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Background: The 21-gene Recurrence Score (Oncotype DX) is a genomic assay that provides prognostic information for distant recurrence risk and is predictive of adjuvant chemotherapy benefit in hormone receptor (HR)-positive, HER-2 negative early-stage breast cancer (EBC). The Breast Cancer Index (BCI) is another molecular gene expression-based assay that evaluates the utility of extending adjuvant endocrine therapy (ET) from 5 to 10 years and predicts risk of distant recurrence. In January 2021, the National Comprehensive Cancer Network (NCCN) Guidelines added BCI to guide duration of adjuvant ET as a category 2A recommendation. The goal of this study was to evaluate the association between BCI and RS in terms of their predicted benefit for adjuvant therapy and risk of distant recurrence. We also assessed the association of various anatomic and biologic tumor features with BCI. Methods: We performed a retrospective chart review of all patients with HR-positive EBC who had a BCI and Oncotype DX performed between 2007-2021. Demographics, tumor characteristics and BCI and RS results were extracted from the electronic medical record. Patients were categorized by BCI predictive of extended ET (formerly BCI high) versus not (formerly BCI low) and RS of low (0-10), intermediate (11-25) and high (26-100). Numerical values for distant recurrence risk were recorded for both BCI and Oncotype DX tests. Multivariable regression models were used to assess the relationship between BCI and Oncotype DX as well as factors associated with each. Results: We identified 153 women with HR-positive EBC with both RS and BCI performed. The median age of the population was 57 years and 25% were premenopausal. 32% (n=49) had a BCI result predictive of benefit from extended adjuvant ET. When comparing patients with BCI predictive of extended ET versus those with BCI not predictive of extended ET, there was no association between BCI and RS based on multivariate logistic regression models, p=0.7. A similar distribution of RS was observed between patients who had a BCI result predictive of benefit from extended ET versus not predictive. Among 49 patients with a BCI predictive of extended ET, 35% had high RS, 63% intermediate RS and 2% low RS. Among 104 patients with a BCI not predictive of extended ET, 24%, 73% and 3% had high, intermediate, and low RS, respectively. Multivariate regression models revealed an association between poorly differentiated tumors and BCI result predictive of extended ET, p=0.002. No associations were observed between BCI and menopausal status, ER%, PR%, tumor size or lymph node positivity. Regarding risk of recurrence, there was an association between BCI and Oncotype DX in terms of their predicted numerical risk of recurrence, p< 0.001. Higher percentage of PR positivity, poorly differentiated tumors, and lymph node positivity were associated with a higher risk of recurrence on the BCI. Conclusions: In our patient population selected to have Oncotype DX and BCI performed, we found no association between the two genomic assays in terms of their predictive benefit. However, there was an association between Oncotype DX and BCI in terms of their prognostic ability. Given the increased use of BCI since its inclusion in national guidelines, it is important to understand its relationship with other genomic assays especially when used to guide clinical decisions and estimate prognosis. Citation Format: Rima Patel, Nicole Casasanta, Zhiqiang Li, Melanie Kier, Julia Blanter, Sophie Sohval, Malin Hovstadius, Catherine Wu, Marc Fink, Xiang Zhou, Brittney Zimmerman, Krystal Cascetta, Rong Chen, William Oh, Amy Tiersten. Correlating Predicted Adjuvant Therapy Benefit and Risk of Recurrence between Breast Cancer Index (BCI) and 21-gene Oncotype DX Recurrence Score (RS) [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 P1-04-09.

Background: The 21-gene RS (Oncotype DX) is a validated genomic signature that provides prognostic information for distant recurrence risk and is predictive of adjuvant chemotherapy benefit in patients with hormone receptor (HR)-positive, HER2-negative early breast cancer (EBC). Ki67 protein expression is a proliferation marker that is determined by immunohistochemistry (IHC) and is a prognostic biomarker in HR-positive EBC. Black race is associated with poorer prognosis in patients with EBC. RS, Ki67 and race have not been evaluated together and the impact of race on the association between Ki67 and RS is unknown. The goal of this study was to evaluate the association between the 21-gene RS and Ki67 based on race in patients with HR-positive EBC using the NCDB. Methods: Women with HR-positive EBC with 0-3 involved lymph nodes, diagnosed between 2018 and 2019, who had available information on RS, IHC-measured Ki67, and race in the NCDB dataset were identified. Patients were stratified by RS of low (0-10), intermediate (11-25) and high (26-100) and categorized into Ki67 low (/=30%) based on the International Ki67 Working Group prognostic classification (PMID: 33369635). Wilcoxon rank test was used to test for continuous variables and chi-square test was used for categorical variables. Agreement between Ki67 and RS was estimated using Fleiss Kappa statistic and corresponding p-value was reported. Results: 43,898 eligible women were included. 17.43% were lymph node positive. 78% were Non-Hispanic White, 7.98% Non-Hispanic Black, 6.42% Hispanic, and 4.26% Asian American/Pacific Islander (AAPI). The table below describes the distribution of Ki67 and RS in the overall population and racial subgroups. The distribution of Ki67 scores was significantly different between races with a higher proportion of Black patients having high Ki67 scores, p< 0.0001. RS distribution varied as well with a greater percentage of high RS in the Black group, p< 0.0001. There was only slight agreement (Kappa 0.01-0.20) between Ki67 and RS in the overall population (Kappa=0.1929, p< 0.0001), low Ki67 subgroup (Kappa=0.069, p< 0.0001) and intermediate group (Kappa=0.066, p< 0.0001). However, there was fair agreement (Kappa 0.21-0.40) between high Ki67 and RS (Kappa=0.351, p< 0.0001). Based on race as a covariate, in the overall population, agreement between Ki67 and RS remained slight for White, Hispanic, and AAPI groups but was fair for Black patients (Kappa=0.2345, p< 0.0001). In the low Ki67 and intermediate Ki67 groups, agreement remained slight across all races, p< 0.0001. While there was fair agreement between high Ki67 and RS in all racial subgroups, agreement between high Ki67 and RS was highest in the Black subgroup (Kappa=0.392, p< 0.0001) followed by the AAPI (Kappa=0.363, p< 0.0001), White (Kappa=0.342, p< 0.0001) and Hispanic (Kappa=0.339, p< 0.0001) groups. Conclusions: In this large patient population from the NCDB, there was only slight agreement between Ki67 and RS in the overall, low Ki67, and intermediate Ki67 groups but fair agreement in the high Ki67 group. Agreement between high Ki67 and RS was greatest in the Black subgroup compared to other races. This may be attributed to the higher proportion of patients with high Ki67 and RS in the Black subgroup. Future analyses on overall survival will determine the impact of race on the prognostic value of Ki67 and RS. Table 1. Distribution of Ki67 and RS by Racial/Ethnic Subgroup AAPI: Asian American/Pacific Islander AIAN: American Indian and Alaska Native Citation Format: Rima Patel, Deukwoo Kwon, Grace Van Hyfte, Joseph Sparano, Amy Tiersten. Associations between the 21-gene Oncotype DX Recurrence Score (RS), Ki67, and Race in Early Breast Cancer (EBC) Using the National Cancer Database (NCDB) [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 PD1-09.

Purpose: Although medical care for transgender and gender nonbinary (TGNB) individuals is rapidly expanding, numerous gaps in the organization of quality care for TGNB individuals remain. In 2018, ...

The relationship between Ki67 assessed by immunohistochemistry (IHC) and the Oncotype DX Recurrence Score (RS) is unclear. The objective of this study was to determine the correlation between the 21-gene RS and IHC-measured Ki67 with the prognostic classification groups recommended by the International Ki67 Working Group (IKWG).The authors performed a retrospective chart review of women who had hormone receptor (HR)-positive, human epidermal growth factor receptor 2-negative early breast cancer with zero to three positive lymph nodes and both Ki67 and the 21-gene RS performed at their institution from 2013 to 2021. Patients were categorized into low (≤5%), intermediate (6%-29%), and high Ki67 groups (≥30%) according to IKWG recommendations. Overall agreement and risk-stratified agreement between Ki67 and RS were assessed with the proportion of agreement and the κ statistic.The study included 525 patients with HR-positive breast cancer. Among the 49% of patients with intermediate Ki67 values of 6%-29%, the distribution of low (0-10), intermediate (11-25), and high RS (26-100) was 19%, 66%, and 15%, respectively. There was slight agreement (κ = 0.01-0.20) between Ki67 and RS (κ = 0.027) in the overall population, although this was not significant (p = .1985). There was fair agreement (κ = 0.21-0.40) between high Ki67 and RS values (κ = 0.280; p .0001). A higher progesterone receptor percentage was associated with lower RS values (p .0001) but not lower Ki67 values. A positive nodal status and a larger tumor size were associated with higher Ki67 values (p = .0059 and p .0001) but not with RS.In this group of patients selected to have a 21-gene RS, there was no significant correlation between Ki67 and RS in the overall population, and there was fair agreement between high Ki67 and high RS values.In patients with early-stage, hormone receptor-positive breast cancer, decisions on adjuvant chemotherapy are based on certain biological features of the cancer and genomic assays such as the Oncotype DX Recurrence Score (RS). The goal of this study was to determine the correlation between Ki67, a marker of proliferation, and the Oncotype DX RS, a 21-gene assay demonstrated to be predictive of an adjuvant chemotherapy benefit in patients with early-stage breast cancer. In 525 patients, the authors did not find a significant correlation between Ki67 and RS.

PURPOSE Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2– MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2– MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

XLS file, 17K, Patient demographics, tumor characteristics, treatment, occurrence and severity of local and systemic adverse events and anti-tumor response per patient (n=10).

PDF file, 282K, A (non-responder 1): In situ TILs analysis by IHC in a patient with minimal T cell infiltrate before treatment (H&E stain and IHC for CD3, CD4, CD8 and FoxP3, 200x). B: (non-responder 2): In situ TILs analysis by IHC in a patient with moderate T cell infiltrate before imiquimod treatment. (H&E stain and IHC for CD3, CD4, CD8 and FoxP3, 200x).

PDF file, 73K.

Background: Aromatase inhibitors (AIs) are part of standard endocrine therapy for hormone receptor (HR)-positive breast cancer (BC) and are used in both adjuvant and metastatic settings. Since AIs work by inhibiting the conversion of androgens to estrogen in peripheral adipose tissue, the higher levels of estrogen in obese patients may lead to incomplete inhibition by AIs and influence their efficacy. A retrospective analysis of the ABCSG-12 trial found that overweight premenopausal patients with early-stage BC treated with anastrozole had a 60% increased risk of disease recurrence and more than doubling in risk of death compared with normal weight patients on anastrozole. Similarly, an exploratory analysis from the ATAC trial found that in post-menopausal women with early-stage BC, overall recurrence rates were lower in patients randomized to anastrozole versus tamoxifen but in women with body mass index (BMI) > 30, there was no significant difference in disease recurrence between anastrozole and tamoxifen. While these findings raise concern for the efficacy of adjuvant AI therapy in obese patients with early-stage BC, this has not yet been demonstrated in the metastatic setting. The aim of this study was to determine the impact of BMI on efficacy of AIs in patients with metastatic HR-positive BC. Methods: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001-2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. PFS was compared across BMI groups using Kaplan-Meier curves and log-rank tests. Cox proportional hazards regression model was used for univariate and multivariate analyses. Results: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. The median age was 59 with 45% of patients White, 29% African American, 16% Hispanic/Latino, 5.5% Asian and remainder other/unknown. 32% (71) had HER-2 positive disease. 82% (179) were on an AI in the first-line setting. Overall, 53% were on letrozole, 42% on anastrozole and 5.5% on exemestane. Of the 219 patients, 56% (123) had a low BMI (defined as < 27 kg/m2) and 44% (96) had a high BMI (≥ 27 kg/m2; based on the Breast Cancer Weight Loss [BWEL] trial). The median PFS was 21.9 months (95% CI, 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI, 14.3 to 27.5) in the high BMI group with no statistically significant difference (p =0.73). There were 8 (6.5%) deaths in the low BMI group and 7 (7.3%) deaths in the high BMI group. Multivariate cox regression model did not demonstrate any significant impact of BMI on PFS when adjusting for age, race/ethnicity, HER2 status, type of AI, line of therapy, drug partner and type of metastatic disease (HR =0.91, 95% CI =0.64 to 1.30, p =0.6 for high BMI group). Subgroup analysis of patients on an AI in the first line setting also did not show a significant difference in PFS with median PFS 19.3 and 18 months in the low and high BMI groups, respectively. Conclusions: In patients on an AI for metastatic HR-positive breast cancer, there was no statistically significant difference in PFS in patients with low versus high BMI. While BMI influences efficacy of AIs in the adjuvant setting, our results demonstrate that in the metastatic setting, BMI does not significantly impact the efficacy of AIs among our patient population. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest. Additional larger studies are needed to confirm this finding. Citation Format: Rima Patel, Zhiqiang Li, Brittney S. Zimmerman, Marc Y. Fink, Jason D. Wells, Xiang Zhou, Kristin L. Ayers, Arielle Redfern, Scott Newman, Rong Chen, William K. Oh, Amy Tiersten. Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic 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 P1-17-06.

Background: Aromatase inhibitors (AI) are standard of care in the treatment of early-stage hormone positive (HR+) breast cancer (BC). Commonly, these medications cause significant side effects which limit tolerability and often require a change in therapy. Supportive therapies are an essential part of treatment plans to improve adherence and quality of life. Studies in the last decade have demonstrated the critical role of supportive management in mitigating side effects from AI, such as the reduction in AI related joint pain with acupuncture or use of low dose oxybutynin for hot flashes. The aim of this study was to evaluate the real world use of supportive therapies for AI toxicities over the last decade and to determine if they were associated with patient adherence to initial AI treatment. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+ BC who were initiated on adjuvant AI therapy between 2011-2020. From the electronic medical record, we collected information on patient demographics, AI side effects (hot flashes, vaginal dryness, joint pains, osteopenia/osteoporosis), use of supportive therapies, and duration of first AI therapy. Primary endpoint was the rate of discontinuation of AI at 1 year among those who used supportive therapies compared with those who did not. The Wilcoxon rank sum test, Fisher's exact test, Kruskal-Wallis rank sum test, and Pearson's Chi-squared test methods were used to compare rates of discontinuation of front-line AI therapy for each group. Results: We identified 990 patients (pts) with early-stage, HR+ BC who were started on adjuvant AI between 2011-2020. Of these patients, 97% (n= 963) had AI related side effects yet only 51% (n=504) received supportive therapies. The overall discontinuation rate within 1 year was 14.8% (147 of 990 pts). Patients who received at least 1 supportive therapy were more likely to remain on AI and had a lower 1 year discontinuation rate of 10% (51 of 504 pts) compared to 20% (96 of 486 pts) for those who did not receive any supportive therapy (p1 year AI treatment group, p=0.003). Race also appeared to have an impact on AI tolerance. Although only 31% (39 of 126 pts; p < 0.001) of Black patients received supportive therapy, this group had the lowest 1 year discontinuation rate at 8.7% (11 of 126 pts). Conversely, 56% (277 of 491 pts) of White patients received at least one supportive therapy, yet had the highest 1 year discontinuation rate at 17% (83 of 491 pts). Conclusions: Supportive therapies are essential to help patients mitigate side effects of AI. Patients who received at least one supportive therapy had increased rates of AI adherence beyond 1 year compared to those who did not receive any supportive treatment. The most commonly used therapies were bone strengthening agents and acupuncture. Use of acupuncture and low dose oxybutynin have increased in the past 3 years and 2 years, respectively, following publication of their efficacy. It is critical to further evaluate the impact that race and age have in relation to duration of treatment and use of supportive management. Further studies on how to improve patient tolerability and adherence to AI therapy are needed. Citation Format: Melanie W Kier, Zhiqiang Li, Brittney S Zimmerman, Rima Patel, Yunchen Yang, Mark Y Fink, Jason D Wells, Xiang Zhou, Scott Newman, Rong Chen, Eric Schadt, William Oh, Amy Tiersten. Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-11.

As sequencing technologies advance, there is increasing interest in the value of more comprehensive molecular profiling techniques. Our laboratory has clinically validated two next generation sequencing (NGS) assays for detecting somatic variants in solid tumors. The Sema4 Signal Solid Tumor Panel, utilizes the Thermo Fisher 161 gene Oncomine Comprehensive v3 assay and the Sema4 Signal Whole Exome/Transcriptome Sequencing (WES/WTS) assay consists of whole transcriptome RNAseq for the tumor and whole exome sequencing for the tumor and normal DNA on the Illumina NovaSeq. We compiled a cohort of 224 breast tumors from 211 patients encompassing 10 histological subtypes (BRCA (102), IDC (74), ILC (21), BRCANOS (11), BRCNOS (4), IBC (1), ACBC (1), IMMC (1), MBC (2), MDLC (2), Other (5)). A total of 209 specimens were analyzed by our Solid Tumor panel, and 15 were analyzed by WES/WTS. ER/PR/HER2 status was available for 212 tumors with 36 triple-negative, 123 ER(+)/PR(+)/HER2(-), and 23 ER(+)/PR(+)/HER2(+). Treatment history was available for 151 patients. Of the 118 patients who self-reported racial identity, 8 identified as Asian, 33 identified as Black or African American, 77 identified as white. Sequencing with either the 161 gene panel or WES/WTS detected clinically significant variants in 95% (213/224) of the tumors sequenced. Targetable PIK3CA variants were reported in 36% (80/224) of tumors, as well as CCND1 amplification (16%, 26/224) and ESR1 resistance variants (10%, 24/224). Tier 1 drugs were reported in 35% (79/224) of tumors, as well as tier 2 drugs (4%, 10/224). At least 2 patients had tumor specimens obtained at time points spanning 18 or more months and acquired ESR1 p.Y537S and p.Y537C resistance mutations in the later specimens. A patient with triple-negative specimens, obtained in 2018 and 2020, had no change in clinically significant variants but had loss of variants of unknown significance in the later sample. Panel sequencing and WES/WTS are comparable in terms of known variant detection, but panel-based testing has considerable limitations for assessing disease progression and genomic complexity. For the 15 WES/WTS specimens, we were able to determine additional molecular features, including complex copy number state, which has relevance to prognostic information, tumor mutation burden, homologous recombination deficiency, and differential gene expression. Moreover, WES of the tumor and normal specimens resolved multiple germline variants that had been reported as somatic variants in a tumor-only report from a patient with triple-negative breast cancer. Our findings support the adoption of tumor/normal WES/WTS as a standard diagnostic tool for breast cancer patients. Citation Format: Kimberly S. Cole, Zhiqiang Li, Amy Tiersten, Wanying Zhang, Hussam Al-Kateb, Feras M. Hantash, Michael R. Rossi, Scott Newman, Xiang Zhou, Eric E. Schadt, Rong Chen, William K. Oh, Marc Y. Fink. Value-added clinical tumor/normal whole exome and whole transcriptome sequencing versus a DNA and RNA tumor only gene panel for managing 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 P3-09-15.

Higher levels of estrogen in obese patients may lead to incomplete inhibition by aromatase inhibitors (AIs). The aim of this study was to determine the impact of body mass index (BMI) on efficacy of AIs in patients with metastatic hormone receptor (HR)-positive breast cancer (BC).We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001 and 2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause.We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. Of the 219 patients, 56% (123) had a low BMI (defined as 27 kg/mWhile BMI influences efficacy of AIs in the adjuvant setting, our results suggest that in the metastatic setting, BMI may not impact the efficacy of AIs. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest.