Gómez, Henry

Importance The Breast Cancer Index (BCI) previously identified premenopausal patients with tumors in which the ratio of expression of HOXB13 relative to IL17BR (hereafter, BCI [H/I]–low tumors) as likely to derive greatest benefit from ovarian function suppression (OFS)–containing adjuvant therapy in the Suppression of Ovarian Function Trial (SOFT) trial. Objectives To assess BCI as a predictive biomarker of benefit from exemestane plus OFS vs tamoxifen plus OFS and to validate BCI as a prognostic biomarker for premenopausal patients. Design, Setting, and Participants This prognostic study used a prospective-retrospective translational design within the Tamoxifen and Exemestane (TEXT) and SOFT trials (enrolled November 2003 to April 2011). Blinded BCI testing in all available tumor samples was completed in March 2024. Premenopausal women with hormone receptor–positive breast cancer randomized to tamoxifen plus OFS or exemestane plus OFS who had BCI assessed were included. Analysis occurred from March to August 2024. Exposure 5 years of adjuvant tamoxifen plus OFS or exemestane plus OFS. Main Outcomes and Measures The primary outcomes were breast cancer-free interval (BCFI) for predictive analyses and distant recurrence-free interval (DRFI) for prognostic analyses after a median follow-up of 13 years in the TEXT cohort. Secondary objectives examined the predictive performance of BCI (H/I) in the combined TEXT and SOFT cohort overall and in prespecified clinical subgroups. Results Of 1782 patients in the TEXT study, 1034 (58.0%) had BCI (H/I)–low tumors; 915 (51.3%) of patients had N0 disease and 1077 (60.4%) were younger than 45 years. Patients with BCI (H/I)–low tumors had a 6.6% absolute benefit in 12-year BCFI (HR, 0.61; 95% CI, 0.44-0.85) for exemestane plus OFS vs tamoxifen plus OFS, while those with BCI (H/I)–high tumors had a 6.3% absolute benefit (HR, 0.78; 95% CI, 0.57-1.07; P for interaction = .29). Results were consistent in the combined TEXT plus SOFT cohort (2896 patients) and adjusting for clinicopathological variables. Clinical subgroup analyses consistently showed benefit of exemestane plus OFS vs tamoxifen plus OFS for BCI (H/I)–low tumors, and more variable relative treatment effects among BCI (H/I)–high tumors, including by age. Post hoc exploratory time-varying estimates suggested the treatment × BCI associations may differ in years 0 to 5 vs greater than 5 years. BCI and BCI N+ as continuous indices were prognostic for distant recurrence in N0 (HR, 1.27; 95% CI, 1.11-1.44; P < .001) and N1 (HR, 1.58; 95% CI, 1.21-2.05; P < .001) cancers. The 12-year DRFI was 96.3%, 90.3%, and 84.9% for BCI low-, intermediate-, and high-risk N0 cancers, respectively. Conclusions and Relevance In this study of premenopausal women with hormone receptor–positive breast cancer, BCI (H/I) status did not clearly predict greater benefit of adjuvant exemestane plus OFS vs tamoxifen plus OFS for women with BCI (H/I)–low tumors than for those with BCI (H/I)–high tumors; BCI continuous indices were reconfirmed as prognostic for premenopausal women. These findings support prior results of SOFT, which compared tamoxifen-alone vs OFS with either exemestane or tamoxifen, indicating premenopausal patients with BCI (H/I)–low tumors may benefit from more intensive endocrine therapy.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor–positive (ER/PgR+) early breast cancer randomly assigned to 5 years of exemestane + ovarian function suppression (OFS) versus tamoxifen + OFS. After a median follow-up of 9 years, exemestane + OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen + OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.90; P < .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98; P = .03), but not overall survival (90.1% v 89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane + OFS over tamoxifen + OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane + OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS. [Media: see text]

522 Background: Our preclinical findings suggest a role for the mevalonate pathway (MVA) in treatment resistance in HER2+ BC by providing alternative growth and survival signaling to bypass potent HER2 blockade, which could be overcome by the MVA inhibitors statins and nitrogen-containing bisphosphonates (NBs). Here we explored the effect of MVA inhibitors’ use on pts’ outcomes in the ALTTO trial (BIG2-06; NCT00490139). Methods: In the ALTTO trial, 8381 pts with HER2+ BC were randomized to 1 year of adjuvant lapatinib (L), trastuzumab (T), L+T, or T→L. All pts with documented treatment start with statins or NBs < 1 year after randomization were considered as MVA inhibitors users. Survival curves, with a median follow-up of 6.9 years, for disease-free survival (DFS), distant relapse-free interval (DRFI), BC-specific survival (BCSS), and overall survival (OS) according to MVA inhibitors use were estimated by the Kaplan Meier method and Log-rank test. All multivariate survival analyses employed a Cox proportional hazards regression model, adjusting for tumor size, nodal status, hormonal receptor (HoR), menopausal status, BMI, timing of chemo, and randomization arm. We considered interactions terms in Cox’s model between MVA inhibitors use and randomization arm, hormonal status, and BMI group. Results: Among the 8381 pts included in this study, 493 and 299 were statins or NBs users, respectively. Table 1 summarizes the significant differences in pts’ characteristics according to MVA inhibitors use ( P <.005). In multivariate survival analyses, only NBs use was associated independently with better BCSS (HR, 0.44; 95% CI, 0.23 - 0.84; P = 0.014). Statin use was not independently associated with prognosis but only in interaction with pts characteristics: worse DFS, BCSS and OS in pts treated with L+T, worse DRFI and OS in pts treated with HoR+ BC (respective interaction P-values <0.05 in the Cox’s model). Conclusions: NBs independently predicted improved BC-specific outcome in pts with HER2+ BC treated with adjuvant anti-HER2 therapy. Statin use was associated with an inferior outcome in pts with HoR+ disease and/or those treated with L+T. Whether this inferior association in statin users may reflect the underlying predisposition factors that can weaken the efficacy of anti-HER2 treatments and whether this effect was observed only in the L+T arm due to the more potent inhibition of the HER2 signaling pathway remain open questions. Further clinical investigations on the impact of MVA inhibitors on the outcome of pts with HER2+ BC are warranted. [Table: see text]

e12579 Background: Triple negative breast cancer (TNBC) seems to be associated with a hereditary disease cause based on the earlier age of onset, the high rate of TNBC cases with a positive family history of cancer, and the higher prevalence of breast cancer susceptibility genes. The impact of family history in breast and/or ovarian cancer (FHBOC) in TNBC overall survival is unclear, we conducted this study to evaluate this factor in a Peruvian cohort. Methods: Retrospectively reviewed the medical files from TNBC patients diagnosed at Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima, Peru, from 2000 to 2014. New cases with histologically confirmed TNBC defined as lack of expression of estrogen and progesterone receptors by immunohistochemistry and HER2- were included. A positive FHBOC was defined as a history of breast and/or ovarian cancer in 1st, 2nd and/or 3rd degree relatives at any age. Patients who had three affected relatives in two generations with two of them being first-degree relatives were considered as exhibiting a clinical autosomal dominant (AD) inheritance pattern. Results: 2006 patients, 99.8% were females. Mean age was 50.2 years old (19 - 95) and 54.6% were postmenopausal. According clinical staging: stage I, 7.2%; stage II, 34.2%; stage III, 51.0%; and stage IV, 6.5%. 76.5% of women underwent surgery. 13% (n=266) had a positive FHBOC. Of these, 44.0% (n=117), 35.0% (n=93), and 13.5% (n=36) had 1st, 2nd, and 3rd degree affected relatives, respectively. An AD inheritance pattern was observed in 20.7% (n=55) of patients with FHBOC. With a median follow-up of 80 months (range 0 - 249), 5y-overall survival (OS) for the whole population was 53.8%. 5 year-OS was significantly better in patients with FHBOC as compared to those without it; 64.5% vs. 52.2%, respectively (HR 0.73; 95% CI [0.60-0.88] p=0.001). FHBOC showed a positive impact on survival rates among patients with stages III and IV (5-year OS 42.3% vs. 32.7%; HR 0.79; 95% CI [0.64-0.99], p=0.041) but not in stages I and II (5-year OS 88.4% vs. 81.3%; HR 0.72; 95% CI [0.49-1.08], p=0.11). The 5y-OS for the patients with an AD inheritance pattern was 70.9%. However, pairwise multiple comparison did not find a significant difference between these patients and those with FHBOC without an AD inheritance pattern (62.8%). On multivariate analysis, FHBOC (HR: 0.80; 95% CI [0.66-0.97], p=0.023), had an independent effect on OS, adjusted for age, menopausal status, clinical stage and surgery. Conclusions: A positive FHBOC was associated with an improved survival in patients with TNBC, suggesting FHBOC as an independent prognostic factor. These results need validation and confirmation through additional retrospective cohorts and analysis in prospective clinical trials.

Abstract Background Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. Methods The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Results Of 9719 eligible women with hormone receptor–positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Conclusions Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.

503 Background: TAILORx established that endocrine therapy (ET) alone is non-inferior to adjuvant chemotherapy (CT) plus ET in EBC and a 21-gene RS of 11-25, with some benefit if ≤50 years (y) with RS 16-25 (PMID: 29860917). We evaluated whether clinical risk (tumor size & histologic grade) provides additional prognostic information to RS, a secondary trial objective. Methods: Clinical risk by was assessed by Adjuvant! (version 8.0) using MINDACT criteria (PMID 27557300), defined as low clinical risk (LCR - tumor ≤3 cm and low grade, <2 cm and intermediate grade, or ≤1 cm and high grade) or high clinical risk (HCR -not meeting LCR criteria). Results: Of 9427 women with RS and clinical risk information, 70% were LCR and 30% HCR, with comparable distribution by age ( ≤50 vs. >50). The RS was 26-100 in 9% of LCR and 27% of HCR patients, with similar distributions by age. Although LCR/HCR provided additional prognostic information in each RS category for iDFS, including RS 0-10 (9-year rates 86.7% vs. 75.7% LCR vs. HCR), 11-25 (85.4% vs. 78.9%), and 26-100 (82.0% vs. 70.4%), iDFS rates were similar irrespective of CT (no vs. yes) in the entire RS 11-25 cohort whether LCR (85.8% vs. 85.1%) or HCR (79.8% vs. 77.9%). DRFI rates were also similar irrespective of CT in the RS 11-25 cohort or > 50y group whether LCR (96.0% vs. 96.1% overall; 96.5% vs. 96.0% > 50y) or HCR (92.3% vs. 89.9% overall; 91.7% vs. 90.7% >50y). For women ≤50y, the absolute reduction in distant recurrence from CT with a RS of 16-20 (N=923) was -0.2% (standard error [SE]±2.1%) for LCR vs. 6.5%(SE±4.9%) for HCR (vs. 1.6%[SE±1.9%] overall), whereas for a RS 21-25 (N=492) it was 6.4% (SE±4.9%) for LCR vs. 8.6% (SE±6.2%) for HCR (vs. 6.5%[SE±3.7%] overall). Conclusions: Clinical risk stratification provides additional prognostic information to the 21-gene RS, but not prediction of CT benefit in the overall TAILORx population or those > 50y, and facilitates more refined estimates of absolute CT benefit for women ≤50y with a RS 16-25. (Funded by National Cancer Institute, Komen Foundation, Breast Cancer Research Foundation). Clinical trial information: NCT00310180.

Abstract Background: Black race is associated with worse outcomes in localized hormone receptor (HR)-positive breast cancer in population-based and in clinical trial cohorts, whether using self-identified race (Albain et al. JNCI 2009 [PMID: 19584328; Sparano et al. JNCI 2012 [PMID: 22250182) or genetically-identified race (Schneider et al. J Precision Oncol 2017 [PMID: 29333527]). This disparity persists after adjustment for treatment delivery parameters (Hershman et al. JCO 2009 [PMID:19307504]). We evaluated clinicopathologic characteristics, treatment delivered and clinical outcomes in the Trial Assigning Individualized Options for Treatment (TAILORx) by race and ethnicity (Sparano et al. NEJM 2018 [PMID: 29860917]). Methods: The analysis included 9719 evaluable TAILORx participants. The association between clinical outcomes and race (white, black, Asian, other/unknown) and ethnicity (Hispanic vs. non-Hispanic) was examined, including invasive disease-free survival (iDFS), distant relapse-free interval (DRFI), relapse-free interval (RFI), and overall survival (OS). Proportional hazards models were fit including age (5 categories), tumor size (&gt;2 cm vs. &lt;=2 cm), histologic grade (high vs. medium vs. low vs. unknown), continuous recurrence score (RS), race, and ethnicity in the overall population and randomized treatment arms in the RS 11-25 cohort. Results: The study population included 8189 (84%) whites, 693 (7%) blacks, 405 (4%) Asians, and 432 (4%) with other/unknown race. Regarding ethnicity, 7635 (79%) were non-Hispanic, 889 (9%) Hispanic, and 1195 (12%) unknown. There was no significant difference in RS distribution (p=0.22) in blacks compared with whites, or in median (17 vs. 17) or mean RS (19.1 vs. 18.2). There was likewise no difference in Hispanic vs. non-Hispanic ethnicity for RS distribution (p=0.72) or median (17 vs. 17) or mean RS (18.5 vs. 18.0). Black race (39% vs. 30%) and Hispanic ethnicity (39% vs. 30%) were both associated with younger age (&lt;/=50 years) at diagnosis. The use and type of adjuvant chemotherapy and endocrine therapy, and duration of endocrine therapy, were similar in black (vs. white) and Hispanic (vs. non-Hispanic) populations. In proportional hazards models, black race (compared with white race) was associated with worse clinical outcomes in the entire population and in those with a RS 11-25 (see table). Hispanic ethnicity was generally associated with better outcomes (compared with non-Hispanic ethnicity). For the cohort with a RS of 11-25, there was no evidence for chemotherapy benefit for any racial or ethnic group. Race (black vs.white) and clinical outcomes in proportional hazards modelsClinical endpointEntire Population (N=693 black) Hazard ratio for eventRS 11-25 (N=471 black) Hazard ratio for eveniDFS1.33 (p=0.005)1.49 (p=0.001)DRFI1.21 (p=0.28)1.60 (p=0.02)RFI1.39 (p=0.02)1.80 (p&lt;0.001)OS1.52 (p=0.005)1.67 (p=0.003 Conclusions: In patients eligible and selected for participation in TAILORx, black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy. This adds to an emerging body of evidence suggesting a biologic basis or other factors contributing to racial disparities in HR-positive breast cancer that requires further evaluation. Citation Format: Albain K, Gray RJ, Sparano JA, Makower DF, Pritchard KI, Hayes DF, Geyer, Jr. CE, Dees EC, Goetz MP, Olson, Jr. JA, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge, Jr. GW. Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-07.