Hormone Receptor-negative Disease Research Articles

Alteration of the Tumor Microenvironment With Intratumoral Dendritic Cells Before Chemotherapy in ERBB2 Breast Cancer

Current chemotherapy regimens for patients with ERBB2 (formerly HER2)-positive breast cancer are associated with considerable morbidity. These patients may benefit from more effective and less toxic therapies. To evaluate the safety, immunogenicity, and preliminary efficacy of intratumoral (IT) delivery of conventional type 1 dendritic cells (cDC1) in combination with ERBB2-targeted therapies. This phase 1 (lead-in phase of a single-center phase 2 trial) nonrandomized clinical trial was conducted at Moffitt Cancer Center (Tampa, Florida). Patients were enrolled from October 2021 to October 2022. Data were analyzed in 2023 Patients with early-stage ERBB2-positive breast cancer with tumors 1 cm or larger were eligible. Treatment included IT delivery of cDC1, 6 times weekly, followed by paclitaxel, 80 mg/m2, intravenously, 12 times weekly. Trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) were administered intravenously every 3 weeks for 6 cycles starting from day 1 of cDC1 injections. Two dose levels (DLs) of IT cDC1 (DL1 = 50 million and DL2 = 100 million cells) were evaluated, including 6 patients in each DL. The primary outcomes were the safety and immune response, and the secondary outcomes were the antitumor efficacy as measured by breast magnetic resonance imaging and residual cancer burden at surgery following neoadjuvant therapy. Twelve ERBB2-positive patients were enrolled and received treatment (DL1 = 6 and DL2 = 6). Nine patients had hormone receptor-positive disease and 3 had hormone receptor-negative disease, with clinical stage I (n = 5), II (n = 4), and III (n = 3). The most frequently observed adverse events with cDC1 were grade 1 to 2 chills (50%), fatigue (41.7%), headache (33%), and injection site reactions (33%). DL2 was associated with a diminished anti-ERBB2 CD4 T-helper 1 blood response with a concomitant increase in innate and adaptive responses within the tumor. Preimmunotherapy and postimmunotherapy breast magnetic resonance imaging results showed 9 objective responses, 6 partial responses, 3 complete responses, and 3 stable diseases. Following surgery, 7 patients had a pathologic complete response. In this nonrandomized clinical trial, the addition of IT cDC1 and trastuzumab/pertuzumab before neoadjuvant chemotherapy was well tolerated with manageable adverse effects. Based on safety and immunogenicity, DL2 was selected for the phase 2 dose. ClinicalTrials.gov Identifier: NCT05325632.

Impact of hormone receptor status and tumor subtypes of breast cancer in young BRCA carriers

Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

Impact of hormone receptor status and tumor subtypes on clinical behavior and outcomes of breast cancer in young BRCA carriers.

504 Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer (BC). Among young patients harboring germline BRCA1or BRCA2 (BRCA) pathogenic variants (PVs), most of the tumors arising in BRCA2carriers express hormone receptors, while most BC cases in BRCA1 carriers do not; however, limited evidence exists on the impact of hormone receptor status on clinical behavior and outcomes in young patients harboring BRCA PVs. Methods: This is an international, multicenter, hospital-based, retrospective cohort study including young patients (≤40 years) diagnosed with invasive BC between January 2000 and December 2020, harboring germline PVs in BRCA genes. Our analysis investigates the impact of hormone receptor status on clinical behavior and outcomes of BC. The type and pattern of recurrence and survival outcomes (disease-free survival [DFS], BC specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to BC subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive BC). Results: From 78 centers worldwide, 4,709 BRCA carriers were included in this analysis, of whom 2,143 (45.5%) had hormone receptor-positive and 2,566 (54.5%) hormone receptor-negative BC. Patients with hormone receptor-positive BC were more likely to harbor BRCA2 PVs while less frequently had grade 3 tumors and nodal involvement. Median follow-up was 7.88 (IQR 4.47-12.61) years. The rate of distant recurrences was higher in patients with hormone receptor-positive BC (13.1% vs. 9.6%, p&lt;.001), while the rate of second primary BC was lower (9.1% vs. 14.7%, p&lt;.001) when compared to patients with hormone receptor-negative disease. The 8-years DFS was 65.8% in patients with hormone receptor-positive and 63.4% in those with hormone receptor-negative BC. No differences in terms of OS nor BCSS were observed. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p&lt;.05 for interactions of hormone receptor status and survival time). Among the 4,363 patients eligible for subtypes analysis, 612 had luminal A-like, 1,038 luminal B-like, 2,373 triple-negative and 340 HER2-positive BC. Patients with Luminal A-like BC had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60.8% in luminal A-like vs. 63.5% in triple-negative vs. 65.5% in HER2-positive and 69.7% in luminal B-like subtype). Conclusions: In young BRCAPVs carriers with early BC, hormone receptor status did not appear to be a positive prognostic factor. The differences in pattern of recurrence and second primary BC among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up strategies and indication for risk-reducing surgery.

Abstract PS18-10: Tumor-Infiltrating Lymphocytes and Breast Cancer Mortality in Racially and Ethnically Diverse Participants of the Northern California Breast Cancer Family Registry

Abstract Purpose: Greater stromal tumor-infiltrating lymphocyte (sTIL) percentage in pre-treatment breast tumor specimens is associated with superior response to neoadjuvant chemotherapy and survival. We hypothesized that sTIL-survival associations vary by race and ethnicity and mediate survival disparities. Patients and Methods: We evaluated pre-treatment percentages of sTILs in deciles for 284 women enrolled in the Northern California Breast Cancer Family Registry and diagnosed with a first primary invasive breast cancer from 1995-2005. We assessed associations of continuous sTIL scores and lymphocyte-predominant breast cancer (LPBC, defined as ≥50% lymphocytic infiltration of tumor stroma or cell nests) with clinical and epidemiologic characteristics using regression analysis and with breast cancer-specific mortality (BCM) and overall mortality (OM) using Cox proportional hazards regression. Results: The cohort was diverse (64% from racially and ethnically minoritized populations) with near-complete (98%) germline BRCA1/2 testing and long-term follow-up (average 16.2 years, range: 1.3-26.7). In multivariable analyses, higher sTIL score was associated with reduced BCM [LPBC versus non-LPBC: HR=0.44 (95% confidence interval 0.20-0.98); and per decile increase in sTIL score: HR=0.80 (0.69-0.93)], with the strongest association in the subset of patients with hormone receptor-negative disease [HR=0.71 (0.57-0.88) and HR=0.37 (0.14-0.94), respectively]. While there was no significant difference in sTIL score between racial and ethnic groups, the continuous sTIL-survival association was statistically significant among non-Hispanic White [HR=0.73 (0.57-0.94)] and Asian American [HR=0.56 (0.35-0.89)] women but was not seen among African American and Hispanic women. Conclusion: We identified novel sTIL-BCM differences by race and ethnicity, with better survival associated with sTIL enrichment among non-Hispanic White and Asian American but not among African American or Hispanic women. Additional studies are needed to determine whether survival and particularly the response to immunotherapy are differentially mediated by immune factors between racial and ethnic groups. Multivariable Cox Proportional Hazards Regression Models of Breast Cancer-Specific and Overall Mortality. Citation Format: Julia Ransohoff, Iain Miller, Jocelym Koo, Vishal Joshi, Allison Kurian, Kimberly Allison, Esther John, Melinda Telli. Tumor-Infiltrating Lymphocytes and Breast Cancer Mortality in Racially and Ethnically Diverse Participants of the Northern California Breast Cancer Family Registry [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 PS18-10.

Abstract PO3-20-01: ASTEFANIA: a Phase III study of ado-trastuzumab emtansine plus atezolizumab or placebo as adjuvant therapy in patients with residual invasive breast cancer after neoadjuvant HER2-targeted therapy and chemotherapy

Abstract BACKGROUND Ado-trastuzumab emtansine (T-DM1) is the standard of care for adjuvant treatment of patients (pts) with HER2-positive early breast cancer (eBC) who have invasive residual disease after preoperative treatment with taxane and HER2-targeted therapy. However, a high unmet need remains in some higher risk subgroups (e.g., inoperable or lymph node-positive, hormone receptor-negative disease) who have 3-year invasive disease-free survival (IDFS) rates of 76%. Exploratory analyses suggest that addition of the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab to T-DM1 results in longer progression-free survival compared with T-DM1 alone in pts with previously treated PD-L1-positive metastatic BC. PD-L1/programmed death-1 inhibitors may have a different effect in eBC, as they result in improved pathologic complete response in early triple-negative BC regardless of PD-L1 status. ASTEFANIA evaluates atezolizumab plus T-DM1 in PD-L1-unselected pts with higher risk residual invasive breast cancer after neoadjuvant treatment. TRIAL DESIGN ASTEFANIA is a Phase III, randomized, double-blind, multicenter, study in pts with centrally confirmed HER2-positive eBC with residual invasive disease at surgery after neoadjuvant chemotherapy and HER2-directed treatment including ≥9 weeks of taxane and ≥9 weeks of trastuzumab. Within 12 weeks of primary surgery, pts are randomized 1:1 to intravenous (IV) T-DM1 3.6 mg/kg every 3 weeks (q3w) plus atezolizumab 1200 mg IV q3w or T-DM1 3.6 mg/kg IV q3w plus placebo IV q3w for 14 cycles. Radiotherapy and/or endocrine therapy is administered per local standards. Randomization is stratified by clinical stage at presentation, hormone receptor status, preoperative HER2-directed therapy, and PD-L1 status. ELIGIBILITY CRITERIA Eligible pts have clinical stage cT4/any N/M0, any cT/N2–3/M0, or cT1–3/N0–1/M0 at presentation. Those with cT1–3/N0–1 disease must have pathologic evidence of residual invasive carcinoma in axillary lymph node(s) at surgery. Pts with cT1mi/T1a/T1b/N0 disease are not eligible. AIMS The primary endpoint is IDFS. Secondary endpoints include overall survival, safety, and patient-reported outcomes. STATISTICAL METHODS The log-rank test will be used to compare IDFS between the treatment arms, according to the protocol-defined stratification factors. The Cox proportional hazards model, stratified by the protocol-defined stratification factors, will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. ACCRUAL As of Jun 28, 2023, 789 pts of the target of 1,700 have been enrolled. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT04873362. Originally presented at the ESMO Congress 2021, 202TiP, Peter Schmid et al. – Reused with permission. Further information is available in Future Oncology 2022; 18:3563–3572. Submitted with permission from Future Medicine &amp; Future Science, part of the Future Science Group. Citation Format: Peter Schmid, Thomas Bachelot, Giampaolo Bianchini, Nadia Harbeck, Sherene Loi, Yeon Park, Aleix Prat, Leslie Gilham, Thomas Boulet, Nino Gochitashvili, Estefania Monturus, Chiara Lambertini, Beatrice Nyawira, Adam Knott, Sara Hurvitz. ASTEFANIA: a Phase III study of ado-trastuzumab emtansine plus atezolizumab or placebo as adjuvant therapy in patients with residual invasive breast cancer after neoadjuvant HER2-targeted therapy and chemotherapy [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 PO3-20-01.

Abstract PO3-16-09: Real-World Experience with Trastuzumab Deruxtecan at a Diverse NCI Comprehensive Cancer Center

Abstract Background: Trastuzumab Deruxtecan (T-DXd) is an antibody-drug conjugate originally approved for use in patients with HER2–positive metastatic breast cancer (MBC). In June 2022, data from the DESTINY-Breast04 trial revealed a near-doubling of progression-free survival (PFS) and significantly improved overall survival (OS) for patients with HER2-low MBC (immunohistochemistry [IHC] grade 1+ or IHC2+ in situ hybridization [ISH]-negative) treated with T-DXd versus standard-of-care chemotherapy. The data from this clinical trial led to the approval of T-DXd for use in patients with HER2-low MBC. However, the DESTINY-Breast studies completed to date have included &amp;lt; 5% black patients. This retrospective study of patients at a racially diverse NCI Comprehensive Cancer Center was designed to study whether T-DXd in a real-world population are comparable to published data. Methods: A retrospective chart review was conducted and identified 72 patients with HER2-low and HER2-positive MBC who received T-DXd between December 2019 and March 2023 at the Winship Cancer Institute at Emory University. Data collected for all patients included demographics, prior breast cancer history, T-DXd -specific and post-T-DXd treatment, and clinical outcomes where applicable. Results: Of the 103 patients who were dosed with T-DXd, 55 (53.4%) had HER2-positive disease, and 48 (46.7%) patients had HER2-low disease. 71 (68.9%) patients had hormone-receptor positive disease and 32 (31.1%) patients had hormone-receptor negative disease. The overall study population was 46% Caucasian; 38% African American; 13% Asian; 4% Unreported. The average number of cycles received was 11 (on treatment an average of 8 months). Pneumonitis occurred in 5 patients (4.9%). HER2-positive patients were typically on T-Dxd for a greater number of cycles than HER2-low patients (Table 1). Additionally, patients with brain metastases were, on average, treated with T-Dxd longer than patients without brain metastases, 14.5 versus 9 cycles. The number of cycles of T-Dxd received, the need for dose reduction, and incidence pneumonitis did not differ significantly between black and white patients. The data for this study is preliminary 48% of the patient population are still actively undergoing T-Dxd treatment. Conclusion: This study reviewed and analyzed T-Dxd treatment in a diverse population of both HER2-positive and HER2-low MBC patients, and in this study, outcomes of treatment did not differ by race. More attention to this topic is needed in future studies of larger populations, along with increased efforts to enroll diverse patient populations in clinical trials. Table 1. Citation Format: Jane Meisel, Maisey Ratcliffe. Real-World Experience with Trastuzumab Deruxtecan at a Diverse NCI Comprehensive Cancer Center [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 PO3-16-09.

Abstract PO4-03-03: Conditional Use of Serial Serum Tumor Markers CA 15.3 and CEA as Predictors of Disease Relapse in Patients with High-Risk Early-Stage Breast Cancer

Abstract Background: Because of the diagnosis at an earlier stage, and the wider availability of more effective therapies, treatment outcomes of patients with breast cancer are getting much better resulting in an increasing proportion of patients surviving their disease, however, a significant percentage of patients with early-stage disease at initial diagnosis may eventually relapse. Residual tumor cells can remain dormant for many years before causing tumor recurrence. Physical examination and mammography are strongly recommended in surveillance guidelines, but data on routine blood tests or imaging is lacking. The revolution made in recent years, following the approval of novel targeted and immunotherapy agents, may have better outcome if started earlier in the disease course with the lowest tumor burden and in patients with good performance status and adequate organs’ function. Additionally, early detection of oligometastatic disease can give a chance for cure for a subset of these patients. Levels of CA15.3 and CEA are used in decision making in the metastatic setting but their role in surveillance is still controversial. We aim to investigate whether serial measurement of tumor markers, when it correlates with tumor bulk (conditional), can detect early asymptomatic recurrence among subset of patients with high-risk early-stage breast cancer. Methods: Patients with high-risk early-stage breast cancer were invited to participate. High-risk features include any of the following: large tumor size (T3/4), grade-3, node-positive, triple-negative, HER2-positive or hormone receptor (HR)-negative disease. Patients were considered eligible if they have elevated CA15.3 and/or CEA at baseline, that subsequently normalize 6 weeks after surgical resection; upfront or following neoadjuvant chemotherapy. Serial testing of the elevated CA15.3 and/or CEA is done every 2 months thereafter, samples are cryopreserved and will not be processed until disease relapse. As such results will not be used for clinical decisions. The study is still ongoing, we here present an interim analysis evaluating the correlation between certain tumor characteristics and elevated serum marker(s) levels. Results: Since the launch of the study, 367 patients deemed high-risk by the above criteria, accepted to participate. Abnormal baseline CA15.3 and/or CEA was found in 110 (30%); 65 (18%) patients had elevated CA 15.3 while elevated CEA was found in 45 (12%) patients. Abnormal CA 15.3 was found in 27% of cases with T3/4 disease compared with 13% in T1/2 disease (p=0.001), and in 21% of node positive disease versus 7% in node negative disease (p=0.002), in 9% of HR negative disease versus 20% in HR-positive (P=0.038). Tumor grade and HER2 status were not associated with significant difference. Regarding CEA, abnormal levels were detected in 24% of HER2-positive disease compared to 5% of HER2-negative disease (P&amp;lt; 0.0001). Other tumor features were not associated with significant difference. Conclusions: Only a third of patients with high-risk early-stage breast cancer had high level of serum tumor markers at initial diagnosis and thus such markers may correlate with tumor presence. Large tumors (T3/4) and node positive disease were associated with high CA15.3 but not CEA. HER2-stutus and tumor grade had no effect on CA15.3 level, while HER2 positive disease correlated well with high CEA. Citation Format: Sarah Edaily, Baha' Sharaf, Maher Sughayer, Lina Yousef, Hala Abu-Fares, Sarah Abdel-Razeq, Hala Abu-Jaish, Mahmoud Abunasser, Suhaib Khater, Anas Zayed, Osama El Khatib, Rahaf Rahal, Hazem Abdulelah, Maria Shraim, Hikmat Abdel-Razeq. Conditional Use of Serial Serum Tumor Markers CA 15.3 and CEA as Predictors of Disease Relapse in Patients with High-Risk Early-Stage 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 PO4-03-03.

Pathologic Complete Response and Individual Patient Prognosis After Neoadjuvant Chemotherapy Plus Anti–Human Epidermal Growth Factor Receptor 2 Therapy of Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer

The achievement of pathologic complete response (pCR) is strongly prognostic for event-free survival (EFS) and overall survival (OS) in patients with early breast cancer (EBC), and adapting postneoadjuvant therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR. We sought to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. We used individual data from 3,710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive EBC with ≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone receptor-positive versus hormone receptor-negative disease, and for patients who had pCR (pCR+; ypT0/is, ypN0) versus patients who did not achieve a pCR (pCR-). The median follow-up overall was 61.2 months. In pCR+ patients, cT and cN were significant independent prognostic factors for EFS, whereas only cT was a significant predictor for OS. In pCR- patients, cT, cN, and hormone receptor status were significant independent predictors for both EFS and OS. Regardless of hormone receptor status, cT, and cN, the 5-year EFS/OS rates were higher in pCR+ patients than in pCR- patients. In most subsets with regards to hormone receptor and pCR status, cT and cN were independent prognostic factors for both EFS and OS, including pCR+ patients. These results confirm that patients achieving pCR have far better survival outcomes than patients who do not. The traditional poor prognostic features, namely tumor size and nodal status, remain important even after a pCR.

Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2-Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti-Human Epidermal Growth Factor Receptor 2 Therapy.

Pathologic complete response (pCR) has prognostic importance and is frequently used as a primary end point, but doubts remain about its validity as a surrogate for event-free survival (EFS) and overall survival (OS) in human epidermal growth factor receptor 2 (HER2)-positive, early breast cancer. We obtained individual-patient data from randomized trials of neoadjuvant anti-HER2 therapy that enrolled at least 100 patients, had data for pCR, EFS, and OS, and a median follow-up of at least 3 years. We quantified the patient-level association between pCR (defined as ypT0/Tis ypN0) and both EFS and OS using odds ratios (ORs, with ORs >1.00 indicating a benefit from achieving a pCR). We quantified the trial-level association between treatment effects on pCR and on EFS and OS using R2 (with values above 0.75 considered as indicating strong associations). Eleven of 15 eligible trials had data for analysis (3,980 patients, with a median follow-up of 62 months). Considering all trials, we found strong patient-level associations, with ORs of 2.64 (95% CI, 2.20 to 3.07) for EFS and 3.15 (95% CI, 2.38 to 3.91) for OS; however, trial-level associations were weak, with an unadjusted R2 of 0.23 (95% CI, 0 to 0.66) for EFS and 0.02 (95% CI, 0 to 0.17) for OS. We found qualitatively similar results when grouping trials according to different clinical questions, when analyzing only patients with hormone receptor-negative disease, and when using a more stringent definition of pCR (ypT0 ypN0). Although pCR may be useful for patient management, it cannot be considered as a surrogate for EFS or OS in neoadjuvant trials of HER2-positive, operable breast cancer.

Abstract P2-01-07: Combination of pyrotinib with trastuzumab, taxanes and platinum as neoadjuvant therapy in patients with HER2-positive early or locally advanced breast cancer: a multicenter phase II trial

Abstract Background: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine have shown clinically and statistically meaningful progression-free survival and overall survival benefits with acceptable tolerability in patients with HER2-positive metastatic breast cancer in phase 3 trials. In this study, we assessed the efficacy and safety of neoadjuvant pyrotinib plus trastuzumab, taxanes and platinum in women with HER2-positive early or locally advanced breast cancer. Methods: In this multicenter, single-arm, phase II trial (ChiCTR2000039286), treatment-naive patients with early or locally advanced (T2-3, N0-3, M0) breast cancer received pyrotinib 400 mg once daily, plus trastuzumab (8 mg/kg loading dose and 6 mg/kg maintenance dose), docetaxel (75 mg/m2) or nab-paclitaxel (125 mg/m2), and carboplatin (AUC=5-7) on day 1 of each 21-day cycle for 6 cycles before surgery. All patients also received 1-year adjuvant pyrotinib combined with trastuzumab after surgery. The primary endpoint of the study was total pathological complete response (tpCR, ypT0/is ypN0) rate. The secondary endpoints were breast pathological complete response (bpCR) rate, objective response rate, adverse events (AEs) and invasive disease-free survival. Results: Between October 2020 and March 2022, a total of 35 patients were enrolled from 7 sites. By the data cut-off date on June 29, 2022, two patients withdrew from the study, and one received other anti-tumor therapies. Thirty-two patients received neoadjuvant therapy and surgery (modified intention-to-treat [mITT] population), and 30 of whom completed the 6-cycle neoadjuvant therapy (per-protocol [PP] population). The local pathologist-assessed tpCR rate was 59.4% (19/32) and 60.0% (18/30) in the mITT and PP populations, and bpCR rate was 65.6% (21/32) and 66.7% (20/30) in the mITT and PP populations, respectively. The tpCR rate was 68.8% (11/16) among patients with hormone receptor-negative disease and 50.0% (8/16) among those with hormone receptor-positive disease in the mITT population. Of 30 patients with preoperative imaging assessments, 26 (86.7%) achieved an objective response. Treatment-related AEs (TRAEs) were reported in 34 (97.1%) of 35 patients, with the most common being diarrhea (82.9%) and platelet decreased (48.6%). The most common grade ≥3 TRAEs were diarrhea (25.7%), platelet decreased (8.6%), neutropenia (8.6%), vomiting (5.7%), and alanine aminotransferase increased (5.7%). No grade 4 or 5 diarrhea events occurred. Conclusions: This study showed similar efficacy with previous reports, neoadjuvant pyrotinib plus trastuzumab-based chemotherapy exhibits promising efficacy and manageable toxicity in patients with HER2-positive early or locally advanced breast cancer. Citation Format: Hao Zhou, Lei Wang, Lei Wang, Zhaoji Guo. Combination of pyrotinib with trastuzumab, taxanes and platinum as neoadjuvant therapy in patients with HER2-positive early or locally advanced breast cancer: a multicenter phase II trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-01-07.

Abstract P1-04-05: Independent validation of the HER2DX genomic test in HER2-positive breast cancer treated with neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP): a correlative analysis from the DAPHNe phase II clinical trial

Abstract Background: HER2DX is a 27-gene prognostic (risk-score) and predictive (pathological complete response [pCR]-score) assay in early-stage HER2+ breast cancer (BC) based on clinical data and the expression of 4 gene signatures (immune, proliferation, luminal differentiation, and HER2 amplicon). Here we aim to evaluate, for the first time, the ability of HER2DX to predict pCR following neoadjuvant THP in HER2+ BC. Methods: Standardized HER2DX was evaluated centrally on baseline pre-treatment FFPE tumor biopsies from the DAPHNe phase II trial (Waks et al. NPJ Breast 2022; NCT03716180), in which patients (pts) with newly diagnosed stage II-III HER2+ BC were treated with neoadjuvant weekly paclitaxel × 12 and HP every 3 weeks × 4. Primary aim was to test the ability of HER2DX pCR-score to predict pCR (ypT0/isN0). Secondary objectives were to test the ability of HER2DX pCR-score to predict pCR independent of clinical-pathological variables and PAM50 subtype (HER2-enriched vs not) and to evaluate the association of HER2DX pCR-score with HER2DX risk-score. Five patients who received additional neoadjuvant chemotherapy after THP were excluded from this analysis. Logistic regression and receiver-operator curve (ROC) analysis were assessed. Statistical analyses were performed in R code 4.0.5. Results: HER2DX was evaluated in 80 of 97 pts (82.5%) enrolled in the DAPHNe trial who received study treatment. Clinical T2-4 disease represented 81.3% of cases (n=65), clinical node-negative disease (cN0) represented 65.0% of cases (n=52), and 70.0% of tumors (n=56) were hormone receptor-positive. The overall pCR rate was 60.0% (95% confidence interval [CI] 49.3-70.7): 87.0% (95% CI 79.6-94.4) in hormone receptor-negative disease and 48.2% (95% CI 37.2-59.1) in hormone receptor-positive disease. The proportion of HER2DX low-, medium- and high-pCR groups was 38.8%, 27.5% and 33.7%, respectively. HER2DX pCR-score (as a continuous variable from 0 to 100) was significantly associated with pCR (odds ratio [OR]=1.05, p&amp;lt; 0.0001). In the overall population, the pCR rates in HER2DX pCR-high, pCR-med and pCR-low groups were 92.6%, 63.6% and 29.0% (pCR-high vs pCR-low OR=30.6, p&amp;lt; 0.0001), respectively. The AUC ROC of HER2DX pCR score (as a continuous variable) and pCR status was 0.835. In the ER-negative population, the pCR rates in HER2DX pCR-high, pCR-med and pCR-low groups were 94.7%, 66.7%, and 0%, respectively (Table 1). HER2DX pCR-score was significantly associated with pCR independent of hormone receptor status, HER2 immunohistochemistry (IHC) score, clinical stage, and PAM50 HER2-enriched subtype. The correlation between HER2DX pCR-score and HER2DX risk-score was weak (Pearson coefficient=-0.12), as previously described (Prat et al. EBiomedicine 2022). 51.3% of patients were categorized as HER2DX low-risk. Conclusion: The 27-gene HER2DX genomic test predicts pCR following neoadjuvant THP in newly diagnosed stage II-III HER2+ BC. Patients with HER2DX pCR-low score and HER2DX high-risk score, representing 22.5% of pts, warrant further attention in order to optimize therapeutic strategies in this subset. The combination of HER2DX pCR-score and risk-score might guide therapeutic decisions by identifying patients who are ideal candidates for de-escalated or escalated systemic and locoregional treatments. Table 1 Citation Format: Adrienne Waks, Esther R. Ogayo, Laia Paré, Mercedes Marín-Aguilera, Fara Brasó-Maristany, Patricia Galván, Oleguer Castillo, Olga Martínez-Sáez, Ana Vivancos, Patricia Villagrasa, Paolo Tarantino, Neelam Desai, Jennifer Guerriero, Otto Metzger, Nadine Tung, Ian Krop, Joel S Parker, Charles M. Perou, Aleix Prat, Eric Winer, Sara Tolaney, Elizabeth A. Mittendorf. Independent validation of the HER2DX genomic test in HER2-positive breast cancer treated with neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP): a correlative analysis from the DAPHNe phase II clinical trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-05.

Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm.

The results of the Phase III DESTINY-Breast04 trial of trastuzumab deruxtecan (T-DXd) are leading to a shift in both the classification and treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. In this trial, T-DXd was associated with a substantial survival benefit among patients with hormone receptor-positive and hormone receptor-negative disease and low expression of HER2, a biomarker previously considered unactionable in this treatment setting. Herein, we discuss the evolving therapeutic pathway for HER2-low disease, ongoing clinical trials, and the potential challenges and evidence gaps arising with treatment of this patient population.

Measuring geographic variation in quality and equity of breast cancer care.

139 Background: Persistent higher breast cancer mortality among Black Americans is partly due to treatment disparities. There is a paucity of surveillance data quantifying racial disparities at local levels, and the relationship of geography to racial disparities in treatment is poorly understood. We sought to develop and apply a claims-based set of breast cancer quality measures, stratified by race, across regions of North Carolina. Methods: We created a retrospective cohort (n = 37,021) of stage I-III breast cancers from 2004-2017 using linked cancer registry and multi-payer claims data. We assessed 4 quality measures derived from ASCO/NCCN and Commission on Cancer including chemotherapy (CT) for hormone receptor negative disease, radiation (RT) after breast conserving surgery (BCS), RT for N2-3 disease, and adjuvant endocrine therapy (ET). Each measure was limited to the ages and tumor features eligible by the ASCO/NCCN/CoC guideline. We estimated age-adjusted overall performance (%) on each measure, and the Black-White gap, at the state level and across 9 geographic sub-regions. We used multivariable Poisson regression to estimate Risk Ratios (RR) comparing quality performance for Black vs. White patients overall and across regions. Exploratory analyses adjusted for patient- and neighborhood-level social determinants of health (SDOH). Results: Median age of the cohort was 68 years and 19% of patients were Black. At the state level, the % of eligible patients meeting quality measures ranged from 73% for adjuvant ET to 95% for RT after BCS. There was significant inter-region variation on all 4 measures. Black patients were less likely to receive adjuvant CT (RR = 0.92, CI 0.87-0.96), post-BCS RT (RR = 0.98, CI 0.97-0.99) and ET (RR = 0.95, CI 0.93-0.98). There was no racial disparity in RT for N2-3 disease. Both overall performance and the magnitude of disparity varied widely across regions and geographic patterns were not consistent across measures. For example, the Charlotte region had the top quality performance for RT for N+ (90%), but worst for ET (70%). Similarly, the Wake region had no racial disparities in CT or RT, but the largest disparity of any region for ET (RR = 0.90, CI 0.84-0.96). Adjustment for SDOH modestly attenuated the relationship between race and quality performance, but significant disparities persisted in the regions with the largest racial gaps. Conclusions: Racial disparities persist in breast cancer care delivery, but with non-uniformity of performance across measures and varying local patterns of disparities. Our findings suggest that cross-cutting interventions spanning the care continuum, and/or interventions adapted to local challenges, may be needed to effectively address racial disparities. The contributions of local resources, structural, and institutional barriers to these patterns remain to be explored. Community-engaged work to share and interpret these findings is ongoing.

Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France

ERBB2-low (ie, ERBB2 immunohistochemistry score of 1+ or 2+ in the absence of ERBB2 gene amplification) breast cancer (BC) is a new entity, with emerging dedicated treatments. Little is known about its prognosis and response to conventional therapy compared with ERBB2-zero breast tumors (ie, those with an immunohistochemistry score of 0). To compare the outcomes for patients with ERBB2-low metastatic BC (MBC) with those of patients with ERBB2-zero MBC. This cohort study was conducted from the Epidemiological Strategy and Medical Economics MBC platform and included patients with MBC treated between 2008 and 2016 in 18 French comprehensive cancer centers. The data analysis was conducted from July 16, 2020, to April 1, 2022. The main outcome was overall survival (OS), and the secondary outcome was progression-free survival under first-line treatments (PFS1). The median (range) age was 60.0 (22.0-103.0) years. Among 15 054 patients with MBC, 4671 (31%) had ERBB2-low MBC and 10 383 (69%) had ERBB2-zero MBC. The proportion of ERBB2-low cancers was higher among patients with hormone receptor-positive MBC than those with hormone receptor-negative disease (4083 patients [33.0%] vs 588 patients [21.0%]). With a median follow-up of 49.5 months (95% CI, 48.6-50.4 months), the median OS of the ERBB2-low group was 38.0 months (95% CI, 36.4-40.5 months) compared with 33.9 months (95% CI, 32.9-34.9 months) for the ERBB2-zero group (P < .001). After adjustment for age, visceral metastases, number of metastatic sites, de novo disease, period of care, and hormone receptor status, patients with ERBB2-low MBC had slightly better OS compared with patients with ERBB2-zero MBC (adjusted hazard ratio, 0.95; 95% CI, 0.91-0.99; P = .02). In contrast, PFS1 did not differ by ERBB2 status (adjusted hazard ratio, 0.99; 95% CI, 0.95-1.02; P = .45). No significant differences in OS and PFS1 were observed in multivariate analyses by hormone receptor status and types of frontline treatment. In this large cohort study, patients with ERBB2-low MBC had a slightly better OS than those with completely ERBB2-zero tumors, but identical PFS1, which could help guide treatment selection.

PREDICT underestimates survival of patients with HER2-positive early-stage breast cancer

The prognostic performance of PREDICT in patients with HER2-positive early breast cancer (EBC) treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies is unclear. Therefore, we investigated its prognostic performance using data extracted from ALTTO, a phase III trial evaluating adjuvant lapatinib ± trastuzumab vs. trastuzumab alone in patients with HER2-positive EBC. Our analysis included 2794 patients. After a median follow-up of 6.0 years (IQR, 5.8–6.7), 182 deaths were observed. Overall, PREDICT underestimated 5-year OS by 6.7% (95% CI, 5.8–7.6): observed 5-year OS was 94.7% vs. predicted 88.0%. The underestimation was consistent across all subgroups, including those according to the type of anti HER2-therapy. The highest absolute differences were observed for patients with hormone receptor negative-disease, nodal involvement, and large tumor size (13.0%, 15.8%, and 15.3%, respectively). AUC under the ROC curve was 73.7% (95% CI 69.7–77.8) in the overall population, ranging between 61.7% and 77.7% across the analyzed subgroups. In conclusion, our analysis showed that PREDICT highly underestimated OS in HER2-positive EBC. Hence, it should be used with caution to give prognostic estimation to HER2-positive EBC patients treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies.

Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II/III Breast Cancer

Addition of immune checkpoint inhibitors to anti-ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant treatment to maximize efficacy and to minimize toxic effects. To determine if neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2-positive early breast cancer warrants continuation to the next phase. This nonrandomized, open label, multicenter, phase 2 trial was conducted by the Korean Cancer Study Group and enrolled patients across 6 institutions in Korea from May 2019 to May 2020. Eligible patients were diagnosed with ERBB2-positive breast cancer (primary tumor size >2 cm or pathologically confirmed lymph node-positive cancer, without distant metastases) with a clinical stage of II or III. Patients received 6 cycles of neoadjuvant pertuzumab (840 mg at first cycle, 420 mg during subsequent cycles), atezolizumab (1200 mg), docetaxel (75 mg/m2), and trastuzumab (600 mg via subcutaneous injection) every 3 weeks, followed by surgery. Patients with pathologic complete response (pCR) received 12 cycles of adjuvant atezolizumab, trastuzumab, and pertuzumab every 3 weeks after surgery. Patients without pCR were treated with 14 cycles of atezolizumab, 1200 mg, plus trastuzumab emtansine, 3.6 mg/kg, every 3 weeks. The primary end point was pCR rate, which was defined as the absence of invasive cancer cells in the primary tumor and regional lymph nodes (ypT0/isN0). Secondary end points included clinical objective response rate, 3-year event-free survival rate according to pCR achievement, disease-free survival, overall survival, toxic effects, and quality-of-life outcomes. A total of 67 women (median [range] age, 52 [33-74] years) were enrolled. Hormone receptor expression was positive in 32 (48%) patients. Curative surgery was performed in 65 patients because 2 patients showed disease progression during neoadjuvant treatment and their tumors became unresectable. The overall pCR rate was 61% (41 of 67 patients). The pCR rate was higher in hormone receptor-negative disease vs hormone receptor-positive disease (27 of 35 [77%] patients vs 14 of 32 [44%] patients) and in programmed cell death 1-positive expression vs programmed cell death 1-negative expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Grade 3 and 4 neutropenia and febrile neutropenia occurred in 8 (12%) patients and 5 (8%) patients, respectively. Grade 3 and 4 immune-related adverse events occurred in only 4 patients (grade 3 skin rash, encephalitis, hepatitis, and fever). No treatment-related death occurred during the neoadjuvant phase. In this nonrandomized clinical trial, treatment with the neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab regimen in patients with stage II or III ERBB2-positive breast cancer appears to have had an acceptable pCR rate and modest toxic effects. Further investigation of this immunotherapy combination in ERBB2-positive early breast cancer is warranted. ClinicalTrials.gov Identifier: NCT03881878.

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

BackgroundAmong breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these “HER2-low” cancers.MethodsWe conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician’s choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor–positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor–positive cohort and among all patients.ResultsOf 557 patients who underwent randomization, 494 (88.7%) had hormone receptor–positive disease and 63 (11.3%) had hormone receptor–negative disease. In the hormone receptor–positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P=0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P=0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician’s choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.ConclusionsIn this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.)

Abstract TF2-3: Molecular heterogeneity in HER2+ breast cancer - can outcomes be predicted?

Abstract HER2+ breast cancer is clinically and biologically heterogenous. In the last 10 years, translational research in this disease has deciphered many biological features, which are associated with clinical outcomes both in early and metastatic disease. Among them, RNA-based gene expression has identified 4 main molecular subtypes (HER2-enriched, Basal-like, Luminal A and Luminal B), and HER2-enriched tumors within HER2+ breast cancer show high HER2 activation and response to anti-HER2 therapy. At the same time, ERBB2 mRNA levels by itself have also been linked to a higher response to anti-HER2 therapy, including T-DM1. Whether these 2 biological features will predict response to novel anti-HER2 therapies such as DS8201a is currently unknown. One important aspect is that levels of the target (i.e., HER2/ERBB2) and the activation of the downstream signaling pathway (i.e., HER2-enriched) are related but different at the same time. In other words, higher levels of ERBB2 mRNA are associated with a HER2-enriched phenotype; however, a substantial proportion of HER2+ tumors with low levels of ERBB2 are also HER2-enriched. Thus, they should not be considered the same, and this could have clinical implications. Similarly, hormone receptor negative HER2+ breast cancer has higher levels of ERBB2 and higher proportion of HER2-enriched disease than hormone receptor-positive. The high sensitivity of hormone receptor-negative and HER2-enriched disease to anti-HER2 therapy has been demonstrated in the neoadjuvant setting as well as studies looking at on-treatment biology after short-course of anti-HER2 treatment. Indeed, in advanced HER2+ breast cancer, the major gains in overall survival with new anti-HER2-based therapies are seen in hormone receptor-negative disease. Finally, tumor microenvironment plays a critical role. Indeed, tumor-infiltrating lymphocytes and immune gene expression signatures are associated with treatment response and better survival outcome. Whether this immune-related variables predict response to antiPD1/PDL1 is currently unknown, although translational studies do suggest that there might be a link. To conclude, the biological heterogeneity that exists within HER2+ disease is now well-known, and these variables, together with clinical-pathological features, should allow the design of new biomarkers to help answer critical clinical questions. Citation Format: A Prat. Molecular heterogeneity in HER2+ breast cancer - can outcomes be predicted? [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 TF2-3.

Abstract P3-14-14: A mediation analysis of racial disparity in breast cancer survival

Abstract Introduction: Non-Hispanic Black (African American, AA) women have the worst breast cancer outcomes of any racial/ethnic group. In comparison to non-Hispanic white (white) women, disparities in breast cancer survival for AA women have persisted over the past several decades, although there has been some recent improvement both at the national level and for AA women in Florida. However, we recently reported that AA women in Florida still have twice the rate of breast cancer death compared to their white counterparts. Therefore, more targeted approaches are needed to eliminate survival disparities for AA women diagnosed with breast cancer. The purpose of this study was to conduct a multiple mediation analysis to identify the most important factors causing the disparity in breast cancer survival for AA women. Identifying the most important mediators will provide opportunities for targeted policies, programs, and interventions to ultimately eliminate the prognostic effect of race/ethnicity for Florida women diagnosed with breast cancer. Methods: The study population is comprised of women in Florida diagnosed with breast cancer between 2004 and 2015 who were reported to the Florida Cancer Data System. The following putative mediators were analyzed in this study: residence in high poverty neighborhoods, having Medicaid or no insurance, advanced disease stage at diagnosis, high tumor grade, negative hormone receptor status, and receipt of surgery, based on our causal diagram. The outcome of interest was 5-year breast cancer-specific death. Sociodemographic and clinical characteristics were compared between African American and white women. The Cox model was used to obtain hazard ratios (HR) with 95% confidence intervals (CI) for the direct effect of AA race/ethnicity and indirect effects via mediators. Age was treated as a confounder in the model and mediators were treated as independent. The relative effect for African American ethnicity and each mediator, which is the percentage of the total effect of AA race/ethnicity explained (directly and indirectly) on breast cancer survival, are also provided. Results: African American women were more likely to be younger at diagnosis, living in high poverty neighborhoods, to be insured via Medicaid or uninsured, to have more advanced disease (stage, grade) with hormone receptor negative tumors, and less likely to receive surgery as treatment. From our mediation model, after accounting for all potential mediators, the direct effect associated with African American ethnicity was a 17% (HR = 1.17: 95% CI, 1.11-1.23) increased rate of breast cancer death, which represented 3.9% of the total racial/ethnic effect. The indirect and relative effects of mediators are provided in Table 1. Conclusions: This analysis identified receipt of surgery, advanced disease stage, hormone receptor negative disease, insurance status, and high tumor grade as the most important mediators of the racial/ethnic disparity in breast cancer survival for African American women in Florida. These results have ramifications for increasing access to screening services, providing options for health insurance, and ensuring prompt receipt of curative surgery to eliminate the prognostic effect of race/ethnicity for African American women diagnosed with breast cancer in the Florida. Study limitations are that these results are hypothesis generating based on the current status of methodology to examine multiple mediators in survival models. Table 1.Direct and Indirect Effects for the Association of African American Race/Ethnicity with 5-year Breast Cancer-Specific SurvivalDirect &amp; indirect effectsCox Proportional Hazard ModelHR95%. CIrel effAA race/ethnicity (Direct Effect)1.171.11, 1.233.9%Surgery3.182.93, 3.4728.3%Advanced stage3.092.84, 3.3627.5%Hormone receptor negative1.581.51, 1.6511.1%Medicaid-Uninsured1.481.40, 1.579.6%High grade1.471.42, 1.539.4%High poverty1.341.23, 1.477.2%Hormone treatment1.111.09, 1.142.5%Immunotherapy1.081.02, 1.151.9%Radiation1.041.03, 1.051.0%Chemotherapy0.910.89, 0.92Total Effect60.1050.8, 71.1100.0%Abbreviations: AA, African American; HR, hazard ratio; CI, confidence interval. Citation Format: Robert B. Hines, Xiang Zhu, Eunkyung Lee, Carolyn Rapp, Albert Volk, Asal M. Johnson. A mediation analysis of racial disparity in breast cancer survival [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-14.

202TiP ASTEFANIA: A phase III study of trastuzumab emtansine (T-DM1) plus atezolizumab or placebo as adjuvant therapy in patients with residual invasive breast cancer after neoadjuvant HER2-targeted therapy and chemotherapy

T-DM1 is the standard of care for adjuvant treatment of patients (pts) with HER2-positive early breast cancer (eBC) who have invasive residual disease after pre-operative treatment with taxane and HER2-targeted therapy. However a high unmet need remains in some higher risk subgroups (eg, inoperable or lymph node-positive, hormone receptor-negative disease) who have 3-year invasive disease-free survival (IDFS) rates of 76%. Exploratory analyses suggest that addition of the PD-L1 inhibitor atezolizumab to T-DM1 results in longer progression-free survival compared to T-DM1 alone in pts with previously treated PD-L1-positive metastatic BC.