Citations

Abstract Purpose: Triple-negative invasive lobular carcinoma (TN-ILC) of breast cancer is a rare disease and the clinical outcomes and prognostic factors are not well-defined. Methods: Women with stage I-III TN-ILC or triple-negative invasive ductal carcinoma (TN-IDC) of the breast undergoing mastectomy or breast-conserving surgery between 2010 and 2018 in the National Cancer Database were included. Kaplan-Meier curves and multivariate Cox proportional hazard regression were used to compare overall survival (OS) and evaluate prognostic factors. Multivariate logistic regression was performed to analyze the factors associated with pathological response to neoadjuvant chemotherapy. Results: The median age at diagnosis for women with TN-ILC was 67 years compared to 58 years in TN-IDC (p<0.001). There was no significant difference in the OS between TN-ILC and TN-IDC in multivariate analysis (HR 0.96, p=0.44). Black race and higher TNM stage were associated with worse OS, whereas receipt of chemotherapy or radiation was associated with better OS in TN-ILC. Among women with TN-ILC receiving neoadjuvant chemotherapy, the 5-year OS was 77.3% in women with a complete pathological response (pCR) compared to 39.8% in women without any response. The odds of achieving pCR following neoadjuvant chemotherapy were significantly lower in women with TN-ILC compared to TN-IDC (OR 0.53, p<0.001). Conclusion: Women with TN-ILC are older at diagnosis but have similar OS compared to TN-IDC after adjusting for tumor and demographic characteristics. Administration of chemotherapy was associated with improved OS in TN-ILC, but women with TN-ILC were less likely to achieve complete response to neoadjuvant therapy compared to TN-IDC.

ImportanceAurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i–resistant MBC is unknown.ObjectiveTo assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)–negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (&amp;lt;10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022.InterventionsAlisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2).Main Outcomes and MeasuresImprovement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%.ResultsAll 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]).Conclusions and RelevanceThis randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i–resistant MBC. The overall safety profile was tolerable.Trial RegistrationClinicalTrials.gov Identifier: NCT02860000

Abstract Background: The prognostic value of stromal tumor-infiltrating lymphocytes (TILs) as a biomarker for triple-negative breast cancer (TNBC) has been extensively demonstrated in patients (pts) receiving (neo)adjuvant systemic therapy. In addition, several small studies suggest that a subset of pts with early-stage TNBC and high TILs have excellent long-term outcomes, even in the absence of systemic therapy [1-3]. However, data on the absolute risk of TNBC recurrence according to TIL levels in the absence of systemic therapy are limited and critical to inform the design of future systemic therapy de-escalation clinical trials. Methods: We conducted an individual patient data pooled analysis of 12 international cohorts of pts with TNBC treated with locoregional therapy but no systemic therapy. TNBC was defined as tumors with estrogen and progesterone receptor of &lt; 1% and HER2 negative (IHC 0, 1+ or IHC 2+ and FISH negative) per local evaluation. TILs were locally assessed in hematoxylin & eosin-stained slides according to the International Immuno-Oncology Biomarker Working Group guidelines (www.tilsinbreastcancer.org). We used the Kaplan-Meier method to assess survival outcomes according to prespecified TIL thresholds: 30% and 50%. Confidence intervals (CI) for survival probabilities were calculated using a percentile bootstrap method. The primary endpoint was invasive disease-free survival (iDFS, STEEP 2.0 definition). Key secondary outcomes included recurrence-free survival (RFS), distant disease-free survival (DDFS) and overall survival (OS). Results: 1,835 pts diagnosed with TNBC between 1982 and 2017 who did not receive systemic therapy were included. The median age at diagnosis was 56 (IQR 38-71). Menopausal status was known in 1,184 women, of whom 78% were post-menopausal. The median tumor size was 2.0 cm (IQR 1.2-2.6). Most pts (87%) had no axillary lymph node involvement (N0). Most tumors were invasive ductal carcinoma (74%) and grade 3 (70%). The median level of TILs was 15% (IQR 5-40). The median duration of follow-up was 30.4 years (95% CI 29.9, 31.1). A total of 950 (52%) iDFS, 828 (45%) RFS, 767 (42%) DDFS events, and 604 (33%) deaths were observed. In multivariable analyses, higher TILs were independently associated with improved iDFS, RFS, DDFS, and OS beyond clinicopathological factors (likelihood ratio p&lt; 10e-6). Each 10% increment in stromal TILs was associated with an 8% (95% CI: 6-11), 10% (95% CI: 7-13), and 13% (95% CI: 10-15) reduction in the risk of experiencing an iDFS, RFS or DDFS event, and with a 12% (95% CI: 9-15) reduction in the risk of death. iDFS, RFS, DDFS and OS rates according to different TIL thresholds and nodal status are shown in the Table. Of note, the RFS estimates (which exclude second non-breast primaries and contralateral breast cancers) were consistently higher than the iDFS counterparts (which include both), consistent with a high rate of contralateral breast cancers and second primary tumors in this cohort. Notably, patients with node-negative—and especially stage I—TNBC with high TILs had excellent survival rates at 10-year follow-up. Conclusion: TILs are highly prognostic in pts with systemically untreated early-stage TNBC. Pts with pN0 (and especially stage I) TNBC with high TILs exhibited very favorable long-term outcomes even in the absence of systemic therapy. These data define the natural history of TIL-rich TNBC pts and are crucial to identifying the optimal patient population for future chemotherapy and immunotherapy de-escalation clinical trials. References: [1] Leon-Ferre et al, 2017, PMID: 28913760 [2] Park et al, 2019, PMID: 31566659 [3] de Jong et al, 2022, PMID: 35353548 Table 5 and 10-year survival endpoints according TIL level, nodal status, and stage Citation Format: Roberto A. Leon-Ferre, Sarah Flora Jonas, Roberto Salgado, Sherene Loi, Vincent De Jong, Jodi M. Carter, Torsten Nielson, Samuel Leung, Nazia Riaz, Giuseppe Curigliano, Carmen Criscitiello, Vincent Cockenpot, Matteo Lambertini, Vera Suman, Barbro Linderholm, John WM Martens, Carolien HM van Deurzen, Mieke Timmermans, Tatsunori Shimoi, Shu Yazaki, Masayuki Yoshida, Sung-Bae Kim, Hee Jin Lee, Maria Vittoria Dieci, Guillaume Bataillon, Anne Salomon, Fabrice Andre, Marleen Kok, Sabine Linn, Matthew P. Goetz, Stefan Michiels. Stromal tumor-infiltrating lymphocytes identify early-stage triple-negative breast cancer patients with favorable outcomes at 10-year follow-up in the absence of systemic therapy: a pooled analysis of 1835 patients [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 PD9-05.

Abstract Mammographic breast density (MBD) has been shown to be a strong, independent risk factor for breast cancer (BC) irrespective of race/ethnicity. Given the risk association of MBD and its potential to mask tumors on a mammogram, state and federal laws have mandated that women receive information regarding their personal MBD in their mammography reports. However, concerns have been raised regarding the impact of MBD notification on patient anxiety, especially written information for women who experience health disparities such as racial/ethnic minorities, lower health literacy, limited English proficiency and lower socioeconomic status. We performed a randomized controlled clinical trial to examine the impact of three different written and interpersonal approaches to MBD notification on patient anxiety, BC worry, and self-perceived BC risk, among Latinas receiving routine mammography screening at a federally qualified medical center (FQHC). We hypothesized that interpersonal education would reduce anxiety and worry, relative to the written notifications alone. The study was performed at the Baseline Clinic of Mountain Park Health Center, a FQHC in Phoenix, AZ. Women between ages 40 and 74 years presenting for screening mammogram were eligible. After providing signed informed consent, participants were randomized equally to usual care (UC- mailed notification letter); enhanced care (notification letter and MBD educational brochure designed for this study): interpersonal care (notification letter, brochure, promotora education via telephone). A stratified block randomization procedure was used with age &gt; 50 years (yes vs no), ethnicity (Hispanic vs non-Hispanic), and language preference (Spanish vs. English) as strata. Study participants completed surveys at the time of enrollment/pre-intervention (T0), at two weeks to six months after intervention was delivered (T1), and about one year after randomization (T2). Anxiety state was measured using the state anxiety subscale of the State-Trait Anxiety Inventory scale (STAI-S) (range from 20-80). BC worry was probed using the question: “How frequently do you worry about getting breast cancer someday”. The self-perceived lifetime risk of BC was rated between 0% (no chance of BC) to 100% (definitely will get BC). The proportion of participants with an increase or persistence of higher level for each outcome between time points was compared between the three study groups. The study was approved by the Mayo Clinic Institutional Review Board. 1332 Latina women were enrolled and randomized between October 2016 and October 2019. All completed the baseline (T0) survey, 928 completed T1, 632 completed T2, and 516 completed both T1 and T2 surveys. At study entry, majority of the participants were young (64.1% between age 40-49 years), had no family history of breast cancer (81.0%), had less than high school education (68.8%), and were married or partnered (67.8%). At T0, the mean (SD) anxiety STAI score was 32.5 (11.1); 51.8% with moderate or severe anxiety (score &gt; 30). With regard to BC worry, 41.3% reported worrying “sometimes”, “often”, or “almost all the time”. Further, 25.4% reported a self-perceived lifetime risk of developing BC of &gt;10% while only 6.6% had a Gail model estimated lifetime risk score of &gt;10%. There was no significant difference in changes in anxiety, BC worry or self-perceived risk from T0 to either T1 or T2 surveys between the intervention groups. In summary, this study found high levels of baseline anxiety and BC worry (despite the majority being 40-49 years old and having no family history of BC) which persisted regardless of how notification and education were delivered. Future work is needed to improve the understanding of factors that could lower anxiety and BC worry and improve risk perception in this population. Citation Format: Karthik Ghosh, Sarah Jenkins, Jennifer Ridgeway, Jessica D. Austin, Bijan Borah, Bhavika K. Patel, Deborah Rhodes, Aaron Norman, Edna P. Ramos, Matt Jewett, Crystal Gonzalez, Valentina Hernandez, Davinder Singh, Vera Suman, Celine Vachon. Breast Density Notification: Impact on anxiety, breast cancer worry, and self-perceived risk among Latinas at a federally qualified medical center. [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 P6-05-38.

Abstract BACKGROUND: The OncotypeDX assay analyzes the expression of 21 genes, including HER2 and Grb7, to assess the predictive effect of chemotherapy in breast cancer recurrence among women with early-stage estrogen-receptor (ER) positive/HER2-negative breast cancer. In this study, we evaluate the distribution of recurrence score from the OncotypeDX assay based on the HER2 expression status by immunohistochemistry (IHC). METHODOLOGY: Utilizing the National Cancer Database, we identified adult women with a diagnosis of stage I – III ER+/HER2- invasive ductal carcinoma of the breast between the years 2010 and 2018. Recurrence scores were classified into low (&lt; 11), intermediate (11-26), and high risk (&gt;26); and the distribution of these recurrence scores cross-tabulated with different IHC scores of HER2 expression (0, 1+, and 2+) by IHC. Women with an IHC score of 2+ had to be negative for HER2 gene amplification by FISH. Multivariate logistic regression model adjusting for age, race, origin, progesterone receptor status, grade, and cancer stage was used to assess the odds of receiving a high OncotypeDx Score (≥26). RESULT: Among 198,931 women with ER+/HER2 negative breast cancer, 59,632 (30.0%) had HER2 IHC score of 0, 102,170 (51.4%) had IHC score of 1+, and 37,129 (18.6%) women were with IHC score of 2+. The median age at diagnosis of breast cancer among all three categories of HER2 expression was 59 years. The median recurrence score for women with IHC scores of 0,1+, and 2+ was 15, 15, and 16 respectively (p &lt; 0.001). A higher proportion of women with HER2 IHC score of 2+ had a high recurrence score compared to women with an IHC score of 0 (15.2% vs. 13%, p &lt; 0.001). In multivariate analysis, compared to women with HER2 IHC score of 0, women with HER2 IHC score of 2+/FISH negative were observed to have higher Odds (OR: 1.16; 95% CI: 1.11 – 1.20, p &lt; 0.001) of receiving high recurrence score. There was no significant difference in the odds of receiving a high recurrence score between women with IHC 0+ and 1+(OR: 0.99; 95% CI: 0.96 – 1.03, p 0.82). CONCLUSION: Women with a HER2 IHC score of 2+ were observed to have a higher odds of receiving high-risk recurrence scores as compared to women with IHC score of 0. This needs to be further correlated with the response to chemotherapy and the risk of recurrence. Citation Format: Anish Shah, Pravash Budhathoki, Suman Gaire, Utsav Joshi, Siddhartha Yadav. Influence of HER2 expression status in the distribution of recurrence score from the OncotypeDx assay among women with early-stage estrogen-receptor-positive/HER2-negative 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 P6-01-41.

Abstract Background: HER2-positive invasive lobular carcinoma (ILC) of the breast is a rare entity. Treatment decisions for HER2-positive lobular breast cancer are often extrapolated from the HER2-positive ductal subtype of breast cancer but the clinical outcomes and prognostic factors are not well defined. Methodology: Women with a diagnosis of stage I to III HER2-positive ILC or invasive ductal carcinoma (IDC) of the breast between 2010 and 2018 were identified from the National Cancer Database. Baseline characteristics were compared between ILC and IDC using Chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. Five-year overall survival (OS) was estimated by the Kaplan Meir method. Multivariate cox proportional hazards regression model including age, race, ethnicity, Charleston Deyo score, grade, TNM stage, and treatment modalities such as type of surgery, chemotherapy, and radiation was used to identify factors associated with OS in HER2-positive ILC. In a subset of patients receiving neoadjuvant chemotherapy, the odds of achieving a complete pathological response were compared between women with ILC and IDC in a multivariate logistic regression model adjusting for age, race, ethnicity, Charleston Deyo score, grade, and clinical stage. Results: A total of 4,197 women with HER2-positive ILC and 116,984 women with HER2-positive IDC were included in the final analysis. The median age at diagnosis was 63 years for women with HER2-positive ILC and 56 years for women with HER2-positive IDC (p&lt; 0.001). The five-year OS among women with HER2-positive ILC was 93.1%, 90.8%,and 78.8% in TNM stages I, II, and III respectively. In multivariate analysis, a significant difference in difference in overall survival was not observed between women with HER2 positive ILC and IDC (Hazard Ratio [HR]: 1.0, 95% Confidence Interval [CI]: 0.9 - 1.1, p=0.55). Among women receiving neoadjuvant chemotherapy, a complete pathological response was observed in 31.7% of women with HER2-positive ILC and 42.7% of HER2-positive IDC. In multivariate analysis, there was no difference in odds of achieving a complete pathological response to neoadjuvant chemotherapy between HER2-positive ILC and IDC (Odds Ratio [OR]: 0.8, 95%CI: 0.7 - 1.0, p=0.12). Higher odds of complete pathological response in HER2-positive ILC were observed for women with estrogen-receptor negative (OR: 2.0, 95% CI: 1.1- 3.8), p= 0.02) and progesterone-receptor negative (OR 2.4, 95%CI: 1.5- 3.7), p&lt; 0.001) tumors. The five-year OS for women with a complete pathological response, partial response, and no response after neoadjuvant chemotherapy in HER2-positive ILC were 89.6%, 84.9%, and 77.3% respectively (p=0.01). Conclusion: This study demonstrates that HER2-positive ILC has comparable clinical outcomes to HER2-positive IDC and response to neoadjuvant chemotherapy correlates with OS in HER2-positive ILC. These findings lend support to the current practice of treating HER2-positive ILC and IDC in a similar manner. Citation Format: Suman Gaire, Pravash Budhathoki, Utsav Joshi, Anish Shah, Grace M. Choong, Siddhartha Yadav. Clinical outcomes of loco-regional HER2-positive invasive lobular carcinoma of the breast [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 P4-06-04.