HER2 Positivity Research Articles

Abstract 1940: Outcomes of patients treated with neoadjuvant chemotherapy for breast cancer at a safety net hospital

Abstract Background: Neoadjuvant chemotherapy (NAC) is administered before surgery and expected to benefit certain breast cancer (BC) patients (pts). This study inspected outcomes of triple negative BC (TNBC), hormone receptor (HR) positive (+) HER2 negative (-), and HER2+ BC pts treated with NAC at John Peter Smith Hospital (JPS) in Tarrant County, TX. Methods: It is an IRB exempted retrospective review of JPS Oncology and Infusion Center’s registry data. Eligible pts were diagnosed with TNBC, HR+ HER2-, or HER2+ BC from 1/1/2016 to 12/31/2019 and underwent NAC. Age, race, NAC regimen, tumor grade, recurrence, and pt survival were collected from EPIC EMR. NCCN guidelines were used to standardize clinical prognostic and pathologic anatomic stages. Decrease in stage by at least one level was considered as improvement. Results: Refer to table for additional results. Total of 104 pts. 22 (21.2%) had recurrence, 14 (14.5%) had died. Using the full cox proportional hazard model, TNBC pts had a 3.214 times higher hazard of death/recurrence compared to other subsets (95% CI: 1.261, 8.193; p= 0.0145). 70 (67.3%) pts showed improvement in stage. 34 (32.7%) achieved pathological complete response (pCR). When compared to pts with residual disease, achieving pCR reduced hazard of death/recurrence by 71.6% (HR: 0.284; 95% CI: 0.095, 0.849; p= 0.0243). Conclusion: A clear unmet need is poor survival of Black TNBC pts. Safety net hospitals, like JPS, disproportionately treat Black pts. We show that attaining pCR correlates with improved survival, but less than a quarter of TNBC pts attained pCR. New NAC regimens with Pembrolizumab has become standard of care for TNBC pts since 2021 due to higher pCR rates. Still, there is a need for better NAC regimens to improve pCR in TNBC overall and clinical trials on new regimens should include Black pts. Also, more than a third of HR+ HER2- pts upstaged in LN after NAC. This suggests a need for pre-NAC radiology staging methods and better NAC regimen testing for this subset. TNBC(32 patients) HR+, HER2-(29 patients) HER2+(43 patients) TOTAL(104 patients, 103 women) Median Age Median Age 58 50 53 53 Racial Distribution of Patients Non-Hispanic White 9(28.1%) 11(37.9%) 11(25.6%) 31(29.8%) Black 18(56.3%) 12(41.4%) 15(34.9%) 45(43.3%) Hispanic 4(12.5%) 2(6.9%) 10(23.3%) 16(15.4%) Asian 1(3.1%) 4(13.8%) 7(16.3%) 12(11.5%) Clinical Prognostic Stage Before NAC and Surgery 1 1(3.1%) 0(0%) 9(20.9%) 10(9.6%) 2 8(25%) 13(44.8%) 20(46.5%) 30(28.8%) 3 22(68.8%) 16(55.2%) 14(32.6%) 52(50%) 4 1(3.1%) 0(0%) 0(0%) 1(0.9%) Pathologic Anatomic Stage After NAC and Surgery pCR 7(21.9%) 3(10.3%) 24(55.8%) 34(32.7%) 1 8(25%) 3(10.3%) 14(32.6%) 24(23.1%) 2 9(28.1%) 9(31%) 3(7%) 21(20.2%) 3 8(25%) 14(48.3%) 2(4.7%) 24(23.1%) 4 0(0%) 0(0%) 0(0%) 0(0%) Tumor Stage Difference Before/After Surgery Improvement 24(75%) 11(37.9%) 35(81.4%) 70(67.3%) Deterioration 1(3.1%) 7(24.1%) 0(0%) 8(7.7%) No Change 7(21.9%) 11(37.9%) 8(18.6%) 26(25%) Recurrence Recurrence 10(31.3%) 4(13.8%) 8(18.6%) 22(21.2%) Patients survived as of 9/19/2022 Survival 25(78.1%) 27(93.1%) 38(88.4%) 90(86.5%) Additional Significant Results Completion of NAC regimen 89 (85.6%) total pts Lymph Node (LN) Upstaging for HR+ HER2- 6 (20.7%) pts showed improvement in LN while 11 (37.9%) upstaged in LN pCR in Black TNBC pts Only 16% of Black pts achieved pCR Citation Format: Prakriti Srivastava, James-Michael Blackwell, Jolonda Bullock, Riyaz Basha, Kalyani Narra. Outcomes of patients treated with neoadjuvant chemotherapy for breast cancer at a safety net hospital [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1940.

High-Grade Ductal Carcinoma In Situ of the Breast With Regressive Changes: Radiological and Clinicopathological Findings.

Tumour regression is defined as continuity of changes leading to the elimination of a neoplastic population and is reflected as periductal fibrosis and intraductal tumour attenuation. The aim of this study was to describe the radiological and clinicopathological characteristics of high-grade breast ductal carcinoma in situ (DCIS) with regressive changes (RC). Thirty-two cases of high-grade DCIS with RC on biopsy specimens followed by excision were included. The mammographic, ultrasonographic (US), and magnetic resonance imaging (MRI) findings of cases were retrospectively reviewed according to the breast imaging reporting and data system (BI-RADS) lexicon. Clinical and histopathological findings [comedonecrosis, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and Ki-67 proliferation index] were recorded. The rate of upgrade to invasive cancer after surgical excision and lymph node involvement were evaluated. The most common mammographic finding was microcalcifications alone (68.8%). The most frequently seen findings on US were microcalcifications only (21.9%), followed by microcalcifications and hypoechoic area (18.7%). On MRI, most lesions presented as clumped non-mass enhancement with segmental distribution. ER/PR negativity (53.1%, 65.6%), HER2 positivity (56.3%) and high Ki-67 (62.5%), which are known to be associated with more aggressive behavior, were found to be proportionally higher. The rate of upgrade to invasive cancer was 21.8%. DCIS with RC lesions present most often as microcalcifications alone on both mammography and US. MRI features are not distinguishable from those of other DCIS lesions. DCIS with RC lesions show biomarker status reflecting more aggressive behavior and high upgrade rate to invasive cancer.

HER2 Expression Associated with Clinical Characteristics and Prognosis of Urothelial Carcinoma in a Chinese Population.

The frequency of HER2 overexpression in bladder cancer is reported as 9%-61%. HER2 alteration correlates with aggressive disease in bladder cancer. Traditional anti-HER2 targeted therapy has failed to show clinical benefits in patients with advanced urothelial carcinoma . The information on pathologically proven patients with urothelial carcinoma with detected HER2 status was collected from the database of Peking University Cancer Hospital. The HER2 expression, as well as its association with clinical characteristics and prognosis, was analyzed. A total of 284 consecutive patients with urothelial carcinoma were enrolled. HER2 was positive (IHC 2+/3+) in 44% of urothelial carcinoma. HER2 positivity was found more frequent in UCB than in UTUC (51% vs. 38%). Stage, radical surgery, and histological variant were associated with survival (P < .05). For metastatic patients, multivariate analysis shows that 3 indicators, including liver metastasis, the number of involved organs, and anemia, are independent risk factors of prognosis. Receiving immunotherapy or disitamab vedotin (DV) treatment is an independent protecting factor. The survival of patients with low HER2 expression was also significantly improved by the treatment of DV (P < .001). HER2 expression (IHC 1+, 2+, 3+) was associated with a better prognosis in this population. DV has improved the survival of patients with urothelial carcinoma in the real world. With the new-generation anti-HER2 ADC treatment, HER2 expression is no longer a poor prognostic factor.

Uncertainty estimation in the classification of histopathological images with HER2 overexpression using Monte Carlo Dropout

Classification of breast cancer tissues with HER2 overexpression into 0, 1+, 2+, or 3+ categories is a crucial clinical task for determining HER2 positivity, and hence, prescribing the adjuvant HER2-targeted therapy. Deep learning-based methods have been fundamental for creating support tools that improve decision-making, and they have provided outstanding performance in the classification of histopathological images. However, the quantification of the uncertainty has been traditionally neglected when deep learning-based methods are used, despite its critical importance in healthcare applications. In this work we propose a new method, using deep learning and the Monte Carlo Dropout, to measure the uncertainty when classifying breast cancer tissue images with HER2 overexpression.The proposed method has four main stages including (1) WSI pre-processing, (2) patch dataset generation, (3) Bayesian deep learning-based classification, (4) and prediction and uncertainty estimation. For efficient computation of the predictive distribution, we propose a 2-step predictive distribution method that decreases significantly the execution time. Furthermore, the method achieves tissue-level classification by training the classifier on a patch-level and using aggregation techniques. The proposed method achieved on average 0.89 accuracy, 0.81 precision, and 0.74 recall for classification on a whole slide tissue-level. The method is also capable of characterizing the higher and lower uncertainty regions in the whole slide tissue images by estimating the predictive entropy and mutual information. This additional piece of information can be very important for practitioners to take decisions in the healthcare domain.

P011 Utility of oncotype in premenopausal women with hormonal receptor (hr) positive her2 negative early breast cancer

P011 Utility of oncotype in premenopausal women with hormonal receptor (hr) positive her2 negative early breast cancer

Cytology of micropapillary mucinous carcinoma: A case report of a clinically and genetically distinct breast carcinoma variant.

Micropapillary mucinous carcinoma (MPMC) is an uncommon histopathological variant of breast cancer accounting for approximately one-fifth of all mucinous breast carcinomas. In contrast to pure mucinous carcinoma, MPMC tends to affect younger women and is associated with decreased progression-free survival, higher nuclear grade, lymphovascular invasion, lymph node metastasis, and positive HER2 status. Typically MPMC histology shows micropapillary architecture with "hobnailing" of cells and reverse polarity. Very few publications document the cytomorphological findings of MPMC. We report a case of MPMC that was suspected in fine needle aspiration cytology (FNAC) and confirmed at histopathology.

Abstract P1-04-01: High HER2/CEP17 ratio is associated with better treatment outcomes in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 2+ or 3+ results

Abstract Background: Dual HER2 blockade with trastuzumab and pertuzumab combined with docetaxel (DHP) is the standard first-line treatment option for patients with HER2-positive metastatic breast cancer. However, HER2 positivity alone often fails to predict treatment outcome of HER2 targeted therapy. The magnitude of HER2 immunohistochemical staining (IHC) and HER2/CEP17 ratio from in situ hybridization (ISH) is a well-known predictive biomarker for HER2 targeted therapy. In the neo-adjuvant setting, patients with HER2 IHC 3+ have higher pathologic complete response (pCR) rate compared to HER2 IHC&amp;lt; 3+ with HER2 ISH positive. In addition, higher HER2/CEP17 ratio is associated with higher pCR rate in HER2-positive breast cancer patients treated with dual HER2 blockade regimens. However, there is no data whether there is an association between HER2/CEP17 ratio and treatment outcome of DHP regimen in patients with advanced of metastatic breast cancer especially among those with HER2 IHC 3+. Methods: We performed a retrospective cohort study with patients with locally advanced or metastatic HER2-positive breast cancer who were treated with first-line palliative DHP regimen between August 2008 and January 2021 at Seoul National University Hospital. In the clinical setting, HER2 IHC 3+ is defined as HER2 positive and no further ISH testing is required. Additional ISH was performed in patients with HER2 IHC 3+ without archival HER2 ISH results. The association between HER2/CEP17 ratio and treatment outcome was assessed. Results: In total, 165 patients were included with a median follow-up duration of 28.0 months. Among the 165 patients, 35 patients had archival ISH result and additional ISH was performed in 53 patients. The correlation between HER2/CEP17 ratio and treatment outcome was assessed in 88 patients. Cox proportional hazard analysis revealed that HER2/CEP17 ratio is correlated with PFS (HR 0.23, 95% CI 0.11-0.49, p &amp;lt; 0.001). When dichotomized by the median HER2/CEP17 ratio of 4.17, patients with higher HER2/CEP17 ratio had significantly longer PFS (37.5 vs. 17.4 months, p = 0.003) and numerically higher ORR (54.5% vs. 34.1%, p = 0.085). Multivariate analysis revealed that HER2/CEP17 ratio is an independent prognostic factor for PFS (HR 0.72, p = 0.001). Of 88 patients with ISH results, 25 had HER2 IHC 1+ or 2+ and 63 had HER2 IHC 3+. HER2/CEP17 ratio was associated with PFS in both HER2 IHC 1+/2+ patients (HR 0.12, 95% CI 0.02-0.88, p = 0.037) and HER2 IHC 3+ patients (HR 0.18, 95% CI 0.07-0.49, p = 0.001). Patients with higher HER2/CEP17 ratio had longer PFS in both HER2 IHC 1+/2+ patients (28.6 vs. 12.9 months, p = 0.003) and HER2 IHC 3+ patients (Not reached vs. 18.3 months, p = 0.005) when dichotomized by the median HER2/CEP17 of 2.95 and 4.75, respectively. Conclusion: This is the first study to report that higher HER2/CEP17 ratio is associated with longer PFS in HER2-positive advanced breast cancer patients treated with palliative first-line DHP. The strength of this study is that we identified prognostic role of ISH even in patients with HER2 IHC 3+. It would be helpful to perform ISH not only in patients whose HER2 IHC is ambiguous, but also in patients with HER2 IHC 3+ to make better prediction of treatment outcome. Table 1. Patient characteristics. Citation Format: Jeongmin Seo, Jiwon Koh, Dae-Won Lee, Han Suk Ryu, Kyung-Hun Lee, Tae-Yong Kim, Seock-Ah Im. High HER2/CEP17 ratio is associated with better treatment outcomes in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 2+ or 3+ results [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 P1-04-01.

Abstract P3-03-28: Clinicopathological Risk Factors of Brain Metastasis in Breast Cancer Patients: A Systematic Review and Meta-analysis

Abstract BACKGROUND: Breast cancer brain metastasis (BCBM) has an incidence rate of 5.1% among Breast Cancer (BC) patients. In BCBM, cancerous cells come from a primary tumor that implant and grow in the brain leading to potentially lethal neurologic symptoms and signs. With more clinical options and therapeutics strategies becoming available, a multi-disciplinary approach for treatment is needed in order to best meet BCBM patients’ needs, however, systematic guidelines for the screening of high-risk asymptomatic patients are still lacking and the BCBM diagnoses are performed only after symptoms manifestation. Therefore, understanding the clinical and pathologic drivers of BCBM aids in improving medical interventions by guiding future research directions. This study aims to determine the clinicopathological risk factors of brain metastasis (BM) among BC patients. METHODS: Retrospective cohort studies on the clinicopathological characteristics of BM versus non-BM (NBM) patients were retrieved through reputable search databases. Review Manager version 5.4.1 was used for statistical analyses. In the presence of heterogeneities, a pragmatic approach was undertaken to employ both random-effects (RE) and fixed-effect (FE) meta-analyses. The statistical significance of the pooled effect estimates was examined by the Z-test. Interstudy variations and heterogeneities were estimated using Cochran’s Q-statistic with P &amp;lt; 0.05 indicating a statistically significant heterogeneity. The risk of bias and the quality of studies were assessed at a study level using ROBINS-I tool. RESULTS: A total of four (4) retrospective cohort studies were included in the analyses. Random-effects meta-analyses with i2 &amp;lt; 50% (P &amp;gt; 0.05) had shown significant association (P &amp;lt; 0.05) on the increased incidences of BCBM development for HER2+ expression [OR: 2.43, 95% CI: 1.88 – 3.12, P &amp;lt; 0.00001] and for pre-menopausal status [OR: 1.77, 95% CI: 1.13 – 2.76, P = 0.01]. Fixed-effect meta-analyses had shown significant association (P &amp;lt; 0.05) on the decreased incidence of BCBM development for TNBC disease [OR: 0.66; 95% CI: 0.47 – 0.92; P = 0.02]. The risk of bias was low to moderate in the majority of studies. CONCLUSION: HER2 positivity and pre-menopausal status are risk factors for increased BCBM development while the absence of regional lymph node metastases and ILC findings are less likely to progress to BCBM. Higher T and N categories, higher histological grade, ER negativity, and PR negativity may be associated with higher risks of BCBM while lower T categories, HER2 negativity, and TNBC may likely be associated to less BCBM development. More powerful relevant and upcoming randomized clinical trials with larger sample sizes among BCBM patients versus non-BM patients must be made exploring certainty on the clinicopathological factors contributing to BM among BC patients. Keyword/s: risk factors, breast cancer, brain metastasis Citation Format: Korina Blanca C. Garcia, April Ann A. Lubay. Clinicopathological Risk Factors of Brain Metastasis in Breast Cancer Patients: A Systematic Review and Meta-analysis [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 P3-03-28.

Abstract PD6-06: PD6-06 Racial and ethnic disparities with influenza vaccine use in long-term survivors of metastatic breast cancer

Abstract Background: Due to therapeutic advancements, people diagnosed with metastatic breast cancer (MBC) are living longer. This is particularly true for elderly patients who are often diagnosed with more indolent disease. However, elderly patients have higher rates of comorbidity and are vulnerable to other adverse health outcomes, but the primary care management of patients with advanced cancer may be sub-optimal. Every year influenza results in hundreds of thousands of hospitalizations and tens of thousands of deaths. Guidelines recommend the influenza vaccine annually for those over the age of 65 as well as those with cancer based on studies showing a 40-60% reduction in hospitalizations and death. Patterns of use in patients with MBC is unknown. Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data. Patients were included if they were diagnosed with stage IV MBC from 1/1/2008 – 12/31/2017, were ≥65 years of age, and had continuous Medicare enrollment for 12 months prior to diagnosis and at least three months after. Our primary outcome of interest was influenza vaccine use identified via CPT codes and defined as any use, use among patients surviving &amp;gt; 3-years, use among patients surviving &amp;gt;5-years, and repeated vaccine use. We then conducted bivariate analyses using demographic variables, including race, ethnicity, SES, age, and marital status, and clinical factors, including chemotherapy use, ER/PR positivity, and HER2 positivity. A multivariable logistic model was used to identify factors associated with influenza vaccine use in each cohort. Results: We identified 5182 patients with stage IV MBC during the study period that met our inclusion criteria. Overall, the median survival was 21 months and only 44% received at least one vaccination at any time after diagnosis. Within the cohort with the &amp;gt; 3-year survival (n=1864), only 1222 (66%) received an influenza vaccination at least one time and only 54% received the vaccine at least two times during 3 years of follow-up. Among patients with at least five-years of survival (n=763), 73% received at least one vaccination and only 65% received the vaccine at least two times during 5 years of follow-up. In a bivariate analysis in the 3-year survival cohort, we found that black race (47% vs 67%, p&amp;lt; 0.001) and Hispanic ethnicity (53% vs 66%, p=0.026), compared to white race and non-Hispanic ethnicity, respectively, were significantly associated with decreased vaccine use. The only factor associated with increased use was chemotherapy exposure. A multivariable model found lower odds of influenza vaccine receipt for black patients (OR=0.44, 95% CI 0.30-0.65, p&amp;lt; 0.001) and Hispanic patients (OR=0.58, 95% CI 0.36-.94, p=0.026). Similar findings were found in the 5-year survival cohort. Ongoing landmark analyses will be presented evaluating the impact of vaccination on survival. Conclusions: Over 50% of survivors with MBC do not receive the influenza vaccine after diagnosis. Importantly black and Hispanic patients with MBC are about half as likely to receive the influenza vaccine as white patients. Given the known impact of influenza vaccination in the elderly, improving access to vaccination could be an important strategy to reduce disparities in health outcomes. Our findings demonstrate primary care access disparities amongst the MBC population and indicate a need for educational and policy-based interventions. Citation Format: Sahil D. Doshi, David DeStephano, Melissa K. Accordino, Elena B. Elkin, Jason D. Wright, Dawn Hershman. PD6-06 Racial and ethnic disparities with influenza vaccine use in long-term survivors of metastatic breast cancer [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 PD6-06.

Abstract P5-02-04: Immune Signatures Display Subtype-Specific Activation in Breast Cancer

Abstract Background. The development of new anti-HER2 therapies for the treatment of HER2-positive breast cancer (BC) is changing the concept of HER2 dichotomization to select and treat this patient population. In addition, different immunotherapies tested in HER2-low BC are gaining continuous interest. However, a comprehensive characterization of HER2 BC subgroups and patients is required to identify the best treatment approach. Materials and Methods. Using 123 BC samples with gene expression and IHC/FISH determined HER2 status we determined cutoff values to identify HER2 positive, HER2 low, and HER2 ultralow cohorts. With the inclusion of hormone receptor (HR) status six clinically relevant cohorts were defined (HR+/HER2+, HR+/HER2-low, HR+/HER2-ultralow, and HR-/HER2+, HR-/HER2-low, HR-/HER2-low). An ingegrated database of 7,624 BC cases were assigned to the six subtypes. Prognosis determination was based on relapse-free survival (RFS), distant-metastasis-free survival (DMFS), and overall survival (OS). Clinical parameters evaluated include MKI67 expression, lymph node status and grade. All together 17 immune signatures resembling immune genes and related activated pathways were tested against the six molecular BC subgroups. Results. We defined a robust cutoff for HER2 expression levels to define six distinct HER2 BC molecular subgroups (&amp;gt;3034 for HER2 positivity and &amp;lt; 1780 for HER2 ultralow). Regardless the HR positivity, the overall distribution of HER2-low, and HER2-ultralow was 23% and 52%, respectively. In the HR+ subgroups the HER2-low showed a better prognosis as compared to the HER2-ultralow and HER2+ (RFS and DMFS P = 0.0048 and 0.0015, respectively) while there was no prognostic effect of HER2 expression in the HR- subgroups. Not surprisingly, an association with higher grade was demonstrated in all HR- as compared to the HR+ subgroups regardless of HER2 status. Overall, all HR- subgroups showed a higher involvement of immune genes as compared to the three HR+ subgroups. Of interest, HER2-low (HR+ and HR-) and HR-/HER2+ showed a significant overlap expression of immune signatures (71%). While the HR+/HER2-ultralow and HR+/HER2+ displayed minimal activation of immune pathways, the HR-/HER2-ultralow was the group most significantly associated with the activation of immune signaling including IFN signaling (67% percent of genes in the panel with altered expression), T cell active cytokines (34% of genes hit), and cytotoxic effector molecules (48% of genes hit). Conclusions. Our study supports a further molecular stratification of breast cancer based on HER2 status. The different tumor-immune background of these BC subgroups highlights that selected patient cohorts may derive benefit from targeted immunotherapy. Citation Format: Gyongyi Munkacsy, Libero Santarpia, Balazs Gyorffy. Immune Signatures Display Subtype-Specific Activation in Breast Cancer [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 P5-02-04.

Abstract P4-07-38: Real-world data of Advanced Breast Cancer (ABC) patients with HER2-positivity before the second-line therapy: data from the observational study GEICAM/2014-03 (RegistEM)

Abstract Background: Over the last years, the treatment of HER2-positive (HER2+) breast cancer (BC) patients (pts) has been changing because of the development of new anti-HER2 agents. In the current analysis, we describe the features, treatment patterns, progression-free survivall (PFS) and overall survival (OS) outcomes of BC pts with HER2 + (immunohistochemistry [IHC] 3+ or IHC 2+ and in situ hybridization [ISH]+), following ASCO/CAP 2018 guidelines in the most recent tumor lesion before the 2nd-line. Methods: The RegistEM study is an ongoing BC registry study that is providing prospective data from around 1900 pts diagnosed with advanced BC (ABC) between 01/Jan/2016 and 31/Dec/2019, in 38 Spanish institutions from GEICAM network. In this analysis, 296 HER2+ BC pts have been included, representing the 18% of pts available in the database at the cut-off date (08/Apr/2022), with ABC diagnosis before 2019 (n=1559). Results: At first ABC diagnosis, 58% (n=173) pts had recurrent disease (&amp;gt;36 months [mo] from initial BC diagnosis in 62%), 41% (n=120) de novo metastatic BC and 1% (n=3) unresectable locally ABC (ULABC); the median age was 58 years, 68% were postmenopausal and there was only 1 male pt. From total 296 pts, 66% had hormone receptor expression [HR+]; the BC subtype was assessed in tumor tissue from the breast (58%) or a metastatic lesion (34%), and in 8% pts, HER2 positivity was observed after the 1st-line. Family history of BC and/or ovarian cancer was reported in 28% pts, and a hereditary-risk genetic test was performed in 26% pts (n=74/282). Germline BRCA1/2 and TP53 genetic testing were reported in 14 and 26 pts respectively, being mutated in 3/14 (21%) and 5/26 (19%) pts. Bone (50%), lymph nodes (49%), liver (35%), lung (31%), soft tissue (8%) and central nervous system (CNS), mostly in brain (8%), were the main metastatic sites. One hundred pts were diagnosed with CNS metastases: 24 at baseline, 48 during the 1st-line and 28 in subsequent lines. Additional data according to HR status and type of ABC are detailed in the table below, showing a worse prognosis in absence of HR expression. In HR- pts, bone metastases were less frequent and lymph nodes metastases more frequent compared to HR+ pts. Visceral disease was present in 69% (66% in HR+ and 74% in HR-; non-statistically significant) pts and ≈80% had ≤3 (54%, ≤2) locations involved. The most common therapies by line were: 1) 1st-line: Chemotherapy (CT) + biological therapy (BT) (38%), CT + BT+ endocrine therapy (ET) (35%), and ET + BT [11%]; 2) 2nd-line: BT (55%), CT + BT (20%) and ET + BT (15%); 3) 3rd-line: CT + BT (49%) and BT (31%). The median (95% confidence interval [CI]) progression-free survival (PFS) on 1st, 2nd and 3rd line was 18 (15-22), 8 (7-9) and 6 (5-8) mo, respectively. The median (95% CI) overall survival (OS) from ABC diagnosis was 43 (40-49) mo. These survival outcomes were higher in HR+ pts, however, the differences were only statistically significant in OS (p=0.006; log-rank). At database cut-off date, death was reported in 47% pts. Conclusions: In spite of the anti-HER2 therapies administered in the advanced setting, the HR expression is a relevant prognostic factor, with a clinically and statistically significant impact in OS, improving the outcomes of HR+ pts. Citation Format: Sara López-Tarruella, Angel Guerrero-Zotano, Josefina Cruz, Silvia Antolin Novoa, Purificación Martínez, María Hernández, César A Rodríguez, J. Ignacio Chacón, Ariadna Tibau, Catalina Falo, Álvaro Rodríguez-Lescure, Mireia Margelí, Sonia Servitja, Raquel Andrés, María Galán-Gramaje, Encarna Adrover, Ana Miguel, Rafael Villanueva, Silvia Varela, Ruth Campo, Mª José Escudero, Susana Bezares, Federico Rojo, Isabel Álvarez. Real-world data of Advanced Breast Cancer (ABC) patients with HER2-positivity before the second-line therapy: data from the observational study GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-38.

Abstract P5-01-05: A Predictive Model for Axillary Pathologic Response after Neoadjuvant Chemotherapy for Clinically Node-Positive Breast Cancer

Abstract Purpose: Neoadjuvant chemotherapy (NAC) has resulted in the eradication of axillary lymph node metastasis in approximately 40% of patients. Sentinel lymph node biopsy (SLNB) could be an alternative surgical procedure for these patients to avoid complications from axillary lymph node dissection (ALND). However, high false-negative rates of SLNB for clinically node-positive patients were reported in previous prospective trials. The aim of the present study was to evaluate clinicopathological factors and imaging characteristics by MRI and ultrasound (US) as predictors of axillary pathologic complete response (ypN0) after NAC, which enables to identify candidates for SLNB in patients with clinically node-positive disease. Patients and methods: We identified 177 patients with clinically node-positive breast cancer who received NAC from May 2009 to May 2021. All patients underwent MRI and US before and after NAC. Patients were judged to be node-positive when they have the cytologically-proven nodal disease by fine-needle aspiration (FNA) or suspicious lymph nodes by diagnostic imaging. Lymph nodes with the cortical thickness (&amp;gt;3.5mm), loss of fatty hilum, or round shape (short-axis/long-axis ratio &amp;gt; 0.5) were defined as suspicious lymph nodes. To develop a predictive model for ypN0, the association between ypN0 status and clinicopathological and imaging characteristics was assessed by multivariate logistic regression analysis. The area under the receiver operating characteristic (ROC) curve was used to evaluate discrimination by the model. The model was further evaluated in the validation cohort with 20 patients who received NAC from March 2021 to December 2021. Results: The median age was 54.0 (range: 22-79) years and the mean tumor size was 3.97 ±2.29cm. Of 177 patients, 90 (50.8%) patients had luminal, 47 (26.6%) had HER2-positive, and 40 (22.6%) had triple-negative disease. Sequential anthracycline and taxane were administered for 157 (88.7%) patients, and 45 (95.7%) patients with HER2-positive-disease received concomitant anti-HER2 agents preoperatively. Overall, 77 (43.5%) patients achieved ypN0. Independent predictors of ypN0 status were clinical stage N1 (odds ratio [OR]: 9.17 vs. cN2-3, p=0.002), absence of lymphadenopathy after NAC (OR: 8.54, p&amp;lt; 0.001), breast complete response (CR) by MRI (OR: 5.96, p&amp;lt; 0.001), HER2 positivity (OR: 3.80, p=0.008), nuclear grade (NG) 3 (OR: 2.77 vs. NG1-2, P=0.020) and hormone receptor negativity (OR: 2.52, p=0.048). In a model using these predictors, the area under the ROC curve was 0.887 (95% confidence interval: 0.839-0.935, p&amp;lt; 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the model were 80.0%, 82.8%, 77.9% and 84.5%, respectively. In the validation cohort, the sensitivity, specificity, positive predictive value and negative predictive value were 66.7%, 90.9%, 85.7% and 76.9%, respectively. Among 84 patients who were predicted ypN0 by the model, SLNB was performed in 42 (50.0%) patients, and the identification rate of SLN was 95.2% (40/42). Overall, ALND was omitted in 38 (45.2%) patients and irradiation to regional lymph nodes was performed in 23 (60.5%) out of 38 patients. After a median follow-up of 53.9 months, 5-year recurrence-free survival was comparable between patients with or without ALND (78.0% vs. 94.4%, p=0.259). Conclusions: Our predictive model based on clinicopathological factors and imaging characteristics by MRI and US could help to identify good candidates for the omission of ALND after NAC in patients with clinically node-positive breast cancer. Citation Format: Akiko Matsumoto, Saki Naruse, Yuka Isono, Yuka Maeda, Ayana Sato, Miki Yamada, Tatsuhiko Ikeda, Hiromitsu Jinno. A Predictive Model for Axillary Pathologic Response after Neoadjuvant Chemotherapy for Clinically Node-Positive Breast Cancer [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 P5-01-05.

Abstract P4-01-22: Clinical outcomes of metastatic breast cancer patients treated with poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi): the Mayo Clinic experience

Abstract Background: Two poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are currently FDA-approved for the treatment of HER2-negative metastatic breast cancer (MBC) in carriers of germline pathogenic variants (PVs) in BRCA1 or BRCA2 (BRCA1/2). This study explores the clinical outcomes of MBC patients treated with a PARPi. Methods: In this retrospective study, we included MBC patients treated with a PARPi between January 2017 and February 2022 at Mayo Clinic (Minnesota, Arizona, Florida, and Mayo Clinic Health Systems). We used the Kaplan Meier method to estimate the time-to-treatment-failure (TTF) and the log-rank test to compare different subsets. In addition, predictors of TTF were identified in a multivariate cox-proportional hazard regression model, including age at PARPi initiation, race, ethnicity, histology, estrogen receptor (ER), progesterone receptor (PR), and HER2 expression of the tumor, the number of prior therapies, type of PARPi, and PV carrier status (germline BRCA1/2 or PALB2 vs. somatic BRCA1/2 vs. other). Results: Sixty-five patients treated with PARPi (olaparib: 51; talazoparib: 14) were included in the final analysis. Fifty-five patients were carriers of germline PVs in BRCA1 (n=24, 37%), BRCA2 (n=27, 42%) or PALB2 (n=4, 6%), whereas ten patients (15%) had no germline PVs but the tumor had a somatic mutation in the homologous recombination-related (HRR) genes (7 in BRCA1/2, 2 in ATM, and 1 in CDKN2A and CDH1). At the data cutoff, 48 (74%) patients had discontinued PARPi due to progression or death. Fifteen (23%) patients required a dose reduction due to side effects. Occurrence of grade ≥ 3 side effects: anemia in 8, fatigue in 4, neutropenia in 2, and thrombocytopenia in 2 patients. Eight (15.7%) patients in the olaparib group and seven (50%) patients in the talazoparib group required a dose reduction for side effects. No patient on olaparib required drug discontinuation due to side effects, whereas two patients on talazoparib were switched to olaparib due to cytopenias and could tolerate olaparib. Median TTF in the overall population was 8 months (95% confidence interval [CI]: 6.4 – 9.6), and there was no difference (p=0.64) in TTF between the olaparib and talazoparib groups. Median TTF in the germline BRCA1, BRCA2, and PALB2 PV carriers were 7, 8, and 11 months, respectively (p=0.57). Among patients with somatic BRCA1/2 mutations, the median TTF was 4 months. Numerically, patients with HER2-positive tumors (n=8) had a shorter TTF compared to HER2-negative tumors (Median TTF: 4 vs. 8 months, p=0.098). No significant difference in TTF was observed by ER or PR status of the tumor, age at initiation of PARPi, the number of prior therapies, and prior use of platinum-based chemotherapy or CDK4/6 inhibitors. In multivariate analysis, HER2 positivity (hazard ratio [HR]: 8.0, 95% CI: 2.2 – 29.4, p=0.002), somatic BRCA1/2 mutations (HR: 7.6, 95% CI: 1.2 – 50.0, p=0.03) and somatic mutations in other HRR genes (HR: 19.1, 95% CI: 3.1 – 118.6, p=0.002) were associated with worse TTF. Conclusions: In the real world, PARPi were well-tolerated with promising time-to-treatment-failure (TTF) benefits comparable to data from clinical trials. Notably, relatively shorter TTF was observed in patients with somatic BRCA1/2 and other HRR gene mutations and HER2-positive MBC. These findings improve our understanding of the role of PARPi in MBC and will help to guide treatment decisions with PARPi in the clinical setting. Citation Format: Nusrat Jahan, Jodi Taraba, Karthik V. Giridhar, Roberto A. Leon-Ferre, Amye J. Tevaarwerk, Elizabeth Cathcart-Rake, Ciara C. O’Sullivan, Prema Peethambaram, Timothy J. Hobday, Kathryn Ruddy, Lida A. Mina, Pooja Advani, Felipe Batalini, Matthew P. Goetz, Tufia C. Haddad, Fergus J. Couch, Siddhartha Yadav. Clinical outcomes of metastatic breast cancer patients treated with poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi): the Mayo Clinic experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-22.

Abstract P6-01-11: A UK prospective multicentre decision impact, decision conflict and economic evaluation of the use of Oncotype DX® to guide chemotherapy in 680 women with hormone receptor positive, HER2 negative breast cancer and 1 to 3 nodes involved

Abstract Introduction: For a test to be of value, it needs to demonstrate that it is changing clinical decisions, improving clinical confidence and of economic benefit. This trial looked at the use of Oncotype DX Breast Recurrence Score ® (RS) assay against these criteria in 680 women with hormone receptor positive (HR+), HER2 negative early breast cancer with 1 to 3 lymph nodes positive (LN+) in the UK National Health Service (NHS) (5 teaching and 9 district general hospitals) between 2017 and 2022. Methods: Patients with LN+ early breast cancer who were willing and fit to receive chemotherapy (CT) were consented to join the trial. At the initial oncologists’ appointment, physicians were asked to state their preference for or against CT and their level of confidence in their decision on a scale of 1 to 5. Following receipt of the RS result physicians were asked to make a final decision for or against CT and similarly record their level of confidence. Descriptive analyses were used to characterize (1) patient and tumour characteristics, (2) change in treatment recommendations post-RS testing (by RS result and nodal status), and (3) change in physicians’ level of confidence post-RS testing (by RS result and nodal status). Average cost for chemotherapy and RS test price were used to estimate overall cost savings. Results: A total of 680 patients were recruited. 16 patients were excluded (5 failed samples, 5 withdrew consent, 3 HER2 positives, 2 with advanced disease, and 1 specimen delayed in transit), leaving 664 assessable patients. The median age was 58 years and 77.1% of women were post-menopausal. Most patients had a RS of 0-17 (n=400, 60.2%); while 206 (31%) had a RS of 18-30 and 58 (8.7%) had a RS of 31-100. Using post-RxPONDER cutoffs, 566 (85.2%) had an RS of 0-25; 98 (14.8%) had an RS of 26-100. Decision impact results: The decision impact results broken down by RS result and nodal status are detailed in Table 1. Of the 662 patients with complete decision impact data, in 359 (54.2%) the recommendation by the physician changed from CT+ hormone therapy (HT) to HT alone. In 286 (43.2%) cases the decision was unchanged and in 17 (2.6%) the recommendation changed from HT alone to CT+HT. Overall 342 (51.7%) cases were spared chemotherapy. Decision conflict results: The change in the physicians’ level of confidence by RS result and nodal status are detailed in Table 2. Of the 660 cases with complete decision conflict data, physicians reported an increase in confidence in their recommendations after receiving the RS in 363 (55.0%), confidence was unchanged in 219 (33.2%) and decreased confidence in 78 (11.8%) cases. Economic analysis: Using the estimates of Burdanov et al, the average costs of a course of chemotherapy in the UK is £6,000 to £7,000. An estimate of the overall cost saving of 342 courses is £2,064,00 to £2,408,000 and the overall cost of 664 RS assays at the list price of about £2580 (although an undisclosed discount applies to the NHS) is £1,713,120. This suggests that the use of RS assay represents a significant saving to the NHS. Conclusion: The use of Oncotype DX assay in node positive early breast cancer leads to about half of women being spared chemotherapy, a significant improvement in clinical confidence for oncologists and an economic saving to the health care system. Table 1 Pre- vs Post-Oncotype DX Treatment Recommendation by Physician According to Recurrence Score and Nodal Status Table 2 Change in Physicians’ Level of Confidence Post-Oncotype DX Testing According to Recurrence Score and Nodal Status Citation Format: Simon D. Holt, Priyadharshini Sai-Giridhar, Mark Verrill, Laura Pettit, Anna Rigg, Tamas Hickish, Caroline D. Archer, Anshu Wadhawan, Marianne Dillon, Jo Dent, Mark R. Nathan, Ludger Barthelmes, Shazza rehman, Paige Innis, Saira Khawaja. A UK prospective multicentre decision impact, decision conflict and economic evaluation of the use of Oncotype DX® to guide chemotherapy in 680 women with hormone receptor positive, HER2 negative breast cancer and 1 to 3 nodes involved [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-11.

Abstract P3-05-32: Positive sentinel lymph node does not affect prognosis in T1 breast cancer patients who undergo breast conserving surgery with sentinel lymph node biopsy

Abstract Backgrounds: The ACOSOG Z0011 trial revealed oncologic outcomes in patients who underwent breast conserving surgery (BCS) and sentinel lymph node biopsy only versus completion axillary dissection to be equivalent. It was also reported that axillary recurrence rate to be not different between axillary dissection group and SLNB only group, despite the positive rate of over 20% in non-sentinel lymph nodes. It led to suspicion that the role of SLNB in local control to be less significant than previously recognized. Currently trials such as SOUND trial and NAUTILUS trial are being conducted in cT1N0 breast cancer undergoing BCS to compare the outcomes between the current standard surgery and no axillary surgery. Purposes: This study aimed to investigate the factors associated with positive SLN in patients with T1 breast cancer, including T substages. We also evaluated the oncologic outcomes according to SLN positivity. Method: We retrospectively reviewed medical records of patients with pT1 breast cancer who underwent BCS including SLNB at Seoul National University Bundang Hospital from 2010 to 2015 (n=986). SLN positive was defined as one or more micro- to macro-metastasis in axillary lymph node specimen. Overall, regional, and systemic recurrence-free survival (RFS, RRFS, SRFS) and overall survival (OS) were estimated by the Kaplan-Meier analysis. Result: Of 986 patients, positive SLN was observed in 116 patients (11.8%). Regarding T substages, T1mic, T1a, and T1b gouprs showed SLN positive rate of 0%, 3.4%, and 8.5% respectively whereas T1c showed 15.3%. Multivariable logistic regression analyses revealed clinical T stage (OR 1.791, 95% CI 1.061-3.023, P=0.029), &amp;gt;C2 finding in preoperative axillary ultrasonograpy (OR 3.021, 95% CI 1.740-5.248, P&amp;lt; 0.001), usual histologic type including invasive ductal carcinoma, invasive lobular carcinoma, and metaplastic carcinoma confirmed in preoperative biopsy (OR 4.406, 95% CI 1.357-14.305, P=0.014) to be independent predictive factors for SLN positivity. The median follow-up period was 103.03 months. The 5 year RFS, RRFS, SRFS, and OS showed no statistical difference between SLN positive group and negative group. In multivariable Cox regression analysis, serum CEA level higher than 5ng/ml at diagnosis (HR 7.534, 95% CI 3.336-17.019, P=0.002) and Ki-67 level higher than 20% (HR 7.534, 95% CI 3.336-17.019, P&amp;lt; 0.001) were shown to be the independent prognostic factors for RFS. Conclusion: Our data implicates that patients with T1c breast cancer should undergo SLNB at all times presently, considering substantially higher SLN positive rate compared to other T1 substages (16.8% vs. 6.1%, P&amp;lt; 0.001) although no survival difference was observed between SLN positive group and negative group. Kaplan-Meier curve of recurrence-free survival and overall survival Kaplan-Meier curve of recurrence-free survival and overall survival Kaplan-Meier analyses revealed no difference of recurrence-free survival, overall survival between SLN-positive and SLN-negative group. Univariable and multivariable model for recurrence-free survival Higher Ki-67 expression, ER negativity, PR negativity, HER2 positivity were shown to be independent risk factors associated with shorter RFS. Multivariable analysis showed higher Ki-67 expression as the sole independent risk factor for shorter RFS. Citation Format: Hyoung Won Koh, Hee-Chul Shin, Eun-Kyu Kim, Eunyoung Kang. Positive sentinel lymph node does not affect prognosis in T1 breast cancer patients who undergo breast conserving surgery with sentinel lymph node biopsy. [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 P3-05-32.

Abstract P5-06-06: TROP2 and HER2 expression by liquid biopsy in women with mTNBC

Abstract Introduction A blood-based biopsy can inform the prognosis for MBC patients when conventional tissue biopsies are not feasible within often biologically heterogeneous sites of metastatic disease. Several anti-Trophoblast cell-surface antigen 2 (TROP2) and HER2 targeted therapies are now available, either as approved therapy options or in clinical trials for MBC patients. Tumor expression of TROP2 is prominent in metastatic cancers, such as HER2-negative MBC and TNBC, with limited treatment options. Technical feasibility data of blood-based TROP2 and HER2 immunofluorescence assays demonstrate the utility of the Epic Sciences platform for this cohort of metastatic TNBC (mTNBC) patients. Methods Cultured cancer cells (expressing TROP2, HER2, or neither) were added to Healthy Donor (HD) blood, creating the model system used in assay development studies. Blood from 11 confirmed mTNBC patients was collected to analyze this clinically relevant population. Immunofluorescence staining and image analysis were performed on replicate blood-based biopsy slides to assess expression for TROP2 and HER2. CTCs were identified and characterized using Epic Sciences digital imaging and machine learning algorithms. Results Three cancer cell lines of various TROP2 expression levels (HEK293, low; MDA-MB-231, intermediate; and A431, high) exhibited immunofluorescence signal ranges of 168 MFI, 2147 MFI, and 26982 MFI, respectively. A fluorescence cutoff of 218 MFI was established following assay optimization to distinguish TROP2 positive CTCs based on a 95% confidence level. Within the cohort of 11 mTNBC patients, 100% of patients with mTNBC had detectable CTCs. 64% of mTNBC patients had TROP2 positivity (MFI, mean: 1328, range: 37-38281)). On the other hand, 0% of mTNBC patients had HER2 positivity (MFI, mean: 128, range: 40-361)). To date, studies with biomarker expression for these two drugs have been limited to tissue biopsy, which may not always yield contemporaneous sampling in the metastatic setting. These results offer a potential liquid biopsy test identifying pts more responsive to trop2 and her2 directed therapies. Discussion Here we report on a liquid biopsy profile combining protein expression of TROP2 and HER2. Blood-based assessment of TROP2 and HER2 expression is a potential marker for selecting MBC patients likely to respond to anti-TROP2 targeted therapies such as Sacituzumab, or Trastuzumab Deruxtecan has shown to improve survival in mTNBC in the ASCENT trial and DESTINY-04 studies. Recent data on the Destiny-04 trial, which allocated HER2 expressing MBC patients into T-DXd treatment, transformed the definition of TNBC. The development of quantitative, reproducible, and more sensitive immunofluorescence assays is becoming crucial for assigning patients whose disease continually evolves to targeted therapies by increasing clinical trial options. Analysis of the clinical utility of the blood-based cell analysis in guiding patient selection strategies for novel anti-TROP2, HER2, and other targeted therapies treatment in MBC is ongoing. Citation Format: David Bourdon, Alessandra Cunsolo, Brandon Guillory, Megan M. Slade, Giuseppe Di Caro, Alisa Tubbs, Toshiaki Iwase, Naoto T. Ueno. TROP2 and HER2 expression by liquid biopsy in women with mTNBC [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 P5-06-06.

Abstract OT2-01-06: Phase II trial of palbociclib plus endocrine therapy followed by combination of pembrolizumab, palbociclib and endocrine therapy in patients with hormone receptor positive metastatic breast cancer

Abstract Background: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is standard-of-care for patients with hormone receptor positive (HR+) HER2- metastatic breast cancer (MBC). Immune modulatory effects of CDK4/6i are well documented preclinically but poorly understood in the clinical setting. Our previous study combining letrozole, palbociclib and pembrolizumab in patients with HR+ MBC (NCT02778685) showed a promising complete response rate of 31%. Dynamic changes in peripheral blood mononuclear cell (PBMC) subpopulations indicated that palbociclib may increase CD8+ TEMRA (terminally differentiated effector memory cells) and CD4+ TEM (effector memory cells) and enable immune activation. The current cohort 3 was designed to study the immune modulatory effect of palbociclib as an immune-priming agent with a biomarker enriched design. Methods: Women with ECOG 0-1, HR+ HER2- MBC, RECIST 1.1 measurable disease, no prior therapy for MBC were enrolled. Patients with endocrine therapy, including aromatase inhibitor +/- ovarian suppression or fulvestrant, were eligible. A palbociclib + ET lead-in design was used, starting on day -28 followed by combination therapy with pembrolizumab added on C1D1. Peripheral blood and tumor biopsy at baseline and on-treatment were collected to allow in-depth analysis of biomarkers predicting response to the combination. The primary endpoint was to evaluate if the palbociclib potentiated immune responses as a “priming” agent through PBMC analysis and on treatment tumor biopsy. Secondary endpoints included other immune cell subsets and changes that follow the combination with pembrolizumab. With 25 patients, assuming a standard deviation of 0.51 in the relative change in classic monocytes in PBMCs, there is 90% power to detect a relative change of log(C1D1/baseline) of 34.5% with a type I error (two-sided) of 0.05. Results: Between August 2020 and April 2022, 16 patients were enrolled in cohort 3. Currently 11 patients have adverse event (AEs) and 16 patients have response data. Median age was 57 years (39-72). 8/11 (73%) were non-Hispanic white, 1/11 (9%) Hispanic, 1/11 (9%) Asian, and 1/11 (9%) African American. 87% patients had grade 3 AEs, and 30% had grade 4 AEs. Grade 3 AEs were 9/11 (82%) neutropenia, 5/11 (45%) leukopenia, 1/11 (9%) elevated LFTs, and 1/11 (9%) each lymphopenia, hot flashes, febrile neutropenia, and pneumonitis. Grade 4 AEs were 1/11 (9%) lymphopenia. 8/16 (50%) patients achieved a partial response (PR), 5/16 (31%) had stable disease (SD), and 1/16 (6%) had progression of disease (PD) by RECIST 1.1. Additionally, 2/16 (13%) patients were too early to determine best overall response. Response rate (CR+PR) was 50%. PBMCs and tumor microenvironment profiling are ongoing. Conclusion: The combination of palbociclib, pembrolizumab and ET is well tolerated, and a response rate of 50% was identified in HR+ MBC patients who received this combination as front-line therapy. Dynamic changes in peripheral blood mononuclear cells and tumor microenvironment profiling are ongoing. Citation Format: Yuan Yuan, Colt A. Egelston, Weihua Guo, Susan E. Yost, Paul H. Frankel, Christopher Ruel, Mireya Murga, Aileen Tang, Norma Martinez, Daniel Schmolze, Daphne Stewart, James Waisman, Kelly Yap, Joanne Mortimer, Niki Tank. Phase II trial of palbociclib plus endocrine therapy followed by combination of pembrolizumab, palbociclib and endocrine therapy in patients with hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-06.

Abstract P5-09-05: A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE trial)

Abstract Background: Tucidinostat (formerly known as chidamide) plus exemestane is approved for postmenopausal patients with advanced, hormone receptor-positive breast cancer. We evaluated the efficacy and safety of tucidinostat plus exemestane as the neoadjuvant strategy in hormone receptor-positive early breast cancer patients. Methods: NeoTEE is an open-label, single-center, phase II study. Patients with HR-positive, HER2-negative and stage II/III breast cancer were enrolled at the First Affiliated Hospital of Sun Yat-sen University. Eligible patients received 25 mg oral exemestane once daily for 2 weeks followed by 30 mg oral tucidinostat twice weekly in combination with 25mg oral exemestane once daily for 24 weeks. GnRHa was used for premenopausal patients. Endpoints assessed here included objective response rate (ORR), complete cell cycle arrest (CCCA, Ki-67≤2.7%) at surgery, disease control rate (DCR), pathological complete remission (pCR) and safety. Results: Between July 2020 and July 2022, 26 patients were enrolled, of whom 24 were evaluable for response per RECIST 1.1 criteria. Partial response (PR) was observed in 18 patients, with an ORR of 75% (18/24). The DCR was 100%. Of the 14 patients with surgery, one patient achieved pCR and 8 patients were exempt from postoperative adjuvant chemotherapy. CCCA at surgery was 64.3% (9/14). The follow-up remains ongoing and updated results will be presented thereafter. Most adverse events (AEs) were grade 1 or 2. Grade 3 AEs occurred in 8 of 26 patients, the most common were neutropenia 19.2%, leukopenia 7.7%, anemia 3.8%, ALT increased 3.8%, pneumonitis 3.8%. Only 1 patient experienced grade 4 neutropenia. Grade 3/4 neutropenia recovered after dose reduction or discontinuation of tucidinostat. No patient received G-CSF. Conclusions: Tucidinostat combined with exemestane was well tolerated and demonstrated meaningful responses in neoadjuvant setting for women with early HR+/HER2- breast cancer. Further investigation is warranted. Clinical trial information: NCT04465097. Citation Format: zhen shan, nan shao, xiaoling zhang, huijuan shi, yanling zheng, jia luo, tiantian zhen, ruping chen, Ying Lin. A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE 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 P5-09-05.

Abstract PD1-07: Racial disparities in neoadjuvant chemosensitivity and survival in early breast cancer: A national database study

Abstract Background: Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancer (BC). Patients (pts) who attained pathological complete response (pCR) with NAC have a better prognosis when compared to those who have residual disease (RD). We analyzed the association of race with neoadjuvant chemosensitivity in early BC and the overall survival (OS) based on the chemosensitivity. Methods: We queried the National Cancer Database for early BC pts who received NAC from 2010-2016. Preoperative chemosensitivity was defined as very sensitive (VS) (ypT0/TisN0), sensitive (S) (pathological TNM stage less than clinical, excluding ypT0N0), and refractory (R) (pathological greater than or equal to clinical). Demographic, clinical, treatment, and survival rates were summarized by race focusing on neoadjuvant chemosensitivity. All associations were compared using Kruskal-Wallis, Pearson’s Chi-Squared, and Fisher’s Exact Tests. Multivariate cox models were generated for the OS. All analyses were conducted in RStudio v4.0.2 at a significance level of 0.05. Results: A total of 103,605 pts who received NAC were analyzed. 43.2% (n= 44,796) were R, 34.4% (n= 35,638) were S and 22.4% (n= 23,171) pts were VS. The 3-year (yr) OS rates for R, S, VS groups were 81%, 88%, 95% respectively (rsp) (p&amp;lt; 0.001). The 5-yr OS rates were 73%, 82%, 92% rsp (p &amp;lt; 0.001). In the hormone-receptor positive HER2 negative (HR+) subtype, only 8.9% (n= 3,837) were VS, while among triple negative breast cancer (TNBC) subtype, 28.4% (n= 9,224) pts were VS, among HER2 positive (HER2+) subtype, 36.7% (n=9,665) pts were VS and in both subtypes around 28-36% were R as opposed to 58.4% with R disease among HR+ subtype. Among HR+ group, pts had more R disease regardless of race (all races R: 54-57%, p &amp;lt; 0.001). Among HER2+ disease, Blacks had lower percentage of VS disease compared to other races (32% vs 37-40%, p&amp;lt; 0.001). Among TNBC, more R disease was seen among Blacks compared to other races (38% vs 30-35%, p&amp;lt; 0.001). In whole cohort, as expected, compared to pts with R disease, pts with S and VS disease had lower overall mortality risk (HR= 0.45, 95% CI= 0.43 – 0.46, P&amp;lt; 0.001, HR= 0.20, 95% CI = 0.19- 0.21, p &amp;lt; 0.001 rsp). In TNBC subgroup among pts with R disease, the median OS of Blacks was significantly lower compared to whites (71.9 vs 101.8 months, p &amp;lt; 0.001). Among BC subtypes, the 3-yr and 5-yr OS for R (65%, 56%) and S groups (83%, 76%) were significantly lower in TNBC when compared to other subtypes (HR+ R: 3-yr- 88%, 5-yr- 79% and S: 3-yr- 90%, 5-yr- 83%; HER2+ R: 3-yr- 85%, 5-yr- 77% and S: 3-yr- 92%, 5-yr- 86%, p&amp;lt; 0.001). In the whole cohort, Blacks with R, S, VS disease had significantly lower 3yr (73%, 85%, 94% rsp) and 5yr OS (63%, 78%, 91% rsp) compared to all other races and this was more prominent in the R and S groups (Table 1). Conclusion: Blacks diagnosed with TNBC were more resistant while other races were more sensitive to NAC. In all BC subtypes, Blacks had lower 3-yr and 5-yr OS regardless of chemosensitivity (including those who attained pCR), though this disparity was more predominant among those with residual disease after NAC (resistant and sensitive group). Since Blacks who do not attain pCR have worse survival compared to other races, it highlights the need to design more effective and personalized treatment strategies for Blacks to help them attain pCR, especially in the TNBC subtype. Table 1: Racial Disparities in Survival in Different Chemosensitivity Groups Citation Format: Arya Mariam Roy, Kayla Catalfamo, Kristopher Attwood, Shipra Gandhi. Racial disparities in neoadjuvant chemosensitivity and survival in early breast cancer: A national database study. [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 PD1-07.

Abstract P2-03-06: Real world treatment of node negative low and intermediate recurrence score breast cancer

Abstract Introduction: Patients younger than 50 years old with node negative hormone receptor (HR) positive her2 negative breast cancer and oncotype Dx recurrence scores (RS) under 16 do not benefit from adjuvant chemotherapy. Those with a RS between 16-25 may have a marginal benefit from the addition of adjuvant chemotherapy, however a similar benefit may be achieved with adjuvant ovarian function suppression (OFS). The aim of this study is to describe real world treatment patterns and outcomes of premenopausal node negative patients with low and intermediate RS, with an emphasis on adjuvant OFS, endocrine therapy (ET), and menopausal status during adjuvant treatment. Methods: We retrospectively reviewed the records of all node negative patients under 50 years old who were sent for oncotype testing between 2008 and 2018. One hundred and sixty-five patients with low or intermediate RS were included in our analysis. Continuous variables were described using medians and interquartile range (IQR). Categorical variables were described as frequencies and percentages. Differences between categorical variables were analyzed with the chi squared test and survival was analyzed using the Kaplan-Meier method. The cox proportional hazards model was used to test the effect of multiple factors on survival. Breast cancer specific survival (bcss) was defined as the time to first breast cancer recurrence (local recurrence, second breast cancer, distant recurrence) and distant disease-free survival (ddfs) was defined as the time to any distant recurrence. Results: The median age was 44 (41-47) and median RS was 17 (14-20). Median follow-up time was 82 (61-108) months. One hundred and three (62.4%) patients had low clinical risk as defined in TailorX and 136 (82.4%) had intermediate RS. Fourteen (8.5%) patients with nodal micrometastases were also included. Only 5 (3%) patients received adjuvant chemotherapy and 74 (44.8%) received adjuvant OFS. Of the 91 (55%) of patients who did not received OFS, 21 (23%) went into menopause or underwent subsequent oopherectomy while on adjuvant ET. One hundred and three (62.4%) patients received adjuvant tamoxifen alone, 16 (9.7%) received an aromatase inhibitor alone, and 40 (24.2%) underwent an endocrine switch with all but 1 beginning treatment with tamoxifen. There were no significant differences in clinical risk or RS risk group between patients that received and did not receive OFS. There were 22 (13.3%) bcss recurrences. Twelve (7.2%) patients had a local recurrence, 5 (3%) patients had second breast cancers, and 5 (3%) had a distant recurrence as their first recurrence. Overall, only 6 (3.6%) patients had a distant recurrence. Both OFS and ET type were not significantly associated with bcss or ddfs. On univariate analysis menopause during ET was significantly associated with improved bcss (HR= 0.2, 95% CI 0.05-0.85), however on multivariate analysis it was no longer significant. Conclusion: With only 6 (3.6%) distant recurrences over a median follow-up of over 6.5 years node negative premenopausal women with low or intermediate RS treated in our institution show an excellent prognosis regardless of treatment type. Our results support the evidence that most of these patients do not need chemotherapy and suggests that most patients do not require OFS as well. Additional data examining the relationship between gene expression profiles and OFS benefit are needed to help guide OFS treatment in premenopausal patients who do not require chemotherapy. Citation Format: Opher Globus, Keren Levanon, Einav Nili-Gal Yam. Real world treatment of node negative low and intermediate recurrence score breast cancer [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 P2-03-06.