Receptor Positive HER2 Research Articles

Abstract P1-10-01: Postmastectomy electron beams radiation therapy (PMERT) : long term results

Abstract Background/Purpose: This study evaluates the toxicity after radiotherapy after mastectomy without reconstruction in patients irradiated to the chest wall using previously reported technique of PMERT. Materials/Methods: We included all women irradiated after mastectomy for not metastatic breast cancer with PMERT between 2007 and 2011 in the Department of Radiation Oncology of the Institut Curie. Previously reported technique using mostly electrons was evaluated in terms of efficacy and toxicity. Acute and late toxicities were assessed retrospectively using CTCAE v.4.0. A clinical exam was weekly performed during radiotherapy and one and three months following the completion of radiotherapy. Patients were then followed as recommended in Institut Curie guidelines (Senorif). Quantitative and qualitative data were described respectively as means and proportions. Statistical comparisons were computed using X² or Fischer’s exact test for categorical data. Recurrence free survival (RFS) was defined as the time between the end of treatment and the date of recurrence or death. Overall survival was the same but recurrences were not taken into account. Patients who did not experienced any event were censored at the date of last news. Results: Among the 796 women included, 51.3% had multifocal lesions, 10.1% a triple negative (TN) status and 18.8% a HER2+ positive status; 196 (24.6%) received a neoadjuvant chemotherapy, and 208 (26.1 %) a systemic therapy during radiotherapy (chemotherapy and/or targeted therapy); 514 (64.6%) had at least one positive lymph node (LN). Internal mammary chain (IMC) was treated in 85.6% of cases, supraclavicular LN (L4) in 88.3% of cases, infraclavicular (L3-2-IP+/- L1) LN in 77.9% of cases and low axilla (L1) in 14.9% of cases. With a median follow up of 113 months [range : 2-164] locoregional recurrence-free survival and overall survival at 10 years were respectively 94.02 (IC95% : 92.13-98.94) and 79.84 (IC95% : 76.83-82.97). The median survival was not reached. In the long term, 29.6% of patients had telangiectasia (grade 1: 23.3%, grade 2: 5.2% Grade 3: 1.1%). Totally 279 patients (35.1%) had breast reconstruction, on average 21 months after the end of radiotherapy. Twenty-five patients (3%) had early esophageal toxicity, not exceeding the grade 1. Of these patients, 21 had had chemotherapy and all were irradiated on the lymph nodes (24 including the IMC). Irradiation of the IMC was not associated with an increased chronic lung toxicity (OR=1.03 [0.98-1.09]). There were 35 patients who developed heart disease after the end of the treatment. Of them, 30 patients had received anthracyclines (p=1.05) and 9 trastuzumab (p =1.09). Four patients developed ischemic heart disease, 3/4 irradiated on the left chest wall, all on the CMI and supra and infraclavicular LN, but all of them presented multiple cardiovascular risk factors (2 to 4). Conclusions: Our series have shown that the PMERT using the Institut Curie technique is effective and well tolerated. Table 1. patients and tumor characteristics (n=796). HR+ : hormonal receptor positive HER2+ : HER-2 overexpressed Cardiovascular risk factor : (smoking, hypertension, dyslipidemia, diabetes, obesity, family history of coronary heart disease or vascular events) as described by the French Health Authority (HAS, Haute Autorité de Santé). Table 2. Efficiency (n=796, median follow-up: 113 months; range : [2-164]). HR+ : hormonal receptor positive HER 2+ : Her-2 overexpressed TNBC : Triple negative or basal-like cancer, OS : overall survival LRFS : local recurrence free survival LRRFS : locoregional recurrence free survival MFS : metastasis free survival Multivariate analysis : long term toxicity IMC irradiation : Irradiation of the internal mammary chain, OR : Odd ratio Citation Format: Souidi Sami, Pierre Loap, Alain Fourquet, Youlia M. Kirova. Postmastectomy electron beams radiation therapy (PMERT) : long term 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 P1-10-01.

Abstract PD1-04: Neighborhood Deprivation Index and Survival in Breast Cancer in the United States

Abstract Introduction: Socioeconomic status (SES) of the individual and neighborhood plays an important role in patients’ (pts) access to the health system and eventually in the outcomes of their disease. Owing to the inequalities in opportunities, education, income, and developmental infrastructures, the area with deprived individual and neighborhood SES may be associated with a poor prognosis of certain malignancies and worse outcomes. We analyzed the association between Neighborhood Deprivation Index (NDI) and survival of early-stage breast cancer (BC). Methods: The NDI created by the National Cancer Institute includes variables from dimensions, such as, wealth and income, education, occupation, and housing conditions which have been used for our analysis. We analyzed the impact of NDI in quintiles (qn). We queried the SEER database from 2010-2016 for all early-stage BC pts and studied the overall survival (OS) and disease-specific survival (DSS) of BC in association with NDI. Cox multivariate regression modeling was performed to measure the association between NDI and OS/DSS. Kruskal-Wallis test was used for comparison for continuous and Chi-Square test was used for categorical variables. All analyses were adjusted for age, race, grade, insurance, surgery (SX), radiation (RN), and chemotherapy (CT). Statistics were performed using SAS. Results: Out of the 88,572 early-stage BC pts, 27.4 % (n= 24,307) were in the most deprivation (MD) qn, 26.5% (n= 23,447) were in the average deprivation (AD) qn, 17% (n= 15,035) were in the above average deprivation (AA) qn, 15.6% (n= 13,838) were in the least deprivation (LD) qn and 13.5% (n= 11,945) were in the below average deprivation (BA) qn. The median age of pts in the LD qn was 59 and MD qn was 61 yrs, p< 0.001. There was a predominance of racial minorities in the MD and AA qn with Blacks being 13-15% and Hispanics being 15% compared to only 8% Blacks and 6% Hispanics in the LD qn (p< 0.001). There was a higher percentage of uninsured pts in the MD qn compared to LD qn (2.2% vs 1.7%, p< 0.001). There were more rural areas in MD qn compared to LD qn (25.9% vs only 0.7%, p< 0.001). There were more pts with grade III disease in MD qn compared to LD qn (34% vs 31.9%, p< 0.001). 96.1% pts underwent SX in MD qn vs 97.1 % had SX in LD qn, p< 0.001. Similarly, 49.7% underwent RN in MD qn vs 56.5% had RN in the LD qn, p< 0.001. Greater percentage of pts received CT in MD qn compared to LD qn (44.6% vs 42.1%, p< 0.001). There was a higher percentage of more aggressive cancers such as triple-negative breast cancer (TNBC) and HER2 positive (HER2+) in MD qn compared to LD qn (14.5%, 17.7% vs 11.7%, 16.5% respectively, p< 0.001). In multivariate analysis, in the overall cohort, those who live in AA qn and MD qn have inferior OS and DSS when compared to those who live in LD qn (OS in AA: Hazard Ratio (HR) 1.3, 95% CI: 1.2-1.4; OS in MD: HR 1.2, 95% CI: 1.1-1.3; DSS in AA: HR 1.3, 95% CI: 1.2-1.5; DSS in MD: HR 1.2, 95% CI: 1.1-1.4, all p< 0.001). Similar results in OS and DSS were observed in hormone receptor-positive HER2 negative (HR+) and HER2+ subtypes, but not in TNBC (Table 1). The 5-year OS rates and DSS rates were also comparatively low in AA qn and MD qn compared to LD qn (OS: AA- 84%, MD- 85%, LD- 98%; DSS: AA- 91%, MD- 92%, LD- 95%, all p< 0.001). Conclusion: Early-stage BC pts from areas with worse NDI have poor OS and DSS, after accounting for the demographic, clinicopathological, treatment-related factors. Investments in poor-resource neighborhoods and policies focusing on improving the SES of areas with high deprivation need to be implemented to reduce health care disparities and improve breast cancer outcomes. Table: Overall Survival and Disease Specific Survival Citation Format: Arya Mariam Roy, Anthony George, Kristopher Attwood, Shipra Gandhi. Neighborhood Deprivation Index and Survival in Breast Cancer in the United States [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 PD1-04.

Pretreatment neutrophil to lymphocyte ratio as prognostic factor in metastatic breast cancer treated with cyclin dependent kinase 4/6 inhibitors.

Cyclin dependent kinase inhibitors (CdK4/6i) changed the course of hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mBC). To date, no factors have been shown to predict response to CdK4/6i. Neutrophil-to-lymphocyte ratio (NLR), an indicator of the host systemic inflammatory response, is an independent prognostic factor for survival in cancers. We conducted this study to evaluate the impact of NLR on survival in mBC patients treated with first line CdK4/6i. All mBC patients treated with first line CdK4/6i between November 2015 and December 2019 were retrospectively included. The biomarker threshold was defined using ROC curves. We analyzed progression free survival (PFS), overall survival (OS), 12-month PFS and response rate according to NLR in univariable and multivariable analysis. A total of 126 patients treated with palbociclib (n=101), ribociclib (n=18) or abemaciclib (n=7) were included, with a median follow-up of 33 months [range: 2.9-57]. Median age was 65 years [29-86], 40% patients had good performance status (ECOG-PS 0). Most patients (71%) were included at the metastatic relapse stage and 29% had only bone metastases. Median PFS and median OS were 27 and 51 months, respectively. High NLR (≥ 2.53) was significantly associated with worse PFS (Hazard Ratio (HR)=0.50, CI95% = [0.32-0.79]) and worse OS (HR=0.45, [CI95%: 0.23-0.87]). In multivariable analysis, NLR and ECOG PS were independently factors associated with PFS (p=0.016 and p=0.001, respectively). High NLR was associated with worse PFS and OS in HR+ HER2- mBC patients treated with first line CdK4/6i. NLR is a reliable and inexpensive prognostic marker, easily accessible in routine clinical practice, which could help optimize the therapeutic strategy. These results need to be confirmed in larger prospective studies.

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer.

Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant+ Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival.

Determinants of pathological complete response to neoadjuvant chemotherapy in breast cancer: A single-institution experience.

Neoadjuvant chemotherapy (NACT) is routinely used in all cases of locally advanced breast cancer and some cases of early breast cancer. We previously reported a pathological complete response (pCR) rate of 8.3%. With the increasing use of taxanes and human epidermal growth factor receptor 2 (HER2)-directed NACT, we conducted this study to understand the current pCR rate and its determinants. A prospective database of breast cancer patients who underwent NACT followed by surgery between January and December 2017 was evaluated. Of the 664 patients, 87.7% were cT3/T4, 91.6% were grade III, and 89.8% were node-positive at presentation (54.4% cN1, 35.4% cN2). The median age was 47 years; median pre-NACT clinical tumor size was 5.5 cm. Molecular subclassification was 30.3% hormone receptor positive (HR+) HER2-, 18.4% HR+HER2+, 14.9% HR-HER2+, and 31.6% triple negative (TN). Both anthracyclines and taxanes were given preoperatively in 31.2% patients whereas 58.5% of HER2 positive patients received HER2-targeted NACT. The overall pCR rate was 22.4% (149/664), 9.3% in HR+HER2-, 15.6% in HR+HER2+, 35.4% in HR-HER2+, and 33.4% in TN. On univariate analysis, duration of NACT ( P < 0.001), cN stage at presentation ( P = 0.022), HR status ( P < 0.001), and lymphovascular invasion ( P < 0.001) were associated with pCR. On logistic regression, HR negative status (Odds ratio [OR] 3.314, P < 0.001), longer duration of NACT (OR 2.332, P < 0.001), cN2 stage (OR 0.57, P = 0.012), and HER2 negativity (OR 1.583, P = 0.034) were significantly associated with pCR. Response to chemotherapy depends on molecular subtype and duration of NACT. A low rate of pCR in the HR+ subgroup of patients warrants reconsideration of neoadjuvant strategies.

Capecitabine efficacy after cycline-dependent-kinase 4/6 inhibitor plus endocrine therapy in metastatic hormone receptor-positive breast cancer

BackgroundThe combination of endocrine treatment with cycline-dependent-kinase 4/6 inhibitor is the new standard of treatment in hormone receptor-positive HER2 negative metastatic breast cancer. The optimal subsequent treatment after CDK4/6 inhibitor remain unclear. As recommended by standard guidelines, capecitabine, an oral chemotherapy is a therapeutic option in endocrine resistant metastatic breast cancer.The objective of this study was to evaluate capecitabine efficacy after disease progression under combination of ET and CDK4/6 inhibitor in a hormone receptor positive metastatic breast cancer population. Patients and MethodsPatients progressing under CDK 4/6 inhibitor plus ET and treated with capecitabine, between January 2016 and December 2020, were retrospectively included. Primary endpoint was time to treatment failure (TTF) on capecitabine. Logistic regression were used to identify predictive factors: exclusive bone versus visceral metastases, first-line versus ≥ 2 lines of combination therapy, aromatase inhibitor (AI) versus fulvestrant. ResultsFifty-six patients with a 62-year median age (IC95% 42–81) were analyzed. The CDK 4/6 inhibitor and ET combination was prescribed in first-line setting in 26 patients (46%). Twenty-five patients (44%) had exclusive bone metastasis.Median TTF was 6.1 months. Six patients discontinued capecitabine due to toxicity. Outcomes were not significantly different regardless of metastases localization, ET, and treatment line of the combination of CDK 4/6 inhibitor and ET. Median PFS was 7.1 months. Median OS was 41.3 months. ConclusionCompared to other data of capecitabine prescribed in patients with hormonal resistant MBC, this retrospective study suggests that capecitabine remains effective after CDK 4/6 inhibitor plus ET progression, regardless of therapeutic-line setting and metastases localization. Micro AbstractCycline dependant kinase 4/6 inhibitor plus endocrine therapy have become the standard of care in metastatic hormone receptor positive (HR+) breast cancer (BC). Few data reported the optimal subsequent therapy after progression under the combination. Capecitabine is a therapeutic option in endocrine resistant HR+/HER2- metastatic breast cancer. Data evaluating efficacy of capecitabine after disease progression on endocrine therapy plus cycline-dependant kinase 4/6 inhibitor are poor. This study showed a 6.1-month median time to treatment failure on capecitabine. Capecitabine remained effective regardless of therapeutic-line setting and metastases localization.

Abstract PR007: Candidate antigens for a ductal carcinoma in situ vaccine, essential for breast cancer cell survival across multiple subtypes, are immunogenic in DCIS and IBC

Abstract Vaccine therapy may to destroy the current ductal carcinoma in situ (DCIS), prevent recurrence, and have little risk of long-term complications. One of the limitations for a DCIS vaccine is identifying appropriate antigens which, when targeted, may be able to treat DCIS and prevent development of IBC. In this study, we identified proteins that were overexpressed in both DCIS and IBC tumors across fifteen human Geo and Array Express data sets. From the 68 candidate proteins, twelve proteins expression was necessary for cancer cell survival across breast cancer subtypes using a high throughput siRNA screen. We chose candidates that increased apoptosis and decreased cell survival in human HER2 positive (HER2), triple negative (TN), and hormone receptor positive HER2 negative (HR) human breast cancer cell lines with decreased expression of the target protein. Twelve proteins (AURKA, KIF11, NDC80, RRM2, SDC1, UBE2C, HJURP, CENPA, CENPF, HIST2H2AA3, KRT8, and TOP2A) were the twelve antigens developed for the vaccine. All twelve targets were immunogenic in women with DCIS and IBC as compared to age matched control women. For example, autoantibodies to four of the antigens (AURKA, NDC80, KRT8, and RRM2) predicted women with DCIS with AUC 0.69 (p=0.005 95% CI 0.56 to 0.80) and IBC with AUC 0.79 (p&amp;lt;0.001 95% CI 0.66 to 0.90) as compared to age matched control women in a discovery set of 59 DCIS patients, 37 IBC patients, and 43 control women. In an independent validation set of serum samples of 50 DCIS, 60 IBC, and 50 control patients, autoantibodies to the four candidate antigens could predict women with DCIS with AUC 0.62 (p=0.04, 95% CI 0.51 to 0.73) and IBC with AUC 0.69 (p&amp;lt;0.001, 95% CI 0.60 to 0.79). Autoantibodies to the four DCIS antigens could identify each subtype of breast cancer subtype as compared to control, HR+(n=20 patients) with AUC 0.69 (p=0.01, 95% CI 0.55 to 0.83), HER2+ (n=20 patients) with AUC 0.70 (p=0.01, 95% CI 0.55 to 0.84), and TN (n=20 patients) with AUC 0.74 (p=0.002, 95% CI 0.61 to 0.87). All these were IgG autoantibodies suggest pre-existing T cells that recognize the candidate antigens because Ig class switching from IgM to IgG requires antigen-specific T cells. These twelve candidate antigens, overexpressed in human breast cancer, are also overexpressed in the TgMMTV-neu and C3(1)Tag transgenic mouse mammary tumor models of breast cancer. Vaccination with human MHC Class II predicted epitopes from KRT8, conserved between mouse and human, inhibited tumor growth in TgMMTV-neu mice by 47% and C3(1)Tag by 62%. The KRT8- specific IFN-g immune response developed was associated with lower tumor volume with mice vaccinated with the human MHC Class II Th1 KRT8 epitopes with the KRT8-specific IFN-g immune response associated with smaller tumors in TgMMTV-neu mice (R2= 0.64, p=0.02). We plan to develop these antigens in a multi-antigen DCIS vaccine that may be able to destroy DCIS and prevent breast cancer across all breast cancer subtypes. Citation Format: Sasha E. Stanton, Jason Schlumbohm, Mary L. Disis. Candidate antigens for a ductal carcinoma in situ vaccine, essential for breast cancer cell survival across multiple subtypes, are immunogenic in DCIS and IBC [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR007.

Expression of c-MET in Estrogen Receptor Positive and HER2 Negative Resected Breast Cancer Correlated with a Poor Prognosis.

Introduction: The mesenchymal-epithelial transition factor (c-MET) receptor is overexpressed in about 14−54% of invasive breast cancers, but its prognostic value in clinical practice is still unclear. Methods: In order to investigate the relationship between c-MET expression levels and prognosis, we retrospectively reviewed the clinical features and outcomes of 105 women with estrogen receptor positive HER2 negative (ER+/HER2-) resected breast cancer. We used the Kaplan Meier method to estimate Disease Free Survival (DFS) and Breast Cancer Specific Survival (BCSS) in the subgroups of patients with high (≥50%) and low (<50%) c-MET expression. Univariate and multivariate Cox proportional regression models were performed to assess the prognostic impact of clinicopathological parameters for DFS an BCSS. Results: High c-MET values significantly correlated with tumor size, high Ki67 and low (<20%) progesterone receptor expression. At a median follow up of 60 months, patients with high c-MET tumor had significantly worse (p = 0.00026) and BCSS (p = 0.0013). Univariate analysis showed a significant association between large tumor size, elevated Ki67, c-MET values and increased risk of recurrence or death. The multivariate COX regression model showed that tumor size and high c-MET expression were independent predictors of DFS (p = 0.019 and p = 0.022). Moreover, large tumor size was associated with significantly higher risk of cancer related death at multivariate analysis (p = 0.017), while a trend towards a poorer survival was registered in the high c-MET levels cohort (p = 0.084). Conclusions: In our series, high c-MET expression correlated with poor survival outcomes. Further studies are warranted to validate the clinical relevance and applicability of c-MET as a prognostic factor in ER+/HER2- early BC.

463P Cost effectiveness of palbociclib and ribociclib in metastatic breast cancer in India using ICER and QALY

Cyclin dependent kinase inhibitors (CDK 4/6) are the mainstay of treatment in metastatic Hormone receptor positive (HR+) HER-2 negative breast cancer, having impressive Progression free survival (PFS) and overall survival (OS) results. The approved agents are Palbociclib, Ribociclib and Abemaciclib. OS data are not yet mature for Abemaciclib. Cost effectiveness of these drugs has not been studied in the Indian context, where most patients resort to out of pocket expenditure (OOP). This study was undertaken to analyse the cost effectiveness of Palbociclib and Ribociclib by calculating the quality adjusted life years (QALY) and Incremental cost effective ratio (ICER).

211 (PB-035) Poster - Breast cancer management with CDK4/6 inhibitors as first line treatment: a single institution retrospective review

Background: The excellent results of phase 3 randomized trials have rendered cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine treatment (ET) as the new standard of care for both endocrine-sensitive and -resistant patients (pts). We performed a single institution retrospective review of pts with metastatic hormone receptor positive (HR+) HER2 negative (HER2-) breast cancer (MBC) receiving CDK4/6i in I line setting.

Abstract 3380: Seven autoantibody panel, validated in two independent patient serum collections, can detect women with DCIS and invasive breast cancer

Abstract Mammography is essential to identify early breast cancer but the sensitivity is dependent on breast characteristics. A serum-based biomarker used along with mammography to identify lesions that need to be biopsied may improve the sensitivity of mammography and reduce the number of biopsies needed. We have identified a panel of autoantibodies found in early breast cancer. An autoantibody biomarker is ideal because antibody immunity can be detected with very low levels of antigen with direct antigen recognition by B cells resulting in clonal amplification of antigen specific plasma cells. Work in our laboratory has identified tumor-associated proteins present in pre-malignant tumors that are necessary for survival of human breast cancer cells across breast cancer subtypes. Increased autoantibodies to seven of these early tumor-associated proteins (PDIA6, KRT8, SERBP1, ARPC2, RRM2, AURKA, and NDC80) were present in the sera of women with DCIS and invasive breast cancer in two independent serum collections but not in control women with no known breast lesions. The presence of autoantibodies in the discovery set was evaluated in 185 individuals: 42 control women, 12 women with hyperplasia, 36 patients with fibroadenoma, 59 patients with ductal carcinoma in situ (DCIS), and 36 patients with invasive breast cancer (IBC). The validation set was evaluated in 228 individuals: 50 control patients, 50 patients with fibroadenoma, 18 patients with hyperplasia, 50 patients with DCIS, and 60 patients with IBC, 20 with hormone receptor positive (HR+) HER2 negative, 20 with HER2+, and 20 triple negative (TN). We defined a positive autoantibody response as over 2 standard deviations above the mean found in control women. All seven autoantibodies could predict patients with hyperplasia, fibroadenoma, DCIS, and IBC in both the discovery and validation sets. For example, the seven-antibody panel could identify DCIS from control women with AUC of 0.95 (95% CI 0.912 to 0.995, p&amp;lt;0.0001) and validation set AUC 0.63 (95% CI 0.52 to 0.74, p=0.026). The seven-antibody panel could identify IBC from control women with AUC of 0.85 (95% CI 0.73 to 0.97, p&amp;lt;0.0001) and validation 0.70 (95% CI 0.60 to 0.79, p&amp;lt;0.0001). Furthermore, the seven-antibody panel could identify women with each of the breast cancer subtypes as compared to control women. Women with HR+HER2- breast cancer could be detected with AUC 0.69 (95% CI 0.55 to 0.83 p=0.014), women with HER2+ breast cancer could be detected with AUC 0.69 (95% CI 0.52 to 0.90, p=0.02), and women with triple negative breast cancer could be detected with AUC 0.69 (95% CI 0.55 to 0.83, p=0.002) in the validation set. Future studies will evaluate this panel in a prospective study at the time of mammography to identify a serum biomarker that will improve sensitivity of mammography. Citation Format: Sasha Elizabeth Stanton, Jason Schlumbohm, Erik Ramos, Charles Drescher, Jeffrey Marks, Mary L. Disis. Seven autoantibody panel, validated in two independent patient serum collections, can detect women with DCIS and invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3380.

RB loss determines selective resistance and novel vulnerabilities in ER-positive breast cancer models.

The management of metastatic estrogen receptor (ER) positive HER2 negative breast cancer (ER+) has improved; however, therapeutic resistance and disease progression emerges in majority of cases. Using unbiased approaches, as expected PI3K and MTOR inhibitors emerge as potent inhibitors to delay proliferation of ER+ models harboring PIK3CA mutations. However, the cytostatic efficacy of these drugs is hindered due to marginal impact on the expression of cyclin D1. Different combination approaches involving the inhibition of ER pathway or cell cycle result in durable growth arrest via RB activation and subsequent inhibition of CDK2 activity. However, cell cycle alterations due to RB loss or ectopic CDK4/cyclin D1 activation yields resistance to these cytostatic combination treatments. To define means to counter resistance to targeted therapies imparted with RB loss; complementary drug screens were performed with RB-deleted isogenic cell lines. In this setting, RB loss renders ER+ breast cancer models more vulnerable to drugs that target DNA replication and mitosis. Pairwise combinations using these classes of drugs defines greater selectivity for RB deficiency. The combination of AURK and WEE1 inhibitors, yields synergistic cell death selectively in RB-deleted ER+ breast cancer cells via apoptosis and yields profound disease control in vivo. Through unbiased efforts the XIAP/CIAP inhibitor birinapant was identified as a novel RB-selective agent. Birinapant further enhances the cytotoxic effect of chemotherapies and targeted therapies used in the treatment of ER+ breast cancer models selectively in the RB-deficient setting. Using organoid culture and xenograft models, we demonstrate the highly selective use of birinapant based combinations for the treatment of RB-deficient tumors. Together, these data illustrate the critical role of RB-pathway in response to many agents used to treat ER+ breast cancer, whilst informing new therapeutic approaches that could be deployed against resistant disease.

The correlation analysis of 21-gene assay use in uninsured and underrepresented minorities with estrogen receptor (ER) positive HER2 negative breast cancer.

e12531 Background: 21-gene breast cancer recurrence-score assay (Oncotype DX) have been used to predict recurrence risks and guide adjuvant chemotherapy. However, access to such tests is limited, especially in a population concentrated with uninsured and underserved patient populations. Previously equations such as the Magee equation has been proposed to predict correlation of the recurrence score and the estimated recurrence score with high concordance rate. This study examines the concordance of such an assay to predicted scores in uninsured and underrepresented minority heavy public hospital. Methods: We performed a retrospective chart review of 68 women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer seen at University Hospital (public safety net hospital in Newark, New Jersey with greater majority of the patient population consists of underrepresented minorities such as Black/African Americans and Latino/Hispanics). 6 patients did not have pathology records, 9 patients did not have the Oncotype information available, and 4 patients were waiting on the results. Of the pre-menopausal eligible patients, two did not have any treatment or follow up information available and were included as part of the correlation assay, however, no. Results: Of the 47 eligible patients with follow-up information, 13 had a low recurrence score of up to 10 if post-menopausal and up to 15 if pre-menopausal, 22 had an intermediate recurrence score of 11 to 25 if post-menopausal and 16 to 25 if pre-menopausal, and 12 had a high recurrence score of greater than 26 according to the national comprehensive cancer network guidelines. The Pearson correlation between the Magee predicted score and Oncotype recurrence score was 0.73 (p &lt; 0.001). All patients received hormone therapy and 5 patients total had recurred. 2 were pre-menopausal and had received adjuvant chemotherapy. 3 were post-menopausal in low and intermediate categories who had not received adjuvant chemotherapy. Conclusions: This study shows a high correlation between the predicted Magee score and Oncotype recurrence score. This reflects a possible use in the prediction scoring system as another resource for prognostication and guidance in treatment especially in the underinsured population.

Defining resistance mechanisms to CDK4/6 inhibition in hormone receptor-positive HER2-negative metastatic breast cancer (MBC) through a machine learning approach applied to circulating tumor DNA (ctDNA).

3055 Background: Although cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are a primary treatment for hormone receptor-positive/HER2 negative MBC, data regarding resistance mechanisms are still an unmet need. The aim of the study was to highlight new resistance pathways using machine learning (ML) to detect multiparametric patterns in complex datasets. Methods: The study retrospectively analyzed a cohort of 610 hormone receptor positive HER2 negative MBC patients (pts) at Northwestern University, Massachusetts General Hospital and Washington University in St. Louis between 2015-2020 with baseline ctDNA testing by Guardant360. Pathways were defined based on previous work (Sanchez-Vega F et al, Cell. 2018) (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Only pathogenic variants according to OncoKB were included in the models. Associations among single nucleotide (SNVs) and copy number (CNVs) variations, pathway classification and previous exposure to CDK4/6i were explored through logistic regression and Gradient boosted machines (GBMs) ML algorithm. Results: at baseline, 322 pts (52.8%) were previously treated with CDK4/6i. The most detected pathway alterations were SNVs in PI3K (37.1%), P53 (31.8%), ER (29.2%) and RTK (22.3%). After stepwise logistic regression, RB1, NF1 and ESR1 SNVs were associated with previous exposure to CDK4/6i (respectively OR: 3.55 P = 0.017; OR: 3.06 P = 0.026 and OR: 1.82 P &lt; 0.001), while SNVs in the ER pathway were associated with CDK4/6i (1.56 P &lt; 0.001). Two GBMs models were designed based on gene variants (training AUC: 0.695, cross validation AUC: 0.631) and oncogenic pathways (training AUC: 0.713, cross validation AUC: 0.619). The highest relative importance (RI) was observed for ESR1 SNVs (RI: 35.35), TP53 SNVs (RI: 11.33), NF1 SNVs (RI: 3.45), SMAD4 SNVs (RI: 3.39) and RB1 SNVs (RI: 3.33). Alterations at a pathway level with the highest RI were ER SNVs (RI: 33.50), P53 SNVs (RI: 14.98), PI3K SNVs (RI: 14.40), RTK SNVs (RI: 10.55), RTK CNVs (RI: 10.26), cell cycle CNVs (RI: 6.99), cell cycle SNVs (RI: 6.77) and RAS SNVs (RI: 6.54). Of the previously highlighted pathway alterations, a significant impact on PFS after ctDNA collection was observed among de novo pts treated with CDK4/6i (165 pts) for ER SNVs (P &lt; 0.0001), RTK SNVs (P = 0.0011), RTK CNVs (P = 0.0006), Cell cycle CNVs (P = 0.0010) and Cell cycle SNVs (P = 0.0143). No impact was observed on PFS for pts who had not received a CDK4/6i-based regimen. Conclusions: The combination of ctDNA-based datasets and machine learning algorithms defined novel resistance pathways for patients treated with CDK4/6i. Although preliminary, these results suggest that alterations of the ER, RTK and Cell cycle pathways might be crucial to optimize treatment strategy and drug development.

Does race influence long-term outcomes after neoadjuvant chemotherapy in breast cancer: A National Cancer Database analysis.

606 Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is a surrogate predictor for long-term survival in breast cancer (BC). Patients who attain pCR have improved relapse-free and overall survival (OS) when compared to patients with residual disease (RD). We examined the pCR in Black and White BC patients who received NACT and their OS after attaining pCR and RD. Methods: The National Cancer Database (NCDB) was queried for Black and White females with non-metastatic BC from the years 2010 – 2016 who received NACT. Logistic regression was used to analyze pCR/RD and Cox proportional hazards regression to analyze OS, with adjustment for age, race, stage, grade, body mass index, treatments received, insurance status and comorbidities. STATA/IC 16.0 was used for analysis and a two-sided p-value &lt; 0.05 was considered significant. Results: A total of 101,014 White and Black BC patients were identified, including 24,852 (Whites - 74.43%, Black - 25.57%) triple negative breast cancer (TNBC), 51,043 (Whites - 84%, Blacks - 16%) hormone receptor positive HER2 negative (HR+HER2-) and 17,818 (Whites - 83%, Blacks - 17%) HER2 positive. Whites had a slightly higher odds of attaining pCR compared to Blacks (adjusted Odds Ratio (aOR) = 1.040, 95% Confidence Interval (CI) = 1.02 - 1.19, p = 0.02). The difference was largest in TNBC subtype (TNBC: aOR = 1.34, 95% CI = 1.20 - 1.56, p &lt; 0.001; HR+HER2-: aOR = 1.1; 95% CI = 1.02 - 1.32, p = 0.038; HER2+: aOR = 1.13, 95% CI = 1.08 - 1.27, p &lt; 0.001). Among those who attained pCR, Blacks had worse OS when compared to Whites in HER2+ subtype (adjusted Hazard Ratio (aHR) = 1.41, 95% CI = 1.04 - 1.93, p = 0.028) but not in TNBC or HR+HER2- subtypes. Among those with RD, Blacks had worse OS in the whole cohort compared to Whites (aHR = 1.43, 95% CI = 1.26 - 1.58, p &lt; 0.001), and in all subtypes: TNBC (aHR = 1.17, 95% CI = 1.11 - 1.23, p &lt; 0.001), HR+HER2- (aHR = 1.38, 95% CI = 1.31 - 1.45, p &lt; 0.001) and HER2+ (aHR = 1.45, 95% CI = 1.32 - 1.59, p &lt; 0.001). Conclusions: Black BC patients with TNBC were less likely to achieve pCR than Whites after NACT. When Black patients with HER2+ subtype did attain pCR, they still had worse OS than Whites. The same racial difference in OS was observed in all BC subtypes - TNBC, HR+HER2- and HER2+ among patients with RD. This highlights the importance to investigate novel personalized treatment strategies for Black patients.

Comparison of predicted benefit using RS clin versus observed benefit in a U.S. registry of stage I ER-positive HER2-negative high oncotype DX RS breast cancer.

544 Background: The 21-gene recurrence score assesses the risk of distant breast cancer recurrence and predicts the benefit of adjuvant chemotherapy in ER positive early-stage breast cancer. However, clinicopathologic risk factors continue to impact absolute benefit of adjuvant chemotherapy. Absolute benefit of adjuvant chemotherapy in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS is an important clinical component of shared decision making. The RSClin clinical tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was found to be more prognostic than RS result alone. We assessed RS Clin predicted benefit and compared to absolute benefit in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS as observed in the NCDB. Methods: Using the National Cancer Data Base (NCDB), we identified female patients age 18-75, ER positive and Her 2 negative, 21 gene signature high risk &gt; 25 with negatives surgical margins, &lt;2cm, lymph node negative breast cancers, who had received endocrine therapy with either Tam or AI diagnosed during 2010 - 2017. Clinicopathologic factors and RS were entered into the RSClin calculator, and a predicted benefit of chemotherapy was calculated for each patient. Using NCDB data, Cox proportional hazards regression models were used to project absolute survival benefit at 10 years from diagnosis for those who did vs those who did not receive chemotherapy. NCDB-derived absolute benefit of chemotherapy was compared to estimated absolute benefit as predicted by the RSClin tool. Results: 18,226 patients were identified. Stages T1a = 670(4%), T1b = 4,289(23%), and T1c = 13,267(73%). Median age 59 years (21-75). Race white 84% (15,365), black 10% (1840), and other 1021(6%). AI use 80% (14,711) was greater than Tam use 20% (3515). Chemotherapy was administered in 75% (13,827) of patients. Most patients had high or intermediate grade disease, G3 45% (8225), G2 46% (8328), and G1 9% (1672). Median duration of follow up was 57 months (2-160). Probability of death T1b at 10yrs with chemotherapy was 8.5%, and without chemotherapy was 15.1% with an absolute benefit of 6.6%. Predicted benefit in T1b using RS Clin at 10yrs was 10.8%. Probability of death for T1c at 10yrs with chemotherapy was 15.1%, and without chemotherapy was 23.5% with an absolute benefit of 8.4%. Predicted benefit in T1c using RS Clin at 10yrs was 14%. Conclusions: Patients with stage IB and IC hormone receptor positive HER2 negative breast cancers with high RS had a lower absolute benefit than predicted by RS Clin. The RSClin tool overestimated benefit of therapy in both IB and IC stages requiring caution when using this tool in patients with the lowest clinicopathologic risks.

CORRELATION OF RECEPTOR STATUS WITH AXILLARY NODAL METASTASIS AND OTHER PROGNOSTIC FACTORS IN CARCINOMA BREAST : INDIAN PERSPECTIVE

Background- nd Breast cancer is the 2 most common cancer globally and it ranks rst in India. The predictive value of various components like hormone receptor status, tumor size, grade to axillary lymph nodal metastasis has been studied previously. Our aim is to study the correlation of receptor status and axillary lymph nodal metastasis in breast cancer patients. Methods- This is a retrospective study carried out in single surgical unit. 104 biopsy proven unilateral breast cancer patients who underwent modied radical mastectomy has been reviewed. The clinicopathological data has been collected from hospital records. Results- The mean age of presentation is 42.2years. Most common age group is 30-49years with clinical stage III(65.38%) with inltrating ductal carcinoma(99.03%). Although axillary lymph node was palpable in 75%, nodal metastasis is present in 63.46% of patients. Positive estrogen receptor, progesterone receptor and Her2 receptors are seen in 45.19%, 34.6% and 59.61% patients respectively. TNBC patients has least while triple positive has maximum nodal metastasis in our study group. Perineural invasion and extra capsular extension is seen in 15.38% each and lymphovascular invasion is seen in 38.4% patient. Although LVI, PNI and ECE is predominant in Her2-enriched subtypes, most patients belonging to HR+/Her2+ subtypes has LVI, PNI and ECE. TNBC and HR+/Her2- subtypes has least LVI, PNI and ECE. Conclusion- Receptor status has signicant role in predicting nodal metastasis. TNBC, although considered most aggressive, has least axillary nodal metastasis suggesting less lymphatic involvement and less LVI, PNI and ECE. Also Her2 over-expression seems to be related to nodal metastasis, LVI, PNI and ECE, suggesting there may be some pathway which is still unrevealed. Thus Her2 receptor positivity can be considered as an independent poor prognostic factor.

Effect of progesterone receptor status on efficacy of aromatase inhibitors and survival time in patients with advanced breast cancer

To investigate the effect of progesterone receptor (PR) on the efficacy of first-line aromatase inhibitor (AI) endocrine therapy and progression-free survival (PFS) in patients with estrogen receptor (ER) positive HER-2 negative advanced breast cancer. The clinical data of 198 patients with advanced breast cancer treated in Henan Cancer Hospital from January 2014 to October 2019 were collected. The Chi-square test was used to compare the difference between the two groups, and the Cox regression model was used to analyze the related prognostic factors. The median progression-free survival time ((PFS)) of PR+and PR- patients were 12.5 months and 9.0 months, respectively, and the difference was statistically significant (P=0.004). The clinical benefit rate (CBR) was 81.1% and 63.1%, respectively, and the difference was not statistically significant (P<0.001). PR is an independent prognostic factor of first-line AI endocrine therapy in ER-positive HER-2-negative patients. PR+type breast cancer has a better response to first-line AI endocrine therapy and longer PFS time than PR- type advanced breast cancer.

Abstract P2-07-02: Genomic predictors of rapid progression to first line endocrine and CDK4/6 inhibitor combination therapy in patients with estrogen receptor positive (ER+) HER-2 negative (HER2-) advanced breast cancer (ABC)

Abstract Background: Endocrine therapy with CDK 4/6 inhibitors (ET/CDK4/6i) represents the 1st line therapy for ER+/HER2- ABC. While majority of patients derive clinical benefit with combination therapy, a subset have refractory disease with progression within 6 months. However, predictive biomarkers for rapid progression are lacking. In this study, we evaluated genomic profiles associated with rapid disease progression on ET/CDK4/6i. Methods: We identified 77 patients who received 1st line ET/CDK4/6i combination therapy (AI or SERD with one of the 3 approved CDK4/6is) and had ctDNA analysis performed via plasma based genotyping utilizing the commercially available Guardant360 assay at three sites: Washington University in St. Louis, MO, Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). We aimed to look at the differences in patient characteristics and genomic profiles of the tumors assessed from baseline ctDNA specimens between the patients with rapid progression (time to progression TTP&amp;lt;=6 months) vs others. In particular, we focused on growth factor receptors (FGFR, EGFR) given that previous studies have shown that activation of FGFR1 and EGFR signaling may be implicated in resistance to endocrine based therapy in breast cancer. Time to progression was estimated by using Cox regression. Variable associations were estimated via logistic regression. Results: In the combined cohort, FGFR1 amplification (FGFR1amp) was detected in 15/77 patients (19.5%). FGFR1amp was seen in 5/10 (50%) of patients with rapid progression, consistent with existing knowledge that FGFR1amp contributes to resistance to CDK4/6i and/or ET. Presence of FGFR1amp was independently associated with shorter TTP (11.2 vs. 34.7 months, HR=3.14, p=0.02). EGFR mutations (EGFRmut) were detected in 8/77 (10.4%) patients, 3 of which were found among patients with rapid progression and another 5 among those with TTP&amp;lt;=15 months. Presence of EGFRmut was also associated with shorter TTP (8.5 vs. 31.7 months, HR=6.50, p&amp;lt;0.001) in multivariable analysis. Of the 4 patients with shortest TTP (&amp;lt;3 months) 3 harbored both FGFR1amp and EGFRmut. In another 3 patients we observed FGFR1amp and co-activation of genes implicated in G1/S phase cell cycle transition, suggesting that FGFR1 amplified cells may require a co-activating downstream event that ultimately, via multiple pathway cross-talk, renders them resistant to ET/CDK4/6 inhibition. Patients with FGFR1 amplified tumors were younger compared to those without FGFR1amp (54.3 vs. 62.7 years, p=0.04). Presence of FGFR1amp was associated with presence of liver (p=0.01) but not bone or lung metastases which could be one of the explanations why patients with higher liver tumor burden are more resistant to ET/CDK4/6i inhibition. PIK3CA and TP53 gene mutations in our cohort were frequent (found in 41% and 30% of the patients, respectively) but were independently not associated with TTP (PIK3CAmut+ HR=1.31, p=0.55, TP53mut+ HR=0.67, p=0.36). ESR1 mutations were rarely encountered (9%) as the cohort had only been exposed to adjuvant endocrine therapy. Conclusions: These findings highlight how ctDNA can be used for patient stratification prior to initiation of first line of therapy in ER+/HER2- ABC since it is evident that not all patients derive the same benefit from ET/CDK4/6i. Certain genomic alterations, particularly in FGFR1, EGFR, and G1/S phase cell cycle transition are associated with rapid progression to 1st line ET/CDK4/6i therapy, and highlight the need for clinical trials investigating combination/novel therapies for this subgroup of patients with HR+/HER2- ABC. Our findings are hypothesis-generating and require further exploration in larger datasets. Citation Format: Marko Velimirovic, Lorenzo Gerratana, Andrew A Davis, Whitney L Hensing, Katherine Clifton, Ami N Shah, Paolo D'Amico, Charles S Dai, Elyssa N Denault, Cynthia X Ma, Seth A Wander, Dejan Juric, Massimo Cristofanilli, Bruce A Chabner, Aditya Bardia. Genomic predictors of rapid progression to first line endocrine and CDK4/6 inhibitor combination therapy in patients with estrogen receptor positive (ER+) HER-2 negative (HER2-) advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-02.

Abstract P1-07-06: Endoxifen exposure after 5 weeks of preoperative tamoxifen is predictive of long-term outcome of operable hormone receptor positive (HR+) HER2 - early breast cancer

Abstract Introduction: Endoxifen exposure, the most active metabolite of tamoxifen, may be a better predictor of tamoxifen efficacy, than CYP2D6 genotypes. However, conflicting results have been reported so far. We evaluated prospectively the impact of 5 weeks of pre-operative tamoxifen on Ki-67 levels in early-stage breast cancer (EBC) patients. We correlated CYP2D6 genotype, exposure of tamoxifen and its metabolites with long-term outcome. Patients and methods: TAM pre-op was an open-label, multicentre, phase 2 trial in which pre and postmenopausal women with WHO performance status 0-1 and HR+ HER2-, operable breast cancer were given tamoxifen (20mg per day orally) for 5 weeks before surgery. Adjuvant treatments were given as standard practice. CYP2D6 genotype was determined at initiation. Plasma concentrations of tamoxifen and its main metabolites (N-desmethyltamoxifen, Z-endoxifen, and Z-4-hydroxytamoxifen) were assessed at baseline (b), week 2 (w2) and week 5 (w5) of treatment, using a validated performed LC-MS/MS method. AUCs, used as marker of exposure, were computed with Monolix© (Lixoft, Antony, France). Tumour Ki-67 variations between baseline (Ki-67b) and w5 (Ki-67w5) were determined to assess the sensitivity to tamoxifen. We used a pre-defined 10% cut-off to dichotomize low versus high Ki-67. All these parameters were associated with disease free survival by Cox regression analyses. Results: Out of the 136 patients enrolled, 98 pts had paired Ki-67 values evaluable. With a median follow up of 78 months (IQR 58-95), 14/136 women had cancer recurrence (12 distant and 2 contralateral) with the proportion free from cancer recurrence at 5 years of 90% (95% CI 83-94). Ki-67b, Ki-67w5 and variations between baseline and week 5 were not associated with DFS. Endoxifen AUC was correlated with CYP2D6 genotype (normal/hyper metabolizer versus low metabolizer) but CYP2D6 genotype was not predictive for DFS (adjusted hazard ratio, 2.24; 95% CI, 0.29 to 17.37; P = 0.44). Endoxifen AUCs at w2 and w5 were similar in patients with low Ki67b and low Ki67w5 (low-low) (n=36), low Ki67b and high Ki67w5 (n=12), high Ki67b and low Ki67w5 (n=14) and high Ki67b and high Ki67w5 (n=30). However, low endoxifen AUC at w5 was a pejorative factor of disease free survival: 5 years PFS 81.8% vs 90.3% (HR 2.70, CI 95% [1.04-7.06], p=0.04). Conclusion: This prospective clinical study shows that endoxifen exposure at w5 of pre-operative tamoxifen is associated with DFS in patients with HR+/HER2- EBC. Translationnal studies are ongoing. N°EUDRACT 2008-007652-10. Citation Format: Jean-Sebastien Frenel, Loic Campion, Antonin Schmitt, Patricia De Cremoux, Elsa Rossignol, Celine Renaudeau, Marie Robert, Jean-Marie Bard, Christine Bobin-Dubigeon, Mario Campone. Endoxifen exposure after 5 weeks of preoperative tamoxifen is predictive of long-term outcome of operable hormone receptor positive (HR+) HER2 - early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-06.