conducted including patients with stage I to III breast cancer diagnosed between January 2010 and December 2017 who underwent surgery and received NACT; median follow-up was 5.8 years, and data analysis was conducted from August 2021 to January 2023. Data were obtained from the National Cancer Data Base, a nationwide, facility-based, oncology data set that captures approximately 70% of all newly diagnosed cases of breast cancer in the US. Pathologic complete response, defined as ypT0/Tis ypN0, was modeled using logistic regression. Racial and ethnic differences in survival were analyzed using a Weibull accelerated failure time model. Mediation analysis was conducted to measure whether racial and ethnic differences in the pCR rate affect survival. The study included 107 207 patients (106 587 [99.4%] women), with a mean (SD) age of 53.4 (12.1) years. A total of 5009 patients were Asian or Pacific Islander, 18 417 were non-Hispanic Black, 9724 were Hispanic, and 74 057 were non-Hispanic White. There were significant racial and ethnic differences in pCR rates, but the differences were subtype-specific. In hormone receptor-negative (HR-)/erb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)-positive (ERBB2+) subtype, Asian and Pacific Islander patients achieved the highest pCR rate (56.8%), followed by Hispanic (55.2%) and non-Hispanic White (52.3%) patients with the lowest pCR rate seen in Black patients (44.8%). In triple-negative breast cancer, Black patients had a lower pCR rate (27.3%) than other racial and ethnic groups (all >30%). In HR+/ERBB2- subtype, Black patients had a higher pCR rate (11.3%) than other racial/ethnic groups (all ≤10%). In mediation analysis, racial and ethnic differences in achieving pCR after NACT could explain approximately 20% to 53% of the subtype-specific survival differences across racial and ethnic groups. In this cohort study of patients with breast cancer receiving NACT, Black patients had a lower pCR rate for triple-negative and HR-/ERBB2+ breast cancer but a higher pCR rate for HR+/ERBB2- diseases, whereas Asian and Pacific Islander patients had a higher pCR rate for HR-/ERBB2+ diseases. Tumor grade and ERBB2 copy number could account for some of these within-subtype disparities, but further studies are warranted. Inability to achieve a pCR can mediate in part, but not entirely, the worse survival outcomes experienced by Black patients.

Introduction: Neoadjuvant chemo-immunotherapy with pembrolizumab (NAC+P) has become the standard care for stage II-III triple-negative breast cancer (TNBC) following the KEYNOTE-522 (KN522) trial, which showed improved pathologic complete response (pCR) rates and event-free survival compared to chemotherapy alone (NAC). We aimed to describe pCR rates by age and treatment in TNBC patients receiving either NAC+P or NAC alone at our institution. Methods: Women aged ≥65 years with stage I-III TNBC treated with NAC+P from 6/2021 to 9/2023 were compared to patients aged <65 years treated with NAC+P and to patients ≥65 who received NAC alone from 03/2010 to 9/2019. Patients with metaplastic breast cancer and neoadjuvant radiotherapy were excluded. Clinicopathological characteristics and pCR rates (ypT0/is pN0) - were compared between groups using Chi-square tests. Logistic regression for univariate (UVA) and multivariable analysis (MVA) was used to evaluate the association between age, treatment, and pCR. Results: 481 patients were included: 69 NAC+P ≥65 years (median age 69, IQR: 67-73); 338 NAC+P <65 years (median age 48, IQR: 38-56); and 74 NAC ≥65 years (median age 69, IQR: 66-73). Compared to younger patients, older patients treated with NAC+P were more likely to have public insurance (87% vs 13%, p<.001), lobular and other non-ductal histologies (6% vs 1.2% and 10% vs 5%, respectively, p= .009), cT1 and cT4 stages (22% vs 11% and 13% vs 3.9%, respectively, p< .001) and cN+ disease at presentation (58% vs 45%, p=.04). In both age groups, 81% received the KN522 backbone regimen with carboplatin, and the remaining mostly received NAC with cyclophosphamide, anthracycline, and taxane. There was no difference in treatment completion rate - defined as the completion of all preplanned neoadjuvant therapy cycles regardless of interruptions, regimen changes, or dose reductions - and in immune-related adverse events (33%) between age groups. However, older patients had a longer time from NAC+P to surgery (38 vs 32 days, p= .002). Breast surgery was similar between age groups, but axillary dissection (ALND) was more common in older patients (32% vs 19%, p= .023). The pCR rates did not differ between older and younger patients (49% vs 58%, p=.2). On MVA, high tumor grade (OR 13.9, 95% CI 4.54-61.7, p< .001) was positively associated with pCR, whereas other histologies (OR 0.13, 95% CI 0.04-0.39, p< .001), cT4 stage (OR 0.10, 95% CI 0.02-0.36, p<.001) and cN+(OR 0.60, 95% CI 0.38-0.95, p= .029) were less likely to facilitate pCR.In patients ≥65 years, those receiving NAC+P, compared to NAC alone, more frequently had lobular and other histologies (6% vs 0% and 10% vs 4.1%, respectively, p= .028), intermediate tumor grade (15% vs 1.4%, p=0.003), and cT1 and cT2 stages (22% vs 16% and 61% vs 46%, respectively, p= .045).NAC+P patients more frequently received carboplatin (81% vs 6.8%, p<.001). There was no difference in NAC completion and time to treatment start, but the NAC+P group had longer time to surgery (38 vs. 30 days, p = 0.039). More NAC patients underwent ALND (56% vs 32%, p= .005), with no difference in cN+ disease and breast surgery. The pCR rates were significantly higher in the NAC+P group (49%) compared to NAC (23%, p=.001). On UVA, NAC+P significantly improved overall pCR (OR 3.26 p=.001). However, on MVA, after adjusting for tumor histology, grade, stage, neoadjuvant carboplatin, and completion rate, the use of immunotherapy was not independently associated with pCR. Conclusions: Within the NAC+P cohort, pCR rates did not differ by age, and no significant increase in irAEs was seen in elderly patients, though we acknowledge a possible selection bias toward healthier elderly patients. Compared to NAC only, NAC+P showed potential for improving pCR in older individuals and could be a viable treatment option for elderly TNBC patients who are likely to tolerate it. Citation Format: Natalia Polidorio, Lauren M. Perry, Srinivasa Sevilimedu Veeravalli, Giacomo Montagna, Nour Abuhadra, Diana Lake, Mark Robson, Monica Morrow, Stephanie Downs-Canner, Iris Zhi. Outcomes in Elderly Patients with Triple-Negative Breast Cancer Receiving Neoadjuvant Chemo-immunotherapy and Chemotherapy Alone [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 P5-11-16.

Simple SummaryApproximately 15–25% of breast cancers are human epidermal growth factor receptor 2 (HER2)-positive. With the progress in medicine, promising results have been shown by dual targeted therapy with new drugs in the neoadjuvant setting. In our study, we compared the effectiveness of three neoadjuvant targeted therapy strategies (H + Py, trastuzumab plus pyrotinib; H, trastuzumab; HP, trastuzumab plus pertuzumab) based on the same chemotherapy regimen (TC, docetaxel and carboplatin) for HER2-positive early breast cancer. The pathological complete response (pCR) rate was 55.6% in the TCH + Py cohort, 32.7% in the TCH cohort, and 56.6% in the TCHP cohort. The pCR rate was higher with TCH + Py than with TCH. There was no significant difference in pCR rate between the TCH + Py and TCHP cohorts.(1) Background: The objective of our study was to provide evidence for choosing the optimal neoadjuvant therapy strategies for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Three neoadjuvant targeted therapy strategies (H + Py, trastuzumab plus pyrotinib; H, trastuzumab; HP, trastuzumab plus pertuzumab) based on the same chemotherapy regimen (TC, docetaxel and carboplatin) were included in the present study; (2) Methods: We retrospectively analyzed patients with HER2-positive breast cancer who were treated with neoadjuvant TCH + Py, TCH or TCHP, followed by surgery. The outcome was the pathological complete response (pCR) rate; (3) Results: In total, 545 patients were enrolled. The pCR rate was 55.6% (35/63) in the TCH + Py cohort, 32.7% (93/284) in the TCH cohort, and 56.6% (112/198) in the TCHP cohort. The multivariate analysis showed that patients who received TCH had less possibility to achieve pCR than those who received TCH + Py (odds ratio (OR) = 0.334, 95% confidence interval (CI): 0.181–0.619, p < 0.001), while patients who received TCHP had comparable possibility to those who received TCH + Py (OR = 1.043, 95%CI: 0.554–1.964, p = 0.896); (4) Conclusions: TCH + Py provides a better pCR rate compared with TCH, and a comparable pCR rate with TCHP among patients with HER2-positive breast cancer in the neoadjuvant setting. The present study supports a novel potential treatment option for these patients. Further studies need to be explored in the future.

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.

e12645 Background: Neural Precursor Cell Expressed Developmentally Downregulated Protein 9 (NEDD9) is a member of the associated substrate family. Our previous studies demonstrated the role of NEDD9 overexpression in early tumorigenesis in HER2-positive (HER2+) breast cancer in vivo. Tissue microarray-based analysis showed a strong correlation between NEDD9 mRNA and relapse-free survival (RFS) and pathologic complete response (pCR) rate in HER2+ breast cancers. In this study, NEDD9 expression in non-metastatic HER2+ breast cancer was evaluated by tissue microarray. Methods: A total of 64 patients with non-metastatic HER2+ cancer of the breast who had received neoadjuvant chemotherapy and had sufficient pathology specimens were included in the study. NEDD9 was stained by tissue microarray, and the expression was subclassified as low, intermediate, and high based on the NEDD9 expression score. The correlations of NEDD9 expression with the clinical/biological characteristics, treatment, and treatment response were analyzed by Fisher Exact test. Results: A total of 64 patients were included in the study, with a medium follow-up duration of 4.6 years. The median age was 54, 1 patient was male, 79.3% of patients had stage 2 disease, 1 patient had inflammatory breast cancer, and 37.5% of patients had ER/PR negative disease. The most common neoadjuvant chemotherapy regimen was TCHP (82.5%), 44.4% of patients underwent lumpectomy, and 67.7% of patients underwent axillary lymph node dissection (ALND). 54% of patients achieved complete pathologic response (pCR), all patients received adjuvant anti-HER2 treatment, 85.7% received adjuvant radiotherapy, and 74.6% received adjuvant endocrine therapy. The NEDD9 expression distribution for low, intermediate, and high were 37.5%, 50.0%, and 12.5%, respectively. NEDD9-high patients had higher tumor stage and grade than NEDD9-low/ intermediate patients (p = 0.004, p= 0.041). More NEDD9-high patients underwent ALND compared to NEDD9- low/intermediate patients (p = 0.09). There is no statistically significant difference in pCR rate between NEDD9 expression groups, although numerically more NEDD9-high patients achieved pCR (75%, 56.2%, and 43.5% in NEDD9-high, intermediate, and low patients). Conclusions: In non-metastatic HER2+ breast cancer, NEDD9 expression is associated with more advanced tumor grade and stage. There is no statistically significant difference in pCR rate between groups, although more patients achieved pCR with a higher level of NEDD9 expression. The sample size limits our study. Additional study is needed to evaluate the correlation between NEDD9 expression and pCR rate following neoadjuvant chemotherapy in HER2+ breast cancer.

Randomized Phase II Study of Primary Systemic Chemotherapy and Trastuzumab for Operable HER2 Positive Breast Cancer

Background Triple-negative breast cancer (TNBC) accounts for approximately 10-15% of breast cancers. Women with TNBC have worse survival outcomes, increased rates of relapse, and distant metastasis as compared to women with non-TNBC. Regardless of subtype, Black women have worse breast cancer outcomes than White women. Early stage treatment of TNBC has focused on neoadjuvant therapy (NACT) with a goal of achieving a pathologic complete response (pCR), which is associated with longer event-free survival and overall survival in TNBC patients. NACT with pembrolizumab was presented at the San Antonio Breast Cancer Symposium in December 2019 and FDA approved in July 2021. The Keynote-522 Trial found that patients who received NACT + pembrolizumab were more likely to achieve pCR than women who received NACT + placebo, regardless of stage. The KEYNOTE-522 trial did not examine race or age differences in treatment efficacy. Since TNBC disproportionately affects younger women and Black women, optimizing pCR rates in these groups is essential. Our objective is to examine racial differences in pCR rates by cancer stage and age among patients with TNBC who completed NACT/pembrolizumab. Methods Patient records from Ochsner Health, a regional network, were reviewed for those with early stage TNBC who had completed treatment with NACT/pembrolizumab from January 2020 to January 2022. Exclusion criteria included no surgical treatment for TNBC, unknown receptor status, and age &amp;lt; 18 years-old. Chi-square and Fisher’s Exact tests were used to examine the relationship between race and pCR stratified by stage at diagnosis and age. Risk ratios and 95% confidence intervals were also estimated to examine the strength of these relationships. Results We identified 92 patients with TNBC who completed treatment with NACT/pembrolizumab and underwent surgery. 52 patients (56%) were Black and 40 patients (43%) were White. 53.85% of Black patients had pCR and 67.50% of White patients experienced pCR (p=0.19). Among patients with stage III disease, only 37.50% of Black patients experienced pCR compared to 69.23% of White patients (p=0.09). Notably, Black patients were 46% less likely to experience pCR than = White patients (RR: 0.54, 95% CI: 0.28-1.02) in the stage III group. Among patients less than 50 years of age, 41.18% of Black patients experienced pCR compared to 84.21% of White patients (p=0.01), where younger Black patients were 51% less likely to experience pCR than younger White patients (RR: 0.49, 95% CI: 0.27-0.89) There were no observed racial differences in pCR rates for stage I/II patients (p=1.00) or patients aged 50 years or older (p=0.64). Discussion These data demonstrate that Black women are at a pCR rate disadvantage receiving NACT/pembrolizumab. This is primarily driven by advanced stage and young age. Black patients with stage III cancers had significantly lower pCR rates than their White counterparts after having received the same treatment. Additionally, young patients who are Black have significantly lower pCR rates. For older patients and those with stage I/II disease, there was no statistically significant difference in pCR rates between Black vs White race. Conclusion While NACT/pembrolizumab offers overall increased rates of pCR, Black women, especially those who are young or with more advanced disease at presentation, still have worse outcomes. Further research is needed to determine underlying predictors or alternative treatments to benefit these populations. Table 1 Distribution of Pathological Complete Response Following NACT/pembrolizumab treatment (Nf91) Table 2 Crude Risk Ratios for the Relationship between Race and Pathological Complete Response by Age and Stage (Nf92) Citation Format: Melanie Sheen, Caitlin Taylor, Rabia Cattie, Melyssa Bratton, Meredith Lakey, Victoria Chung, Erin Biggs. Impact of age and stage on pathologic complete response rates in Black vs White patients with triple negative 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 PO5-03-07.

606 Background: Metaplastic breast cancer (MpBC) is a rare aggressive histologic type of breast cancer that is often resistant to standard chemotherapy with pathologic complete response (pCR) rates ranging between 2-23%. PDL1 expression has been reported in up to 95% of primary MpBCs suggesting that response rates may be improved with addition of immune checkpoint blockade (ICB). Here we evaluate pCR rates (ypT0/is ypN0) in stage I-III MpBCs receiving neoadjuvant chemo-immunotherapy (NAT). Methods: The Memorial Sloan Kettering Cancer Center Rare Breast Cancer Program (CARE-4-RARE) is a new clinical and translational program dedicated to the study of rare breast cancers. Since the start of the program, 15 patients (pts) with early-stage MpBC have completed treatment with the neoadjuvant KEYNOTE-522 regimen. Wilcoxon rank-sum and Fisher’s exact tests were used to compare characteristics according to pCR status. All statistical tests used a significance level of 5%. Results: Median age at diagnosis was 50 (range, 43-60). All pts were female, 13% self-identified as Asians, 33% as Black and 53% as White. All tumors were poorly differentiated and of triple-negative phenotype, median tumor size was 3.2cm, 80% had stage II disease and 20% were clinically node positive. Metaplastic subtypes included 5 matrix-producing (33%), 3 spindle (20%), 4 squamous (27%), 3 mixed (20%). Of the 15 pts, 4 (27%) achieved a pCR, which suggest the possibility of a higher than expected pCR rate in MpBC with the addition of ICB to chemotherapy. We did not observe a significant difference in clinicopathological features between pCR vs. non-pCR groups. We observed numerical differences in pCR between MpBC subtypes though the p-value was not significant due to limited sample size. Of these 4 pts, 2 had matrix-producing and 2 had mixed subtypes. Two pts with pCR only received Cb+P+Pem. Three pts (20%) experienced PD (squamous n = 2, spindle n = 1) necessitating discontinuation of NAT and expediting surgery. Conclusions: This is the first prospective study to evaluate neoadjuvant ICB in MpBC. These data suggest the possibility of a higher than expected pCR rate in MpBC with the addition of ICB to chemotherapy (27%). This work suggests that neoadjuvant ICB should be considered in MpBC with close monitoring. Notably, 50% of reported pCR in this cohort were in pts who only received Cb+P+Pem. In spite of improved pCR rates, 20% of pts progressed during NAT highlighting the need for better treatment strategies in this treatment-refractory subset of MpBC and close monitoring to allow resection before progression to inoperability. The dichotomy in responses to ICB (super-responsive vs. super-refractory) may suggest the presence of unique biomarkers for immune response in MpBC. By the 2023 ASCO Annual Meeting a total of 26 pts will have completed NAT; we will report updated outcomes along with correlative immune biomarkers (sTIL, PDL1, TMB).

Background and Significance: Recently, the addition of the immune checkpoint-inhibitor PEM to CHT was shown to increase pCR rates and invasive event-free survival in the Keynote-522 (KN522) trial. Several irAEs are known to occur during use of PEM in various cancer entities. In our multicenter analysis we aimed to identify real-world occurrence rates of irAES and pCR rates in women receiving PEM and CHT, analogously to KN522, for eTNBC treatment. Methods: All patients receiving CHT + PEM for eTNBC treatment at participating centers were followed prospectively and monitored for occurrence of irAEs and neoadjuvant treatment outcome as defined by pCR from October 2020 until data cut-off on September 15th 2022. Only patients who underwent surgery for their primary tumor before data cut-off were included. Results: A total number of 22 patients with available pCR outcomes were included. All patients were female. Median age was 51 years (range 25-72). Mean tumor size at baseline was 29mm (range 10-75). 41% (9/22) of patients exhibited nodal involvement according to baseline radiological findings. Median MIB-1/Ki67 expression at biopsy was 70%. Patients received a median of 8 (range 1-8) neoadjuvant cycles of PEM and exhibited a median duration of CHT of 24 weeks (range 4-24). Neoadjuvant PEM was discontinued in 32% (7/22) of patients. Discontinuation of neoadjuvant treatment before week 18 occurred in 22,7% (5/22) of patients. We report irAE rates of any kind and all grades of 50% (11/22) and of grade 3-4 in 9% of patients (2/22). Steroids were administered in 7/11 patients experiencing irAEs (64%). 8 irAEs occurred during the neoadjuvant treatment phase, 3 during postneoadjuvant treatment with PEM. No grade 5 toxicity was observed. irAEs observed were hypothyroidism (n=3, all grade 2), arthritis (n=3, all grade 2), myocarditis (n=2, one grade 3/one grade 4), and single cases of hepatitis (grade 2), nephritis (grade 3) and pneumonitis (grade 1). 18% (4/22) of patients underwent mastectomy and 36% (8/22) of patients underwent axillary dissection. Lastly, upon definitive surgery of the primary tumor, we observed pCR in 50% (11/22) of cases. Patients who completed &amp;gt;18 weeks of neoadjuvant therapy exhibited a pCR rate of 59% (10/17), whilst patients who completed ≤18 weeks of neoadjuvant therapy reached pCR in 20% of cases (1/5). Conclusion: We report real-world prospective data about irAE as well as pCR rates during eTNBC treatment with PEM and CHT. irAEs occurred in similar rates as observed in KN522, although numerically higher for irAEs of all grades. The pCR rate within our cohort was numerically lower than reported for KN522, most probably due to a low pCR rate observed for 5 of 22 patients included in this analysis who completed ≤18 weeks of neoadjuvant treatment. Looking at our data, we hypothesize that clinical benefit from combination therapy of PEM and CHT depends on reaching an adequate duration of &amp;gt;18 weeks of neoadjuvant treatment. Citation Format: Maximilian Marhold, Simon Udovica, Kerstin Wimmer, Zsuzsanna Bago-Horvath, Tim Robinson, Florian Fitzal, Kathrin Strasser-Weippl, Rupert Bartsch. Immune-related adverse events (irAEs) and pathological complete response (pCR) rates in patients receiving neoadjuvant chemotherapy (CHT) and pembrolizumab (PEM) for early triple-negative breast cancer (eTNBC) [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 P3-06-10.

Background: Lymphocyte predominant breast cancers (LPBC) account for 5-30% of TNBCs; 65-80% of TNBCs have low/moderate levels of sTILs and 15-20% have no lymphocyte infiltration. TNBCs with high stromal tumor infiltrating lymphocytes (sTILs) have higher rates of pathological complete response (pCR) with anthracycline-taxane (AT) neoadjuvant chemotherapy (NACT), but the effect of carboplatin (Cb) is unclear. In GeparSixto, Cb increased pCR rates in LPBC but there was no interaction between LPBC and Cb in TNBCs. This study examines the predictive role of sTILs in TNBCs, focusing on the association between sTILs and pCR with and without Cb based NACT. Methods: Patients diagnosed with TNBC and treated with NACT in University Hospital Galway, Ireland from 2004-2016 were identified. Patients were treated with a carboplatin-anthracycline-taxane regimen (Cb-AT) (n=30) or an AT regimen (n=54). As per the International TILs Working Group, sTILs were scored on digitized slides of full-face tumor sections from diagnostic needle core biopsies. sTILs were categorized as 0-10%; 11-25%; 26-49%; ≥50% (LPBC). Odds ratio (OR) was calculated using non-pCR as the baseline. pCR was defined as ypT0/isN0. Results: Eighty-eight (n=88) cases with sufficient sTILs for analysis were identified. The median sTIL count was 12.5% (range 0-75%): 50% of cases (n=44) had sTILs 0-10%; 25% (n=22) had sTILs 11-25%; 14% (n=12) had sTILs 26-49% and 11% (n=10) had sTILs ≥50%. Cases with sTILs &amp;gt;10% had higher rates of pCR compared to those with sTILs ≤10% (52% vs 29%; p=0.021). In cases treated with an AT regimen, tumors with sTILs &amp;gt;10% had higher pCR rates than those with sTILs ≤10% (46% vs 12%; p=0.005). In cases treated with a Cb-AT regimen, there was no difference in pCR rates between sTILs &amp;gt;10% tumors and sTILs ≤10% tumors (60% vs 53%; p=0.500). In this cohort, pCR rates were higher in LPBC compared to non-LPBCs (80% vs 36%; p=0.010). In cases treated with AT, pCR rates were higher in LPBC than non-LPBC (83% vs 23%; p=0.007). However, in cases treated with Cb-AT, there were no differences in pCR rates between LPBC and non-LPBC (67% vs 56%; p=0.603). In LPBC, the choice of chemotherapy did not affect pCR rates: 67% vs 83% for Cb-AT and AT regimens respectively (p=0.583). In non-LPBC, pCR rates increased with Cb: 56% vs 23% for Cb-AT and AT regimens respectively (p=0.005). By univariate analysis, there was a significant association between sTILs and pCR. The association was greatest in LPBC (OR 0.14; p=0.016) and remained significant in those treated with AT (OR 0.06; p=0.014) but not in cases treated with Cb-AT (OR 0.63; p=0.714). In a multivariable model, with tumor grade and Cb use as co-variables, LPBC was independently associated with pCR (OR0.14; p=0.030). In cases treated with AT, sTILs were associated with pCR (OR 0.18, p=0.019 for sTILs &amp;gt;10%; OR 0.08, p=0.029 for LPBC). In cases treated with Cb-AT, sTILs were not associated with pCR (p=0.372 and p=0.622 for sTILs &amp;gt;10% and LPBC respectively). Conclusions: In TNBC, sTILs are predictive of response to NACT: as sTILs increase, pCR rates increase. The likelihood of a pCR increased by 86% for LPBC vs non-LPBC. The effect of sTILs on pCR was most notable in LPBC treated with AT based NACT where the odds of a pCR increased by 94%. In cases treated with Cb-AT, there was no association between sTILs and pCR. This study suggests that tumors with high sTILs are more chemosensitive than tumors with low sTILs. High sTIL tumors had high pCR rates with AT based NACT but the addition of Cb did not increase pCR rates. Cb-AT NACT could be reserved for patients with low sTIL tumors, in order to increase the rates of pCR in that subgroup, who had low rates of pCR in this study. In the future, sTILs could be used as a predictive biomarker to guide chemotherapy selection. Citation Format: Elaine M Walsh, Mark O'Loughlin, Aliaa Shalaby, Mark Webber, Michael J Kerin, Sharon A Glynn, Grace Callagy, Maccon M Keane. Pathological complete response after carboplatin-based neoadjuvant chemotherapy in triple negative breast cancer: The importance of stromal tumor infiltrating lymphocytes as a predictive biomarker [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 P1-10-11.

Preoperative chemotherapy (preopCT) is gaining importance in management of breast cancer, as it allows to avoid axillary clearance in responders. In case of axillary surgery the pathological complete response (pCR) of involved nodes is required to omit lymphadenectomy. Selecting the patients (pts) for axillary-sparing surgery is a challenging task, as currently it is reserved for N1 stage, but no more detailed criteria exist. FDG-PET/CT is a valuable tool to assess the extent of systemic disease in breast cancer before chemotherapy, used in stage III and selected stage IIB patients. The axillary nodal burden assessed in PET/CT could potentially affect the chances of pCR, and thus influence the decisions whether to clip the involved LNs and whether to proceed with either SNB or primary lymphadenectomy. The aim of the study was to assess the sensitivity of PET/CT to diagnose involved axillary LNs and to verify whether FDG-PET/CT axillary staging is associated with the rate of pathological complete response after preopCT. Material and Methods. The study group consisted of 287 pts with breast cancer with regional lymph node involvement, treated by preopCT, within the prospective trial analyzing the clinical and molecular predictors of response to preopCT, upon the approval of Ethics Committee at our Institution and after patients’ informed consent. Among them 16 (5.6%) had cT1 tumor, 131 (45.6%) T2, 69 (24.0%) T3 and 66 (23.0%) T4. Clinical nodal stage was N1 in 164 pts (57.1%), 94 (32.8%) had N2 and 29 (10.5%) N3 disease. 24 tumors were grade 1 (8.7%), 83 tumors grade 2 (30.1%) and the majority - 157 of tumors (56.9%) - grade 3. There were 81 pts (28.2%) with HER2-positive subtypes, 151 pts with luminal HER2-negative subtypes (52.6%) and 55 pts with TNBC (19.1%). 260 pts (90.6%) showed sufficient tumor regression to undergo surgery. Results. In 55 pts we observed pCR (21.6%), in 205 pts (78.9%) no pCR was found. When the regional lymph nodes were assessed by PET/CT pre-chemotherapy (data obtained in 259 pts, 90.2%), in 42 patients (16.2%) no uptake was found (despite positive thin-needle biopsy), in 65 pts (25.1%) there was uptake in single lymph node (LN), in 47 pts (18.1%) in two LN, and in 105 (40.5%) uptake was found in three or more LNs - thus, the vast majority (86%) exhibited uptake on PET/CT. Median of maximal SUV in lymph nodes was 4.9 (IQR 2.1-9.8), median of SUV in breast was 7.6 (IQR 4.4-12.0). In 160 patients (70.8%) SUVmax in LNs was lower than in breast (ratio&amp;lt;1), in 66 patients (29.2%) SUVmax in LNs was higher than in breast. Median of breast/axilla SUVmax ratio was 71.4% (IQR 38.1%-110.1%). pCR rate did not depend on regional nodal burden: in patients with cN1 disease, pCR rate was 21.8%, in cN2 19.8% and in cN3 22.2% (non-significant, n.s.). When number of nodes, as assessed by FDG PET was taken into account, pCR rate in pts with no uptake in LNs was 17,5%, in pts with uptake in 1-2 LNs pCR rate was 20.9% and in pts with 3 and more LNs pCR rate was 20.7% (n.s.). When the ratio of tumor/nodes SUVmax was analyzed, no difference in pCR rate between pts with ratio below 1 (22.2%) and above &amp;gt;=1 (16.4%; n.s.) was found. However, pCR rate was associated with biological tumor features: higher in G3 tumors, TNBC and HER2 subtypes, as well as in tumors with small diameter (data not shown). Conclusions. Patients with higher burden of regional lymph node involvement exhibit equal chance of pathological complete response as compared to low-volume/low-uptake individuals. The feasibility of limited surgery in higher stage regional nodal disease with pCR after chemotherapy shall be tested in prospective trials. The study was supported by the Polish National Center of Research and Development MILESTONE project - Molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant no. STRATEGMED 2/267398/4/NCBR/2015. Citation Format: Marcin Kubeczko, Andrea D'Amico, Anna Polakiewicz-Gilowska, Agnieszka Badora-Rybicka, Damian Borys, Izabela Gorczewska, Marco Di Pietro, Olgierd Chrabański, Wiesław Bal, Anna Michalik, Mateusz Raus, Agnieszka Pasierbek, Rafał Tarnawski, Barbara Bobek-Billewicz, Michał Jarząb. Association of nodal stage as assessed by FDG PET/CT with pathological complete response rate after preoperative chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-12.

Background The presence and extent of residual invasive cancer after neoadjuvant treatment (NACT) is a strong prognostic factor for risk of recurrence, especially in triple-negative (TN) and human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Recent advances in the standard-of-care NACT improved pathological complete response (pCR) rates in published clinical trials. We evaluated the pCR rates, defined as ypT0-is ypN0, in our real-world BC population and in estrogen receptor-positive [ER+] HER2-, HER2+ and TN subgroups and their association with tumour, patients' characteristics and disease-free survival (DFS). Methods We retrospectively identified early BC patients receiving NACT between January 2013 and December 2017. Demographics, patient and disease characteristics, pathological responses, toxicities, dose delays and reductions were recorded. Simple statistics, Fisher's exact test, chi-squared method and Cox regression were used as appropriate. Results 794 patients identified had median age of 50 years (range 24-87) and 93.9% (745 patients) ECOG performance status (PS) 0. 3.0% (24) had clinical stage I disease, 68.0% (540) stage II and 29.0% (230) stage III. 71.0% (564) had grade 3 disease and 91.8% (729) ductal histology. 33.7% (257) had ER+/HER2-, 25.8% (205) had TN and 38.0% (301) HER2+ disease. Overall, 6.8% (54) patients received platinum. 36.6% (291) patients had dose reductions and 24.3% (193) dose delays. Along with NACT, 51.6% (147) of the HER2+ patients received Trastuzumab and Pertuzumab and 48.4% (138) Trastuzumab alone. pCR rate was 33.1% in the overall population and significantly different in ER+/HER2-, HER2+ and TN subgroups (12.84% versus 52.0% versus 28.43% respectively, p&amp;lt;0.001). pCR was influenced by grade (1: 0%; 2: 24.3%; 3: 36.1%, p 0.005) and histology (ductal: 34.2%; lobular: 10.0%; mixed 25.0%; p 0.01). In the HER2+ subgroup, there was a trend for improved pCR rates for patients receiving Pertuzumab and Trastuzumab (57.0%) versus Trastuzumab alone (51.0%). No statistically significant differences were seen based on patients' characteristics including age and PS or in case of treatment dose reductions and delays. Early discontinuation of NACT was associated with lower pCR rates (20.5% vs 36.29%, p &amp;lt;0.001). Of interest, pCR rates remained consistent across the period 2013-2017 in the overall population. We observed a trend for improved pCR in the HER2+ (2013: 47.5%; 2014: 44.4%; 2015: 66.7%; 2016: 51.0%; 2017: 51.4%) and TN cohorts (2013: 23.5%; 2014: 25.0%; 2015: 25.0%; 2016: 33.3%; 2017: 34.1%) but not in the ER+/HER2- group. Median DFS was 83.8 months (95% CI 62.0-NR) in the overall population. Although not reached in the TN cohort, median DFS was different according to disease subgroups (HER2+: 83.78 months; TN: NR; ER+/HER2-: 62.0 months, p &amp;lt;0.0001). Conclusions In our analysis pCR rates are consistent with data published in literature and higher in HER2+ and TN disease. The impact of new agents had a relatively low impact on pCR rates in our overall population over the last 5 years, although they produced gradual improvements in the HER2+ and TN subgroups. Citation Format: Battisti NML, True V, Chaabouni N, Chopra N, Lee K, Shepherd S, Shapira-Rotenberg T, Joshi R, Mohammed K, Allen M, Ring A. Pathologic complete response rates following neoadjuvant systemic therapy in 794 patients with early breast cancer: The Royal Marsden experience [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-08.

Rationale. BRCA1 associated triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. At the same time, carcinomas that develop in carriers of BRCA1 mutations are characterized by extremely high sensitivity to DNA-damaging chemotherapy. Mitomycin C alone or in combination with platinum agents has already demonstrated promising results in the treatment of BRCA-associated ovarian cancer (OC) and metastatic breast cancer. In this article, we present the results of a retrospective study aimed at comparing standard neoadjuvant chemotherapy regimens (NACT) with mitomycin-based regimens for primary locally advanced BRCA1-associated TNBC.The aim of the study is to determine the effectiveness of the combination of mitomycin and platinum compounds during neoadjuvant therapy in patients with primary locally advanced BRCA1 – associated TNBC.Materials and methods. The study included 89 patients diagnosed with primary locally advanced BRCA1-associated TNBC. Patients were divided into three groups depending on the therapy: 1) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel (n = 48) (AC + T), 2) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel and carboplatin (n = 27) (AC + TCbP), 3) mitomycin C plus platinum followed by 12 weekly injections of paclitaxel (n = 14) (MR + T). Pathological complete response (pCR) rates were compared.Results. The pCR rate in the MP+T group was 10/14 (71%). In patients with BRCA1-associated breast cancer who received AC + T and AC + TCbP regimens as NACT, the pCR rate was 17/48 (35%) and 19/27 (70%), respectively. The difference in pCR rate between mitomycin-containing therapy and the standard AC + T regimen was statistically significant (p = 0.03); the frequency of regressions was comparable to the frequency in the AC + TCbP group. During the 20-month follow-up period, no relapses were observed in the MR + T group. Relapses were more frequent in the AC + T group compared with the AC + TCbP group (16/48 (33%) vs 1/27 (4%), p = 0.003, Fisher’s exact test). The toxicity profile of the mitomycin-containing regimen included hematologic adverse events, the most common of which were anemia and leukopenia. Compared to standard regimens, nausea was significantly less pronounced. No patients reported alopecia with this regimen.Conclusions. The addition of mitomycin C to neoadjuvant therapy for BRCA1-associated TNBC may be a promising treatment option for this category of patients and merits further study.

Abstract Title: Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Despite the significant improvement in pathological complete response (pCR) and event-free survival rates across all patients, the landmark trial included only 4.5% Black patients. It is essential to assess outcomes in representative treatment populations. We assessed real-world toxicity and treatment outcomes across Black and White patients who received standard-of-care treatment per KEYNOTE-522. Methods: In this retrospective, multicenter study, we examined patients with early-stage TNBC who received planned treatment per KEYNOTE-522 as standard-of-care (SOC) therapy. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment-related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: Of the 577 patients who initiated treatment with chemotherapy and immunotherapy, 534 patients were included in this analysis with 105 patients who self-identified as Black (19.7%) and 429 who self-identified as White (80.3%). There were no statistically significant differences in clinical and pathological characteristics between the two groups. White women were more likely to have grade 3+ immune-related adverse events (irAEs) compared to Black women (33.8% vs 20.9%, P=0.011). There was no significant difference across Black and White patients with respect to grade 3+ chemotherapy-related adverse events. Out of the 444 patients who have completed surgery, no difference in pCR rate was observed between Black and White women (45/86 52.3% vs 200/358 55.9%) (p = 0.6). The authors also saw no difference in the rates of hospitalizations between Black and White women (39% vs 36% p = 0.5), and rates of acute care utilization (38% vs 38% p = 0.9). Conclusions: We report safety and efficacy across Black and White women in a real-world analysis of patients who received treatment per KEYNOTE-522. Notably, White patients had a significantly higher frequency of grade 3+ irAEs, although the reason for this finding is unclear based on this analysis. Black patients had similar pCR rates and rates of treatment-related hospitalizations compared to White patients. Assessment of outcomes and toxicity by race in clinical trials and real-world analyses are critical in drug development. Citation Format: Mara Hofherr, Andrew Davis, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Wiliam Adler, Traci White, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Katherine Clifton. Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 [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 PS14-02.

BackgroundNeoadjuvant chemotherapy with dual-targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)-positive breast cancer. Although the dual-targeted therapy has significantly improved the pathological complete response (pCR) rate, further investigation is needed to identify biomarkers that predict the response to neoadjuvant therapy.MethodsThis retrospective study analyzed 353 patients with HER2-positive breast invasive ductal carcinoma. The correlation between clinicopathological factors and pCR rate was evaluated. A nomogram was constructed based on the results of the multivariate logistic regression analysis to predict the probability of pCR.ResultsThe breast pCR (b-pCR) rate was 56.1% (198/353) and the total pCR (t-pCR) rate was 52.7% (186/353). Multivariate analysis identified ER status, PR status, HER2 status, Ki-67 index, and neoadjuvant chemotherapy regimens as independent indicators for both b-pCR and t-pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.73 (95% CI: 0.68–0.78). According to the nomogram, the t- pCR rate was highest in the ER-PR- HER2-positive patients (131/208) and lowest in the ER + PR + HER2-positive patients (19/73). The subgroup analyses showed that there was no significant difference in pCR rate among the neoadjuvant chemotherapy regimens in ER positive, PR positive, HER2 IHC 2 + , Ki67 index < 30% population. However, for ER-PR-HER2-positive patients, the neoadjuvant chemotherapy regimen has a great influence on the pCR rates.ConclusionsPatients with ER-negative, PR-negative, HER2 3 + and high KI-67 index were more likely to achieve pCR. THP may be used as an alternative to AC-THP or TCbHP in selected HER2-positive patients.