Hormone Receptor-negative Disease Research Articles

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

Abstract PD10-06: Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study

Abstract Background: Young breast cancer patients (pts) carrying a germline BRCA mutation (mBRCA) have similar outcomes as non-carriers. However, there is currently lack of evidence regarding the impact of mBRCA type and hormone receptor status on clinical behavior and outcomes of mBRCA breast cancer. We aim to address these questions in the largest dataset to date of young mBRCA breast cancer pts. Methods: This was an international, multicenter, hospital-based, retrospective cohort study. Women harboring deleterious germline mBRCA1 or mBRCA2 that received a diagnosis of stage I-III invasive early breast cancer at age ≤40 years between January 2000 and December 2012 were included. Baseline pts, tumor, and treatment characteristics, pattern and risk over time of disease-free survival (DFS) events, and survival outcomes (DFS, distant recurrence-free interval [DRFI] and overall survival [OS]) were compared between mBRCA1 and mBRCA2 pts overall and by hormone receptor status. Multivariate Cox proportional hazard models were used to compare hazard rates (HRs). Results: 1,236 young mBRCA breast cancer pts were included. Among 808 and 428 pts with mBRCA1 or mBRCA2, respectively, 191 (23.6%) and 356 (83.2%) had hormone receptor-positive tumors while 617 (76.4%) and 72 (16.8%) hormone receptor-negative disease (p<0.001). Compared to mBRCA2 breast cancer pts, those with mBRCA1 were younger, more likely to have reported Jewish ancestry, had more grade 3 tumors, less nodal involvement, lobular histology and HER2 positivity, and received more frequently chemotherapy (all p<0.001). More mBRCA1 pts with hormone receptor-positive tumors did not receive adjuvant endocrine therapy (14.7% vs. 4.2%, p<0.001). No difference between mBRCA1 and mBRCA2 pts was observed in risk-reducing mastectomy (43.9% vs. 46.0%; p=0.371) or salpingo-oophorectomy (48.3% vs. 48.8%; p=1.0). Median follow-up was 7.9 years (range 5.6-10.6 years). Second primary breast cancers (17.0% vs. 12.2%, p=0.025) and non-breast primary malignancies (4.3% vs. 1.9%, p=0.033) were more frequent among mBRCA1 pts compared to mBRCA2 pts, while distant recurrences were less frequent (10.4% vs. 15.4%, p=0.013). 8-year DFS was 62.8% and 65.9% for mBRCA1 and mBRCA2 pts, respectively (adjusted HR 0.76; 95% CI 0.60-0.96). The worse DFS in mBRCA1 was observed regardless of hormone receptor status (pinteraction=0.848): hormone receptor-positive (adjusted HR 0.77; 95% CI 0.58-1.03) and hormone receptor-negative (adjusted HR 0.73; 95% CI 0.48-1.13). No differences in DRFI and OS were observed between mBRCA1 and mBRCA2 pts. Compared to pts with hormone receptor-negative disease, those with hormone receptor-positive breast cancer had higher chances of developing distant (± loco-regional) recurrences (16.1% vs. 9.0%; p<0.001) and less frequent second primary malignancies (BC: 12.1% vs. 17.9%, p=0.005; non-BC: 2.8% vs. 4.0%, p=0.216). No differences in DFS and OS were observed between pts with hormone receptor-positive or negative breast cancer. However, there was a trend towards worse DRFI in women with hormone receptor-positive breast cancer as compared to those with hormone receptor-negative disease (8-year DRFI: 83.4% vs. 90.1%; adjusted HR 1.39; 95% CI 0.94-2.05). Conclusions: In this large unique dataset, young mBRCA1 breast cancer pts had worse DFS than those with mBRCA2 mostly due to higher rates of second primary malignancies. Hormone receptor positivity had no positive prognostic value in young mBRCA breast cancer pts with a trend towards worse DRFI in those with hormone receptor-negative disease. These results provide important information for counseling young mBRCA breast cancer pts regarding treatment, prevention and follow-up care strategies. Citation Format: Matteo Lambertini, Marcello Ceppi, Anne-Sophie Hamy, Olivier Caron, Philip D. Poorvu, Estela Carrasco, Albert Grinshpun, Kevin Punie, Christine Rousset-Jablonski, Alberta Ferrari, Shani Paluch-Shimon, Angela Toss, Claire Senechal, Fabio Puglisi, Katarzyna Pogoda, Jose Alejandro Pérez-Fidalgo, Laura De Marchis, Riccardo Ponzone, Luca Livraghi, Maria Del Pilar Estevez-Diz, Cynthia Villarreal-Garza, Maria Vittoria Dieci, Florian Clatot, Francois P. Duhoux, Rossella Graffeo, Luis Teixeira, Octavi Córdoba, Amir Sonnenblick, Arlindo R. Ferreira, Ann H. Partridge, Antonio Di Meglio, Claire Saule, Fedro A. Peccatori, Marco Bruzzone, Lucia Del Mastro, Lieveke Ameye, Judith Balmaña, Hatem A. Azim, Jr. Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-06.

Abstract PD13-09: Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial

Abstract Background: The development of central nervous system (CNS) metastases presents a considerable challenge in metastatic breast cancer (MBC) due to the limited availability of evidence-based treatments. Up to 50% of patients with HER2-positive (HER2+) MBC develop CNS metastases during the course of their disease. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated activity against CNS metastases in HER2+ MBC in two phase 2 studies (NEfERT-T, TBCRC 022) and one phase 3 study (NALA); significant benefits for predefined CNS endpoints were reported in NEfERT-T and confirmed in NALA. Here we present an exploratory analysis of patients from NALA with CNS involvement at enrollment. Methods: NALA was an international, randomized, open-label, active-controlled, phase 3 study in patients with HER2+ MBC who had received ≥2 lines of HER2-directed therapy in the metastatic setting (ClinicalTrials.gov: NCT01808573). Patients with asymptomatic metastatic brain disease managed with stable doses of corticosteroids for ≥14 days prior to randomization were eligible, whereas patients with symptomatic or unstable brain metastases were excluded. Patients were randomized (1:1 ratio) to neratinib (N; 240 mg qd po) + capecitabine (C; 750 mg/m2 bid po) or lapatinib (L; 1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Intervention for symptomatic metastatic CNS disease was a secondary endpoint. CNS disease at baseline was defined as patients with treated or untreated disease in the ‘brain’ assessed by investigator at enrollment. CNS imaging was not mandatory at screening. Results: Of the 621 patients enrolled in NALA, 101 (16%) had documented baseline CNS disease and 520 (74%) had no CNS disease at baseline. Patients with CNS disease had a lower performance status and were more likely to have hormone receptor-negative disease than those with no CNS disease; no major imbalances of baseline characteristics were noted between treatment arms. Overall, 78 (77%) patients had previously received CNS radiation [whole brain, n=59 (58%); stereotactic, n=17 (17%); unknown, n=2 (2%)], and 5 (5%) patients had undergone CNS surgery. Median treatment duration was 5.7 (IQR 2.8-8.5) months for N, and 3.5 (IQR 2.1-6.9) months for L. PFS, OS, and cumulative incidence of interventions for symptomatic CNS disease are summarized in the table. No new safety signals were detected. Conclusions: Regardless of the status of CNS metastases at baseline, patients appeared to have better outcomes in the N+C arm compared with the L+C arm. Table. Efficacy outcomes in patients with and without CNS disease at baselineIntention-to-treat (n=621)CNS metastases at baseline – Yes (n=101)CNS metastases at baseline – No (n=520)N+C (n=307)L+C (n=314)N+C (n=51)L+C (n=50)N+C (n=256)L+C (n=264)PFSaHazard ratio (95% CI)0.76 (0.63–0.93)0.66 (0.41–1.05)0.76 (0.62–0.94)P-value0.00590.07410.0099Restricted mean PFSb, months8.86.67.85.59.06.9Difference, months2.22.32.1OSHazard ratio (95% CI)0.88 (0.72–1.07)0.90 (0.59–1.38)0.85 (0.68–1.06)P-value0.20860.63520.1517Restricted mean OSb, months24.022.216.415.425.623.6Difference, months1.71.02.0Incidence of CNS interventionOverall cumulative incidencec, %22.7629.1940.1347.7919.1624.65P-value0.0430.4300.067aCentrally confirmed; bRestriction prespecified as 24 months for PFS, and 48 months for OS; c % requiring intervention for CNS disease (competing risk model) Citation Format: Cristina Saura, Larisa Ryvo, Sara Hurvitz, William Gradishar, Beverly Moy, Suzette Delaloge, Sung-Bae Kim, Mafalda Oliveira, Maureen Trudeau, Ming-Shen Dai, Barbara Haley, Ron Bose, Luciana Landeiro, Judith Bebchuk, Aimee Frazier, Kiana Keyvanjah, Richard Bryce, Adam Brufsky. Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-09.

Abstract GS3-09: Chances of pregnancy after breast cancer, reproductive and disease outcomes: A systematic review and meta-analysis

Abstract Background: Pregnancy-related issues are a priority for young breast cancer (BC) patients. Increasing evidence has shown that pregnancy after prior BC diagnosis is feasible. Nevertheless, few BC survivors conceive following anticancer treatment completion and many physicians remain concerned about the potentially detrimental effects of pregnancy after BC in terms of fetal/obstetrical outcomes and maternal prognosis. This systematic review and meta-analysis aims at providing updated and solid evidence on these important issues. Methods: A systematic literature review up to January 31, 2020 with no language restriction was conducted to identify studies including patients with a pregnancy after prior BC diagnosis. Chances of pregnancy after BC, fetal and obstetrical outcomes, disease-free survival (DFS) and overall survival (OS) were assessed. Pooled relative risks (RRs), hazard ratios (HRs) or odds ratio (ORs) with 95% confidence intervals (CI) were calculated using the random effects models. The study is registered with the PROSPERO registration number CRD42020158324. Results: Overall, 39 studies were included. Out of the 8,265,713 young women included in these studies, 8,093,401 were from the general population, 57,739 had cancers other than BC, 114,573 had BC. Among the 114,573 BC patients, 7,505 had a pregnancy after BC diagnosis and 107,068 did not. Compared to women from the general population, BC patients had 60% reduced chances of having a pregnancy following anticancer treatment completion (RR 0.40, 95% CI 0.32-0.49). Among other cancer patients, only women with prior cervical cancer had lower pregnancy rates (RR 0.33, 95% CI 0.31-0.35) than BC patients. Compared to the general population, BC survivors had significantly increased risks of low birth weight (OR 1.50, 95% CI 1.31-1.73), small for gestational age (OR 1.16, 95% CI 1.01-1.33), preterm delivery (OR 1.45, 95% CI 1.11-1.88) and caesarean section (OR 1.14, 95% CI 1.04-1.25). No significant increased risk of congenital abnormalities (OR 1.63, 95% CI 0.89-2.98) or other pregnancy or delivery complications (spontaneous or induced abortion, gestosis, antepartum or postpartum hemorrhage) was observed. Prior chemotherapy exposure or short pregnancy interval (defined as <2 or <5 years after BC diagnosis) were not associated with additional increased risk of complications. Pregnancy after BC was not associated with a negative impact on patients’ outcomes. Compared to BC patients without subsequent pregnancy, those with pregnancy after BC had better OS (HR 0.56, 95% CI 0.46-0.67) and DFS (HR 0.73, 95% CI 0.56-0.94). Similar results were observed in the studies correcting for the potential “healthy mother effect” (OS: HR 0.52, 95% CI 0.42-0.65; DFS: HR 0.74, 95% CI 0.58-0.96). No detrimental prognostic effect of pregnancy after BC was observed in patients with hormone-receptor positive disease (DFS: HR 1.10, 95% CI 0.73-1.66), while better outcomes were observed for those with hormone-receptor negative disease (DFS: HR 0.72, 95% CI 0.55-0.95). The safety of pregnancy after BC was observed irrespective of BRCA status, nodal status, previous chemotherapy exposure, pregnancy interval and pregnancy outcomes. Conclusions: This large meta-analysis provides solid evidence on the safety of pregnancy after prior BC diagnosis. The increased risk of fetal and obstetrical complications (but not of congenital abnormalities) calls for ensuring a closer monitoring of these pregnancies. The significantly reduced chances of conceiving as compared to the general population and other cancer patients should raise further awareness on the need to improve the oncofertility counseling of young BC patients wishing to complete their family planning following anticancer treatment completion. Citation Format: Eva Blondeaux, Marta Perachino, Marco Bruzzone, Richard A. Anderson, Evandro De Azambuja, Philip D. Poorvu, Hee Jeong Kim, Cynthia Villarreal-Garza, Barbara Pistilli, Ines Vaz-Luis, Cristina Saura, Kathryn J. Ruddy, Maria Alice Franzoi, Chiara Sertoli, Marcello Ceppi, Hatem A. Azim, Jr., Frederic Amant, Isabelle Demeestere, Lucia Del Mastro, Ann H. Partridge, Olivia Pagani, Fedro A. Peccatori, Matteo Lambertini. Chances of pregnancy after breast cancer, reproductive and disease outcomes: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-09.

Abstract PD3-04: Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial

Abstract Background: In HER2-positive breast cancer patients, timing from the end of (neo)adjuvant trastuzumab (T)-based therapy to diagnosis of metastatic breast cancer is the key factor in determining the optimal first-line treatment. There is currently lack of clear evidence to support the possible prognostic role of this interval and 12 months has been mostly empirically used. The present analysis aimed to investigate patterns of relapse, first-line choice and survival outcomes of patients with HER2-positive early breast cancer who relapsed after adjuvant T-based therapy depending on T-free interval (TFI, i.e. timing from end of adjuvant T to diagnosis of distant metastases). Methods: In ALTTO, HER2-positive early breast cancer patients were randomized to 1 year of either T alone, lapatinib (L) alone, their sequence (T–>L) or their combination (T+L). This exploratory analysis included only pts in the T or T+L arms who experienced a distant disease-free survival (DDFS) event. Two cohorts of patients were defined depending on TFI: group A (TFI of <12 months) and group B (>12 months). Baseline characteristics, patterns of relapse, first-line choice and overall survival (OS) were compared. OS was defined as time between date of DDFS event to death; age at diagnosis, tumor size and hormone receptor status were the variables included in the final multivariate models. Results: Out of 8,381 patients included in ALTTO, 404 patients in the T and T+L arms developed a DDFS event, of whom 201 occurred <12 months (group A) and 203 >12 months (group B) after the end of adjuvant T. Patients in group A were older (p=0.013), had larger tumors (p=0.004) and more frequently hormone receptor-negative disease (p<0.001). No significant difference in patterns of first DDFS event was observed (p=0.073); however, a numerically higher number of patients in group A compared to group B developed brain metastasis (26% vs. 15%). First-line anti-HER2 therapy was received by 57% of the patients. Choice of first-line anti-HER2 therapy was different between the two groups (p=0.022): the majority of patients received T in both groups (61% vs. 65% in groups A and B, respectively), while more patients in group A received L (25% vs. 11%) and less received pertuzumab (8% vs. 17%). OS survival was significantly shorter in group A compared to group B: median OS was 18.4 and 29.3 months in groups A and B, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). Similar results were observed after the exclusion of patients treated with first-line pertuzumab-based therapy (n=29): median OS was 18.2 and 26.8 months in groups A and B, respectively (adjusted HR 0.66; 95% CI 0.51-0.86; p=0.002). Better outcomes in terms of OS for patients in group B was observed across all analyzed subgroups with no interaction according to hormone receptor status (p=0.814) nor type of adjuvant anti-HER2 treatment (p=0.233): hormone receptor-positive (adjusted HR 0.69; 95% CI 0.48-0.99), hormone receptor-negative (adjusted HR 0.68; 95% CI 0.48-0.98), T+L arm (adjusted HR 0.55; 95% CI 0.38-0.80) and T arm (adjusted HR 0.80; 95% CI 0.55-1.17). Conclusions: In the ALTTO trial, HER2-positive early breast cancer patients who experienced shorter TFI (i.e. <12 months vs. >12 months) following adjuvant T-based therapy had inferior OS after the diagnosis of distant recurrence. Given its prognostic value, TFI can help to individualize clinical recommendations and to design future trials in the metastatic setting for patients relapsing after prior exposure to anti-HER2 therapy for early disease. Citation Format: Matteo Lambertini, Dominique Agbor-Tarh, Otto Metzger-Filho, Noam Ponde, Francesca Poggio, Florentine Hilbers, Larissa A Korde, Saranya Chumsri, Olena Werner, Lucia Del Mastro, Rafael Caparica, Volker Moebus, Alvaro Moreno-Aspitia, Martine Piccart, Evandro de Azambuja. Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-04.

Treatment response correlation between primary tumor and axillary lymph nodes after neoadjuvant therapy in breast cancer: a retrospective study based on real-world data.

Excellent response of the primary tumor after neoadjuvant therapy may indicate a better axillary status in breast cancer. However, this treatment response correlation has not been investigated in Chinese breast cancer patients. Patients diagnosed with breast cancer and treated with neoadjuvant therapy were included in this retrospective study, conducted at a comprehensive breast cancer institution in China. Clinicopathological factors at baseline were analyzed by univariate and multivariate analyses. Furthermore, association rules analyses were used to investigate the correlation between the pathologic response of the primary tumor and that of the axillary lymph nodes based on such factors. Multivariate logistic regression analysis showed that breast pathologic response was influenced by tumor size, classification of regional lymph nodes, histological grade, progesterone receptor status, and Ki67 expression. The potential influencing factor for the pathologic response of the axilla was found to be regional lymph node classification. The findings from association rules analyses demonstrated that when a pathologic complete response (pCR) in the breast was achieved among patients with cT2N0 and hormone receptor-negative disease, the axilla response in these patients was also highly likely to be pCR (the likelihood for axilla pCR was more than 90%). However, cT3N1-2 patients hardly achieved pCR for both the primary tumor and axillary lymph nodes (mean confidence, 0.9637). The clinicopathological factors accounting for the inconsistent response between the breast and the axilla were found to be hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, and low Ki67 expression. Our findings suggest a strong correlation between breast pCR and axilla pCR among patients with specific characteristics. These findings provide a basis for the selection of candidates for clinical trials on the omission of axillary surgery.

S1616 A Nonspecific Gastrointestinal Symptom Leads to a Rare Colonic Metastasis in a Patient With Remote History of Breast Cancer

INTRODUCTION: Breast cancer is the second most common malignancy in women and can metastasize to the lungs, bone, and liver; colonic metastases are exceedingly rare. We discuss a breast cancer survivor who presented with non-specific GI symptoms and was found to have metastatic breast cancer in the colon. CASE DESCRIPTION/METHODS: This is a 74-year-old female with a remote history of localized right breast cancer initially managed with breast-conserving surgery and radiation in the late 1980s, then maintained on an estrogen receptor (ER) antagonist before receiving a mastectomy in the late 1990s. She adhered to mammogram surveillance that confirmed her remission for the following two decades. At our clinic, she complained of decreased stool caliber and constipation refractory to over-the-counter laxatives. Symptoms were present for four weeks, associated with nausea, and without weight loss, abdominal pain, or blood in stool. She was up-to-date with colonoscopies. Exam revealed a soft abdomen with a firm focus near the umbilicus without tenderness on palpation. Colonoscopy revealed a region of erythematous friable mucosa with ulcerations at the transverse colon measuring 3 cm wide (Figure 1A). Pathology revealed a poorly differentiated carcinoma and GATA3, a breast carcinoma marker, was strongly positive (Figure 1B/D). E-cadherin was negative indicating this is most likely lobular carcinoma and ER, progesterone receptor, and HER-2 were all negative. Subsequent imaging confirmed metastases to the colon and retroperitoneum. She established care with oncology and has since been initiated on chemotherapy. DISCUSSION: Breast cancer metastases to the colon are a rare finding. The frequency at which metastases occur and the time at which they present depends on histologic subtype and hormone receptor status, respectively. Lobular carcinomas, as in our patient, tend to metastasize more than other subtypes. Also, hormone receptor-negative disease tends to metastasize earlier than hormone receptor-positive disease, with the former typically appearing within five years after initial diagnosis and the latter presenting well beyond that. Although our patient has lobular carcinoma, she also has triple-negative disease confirming exceptions to these rules. We present this case not only to highlight an atypical presentation of a common malignancy but to emphasize that providers should maintain a high index of suspicion for cancer recurrence when evaluating nonspecific gastrointestinal complaints in cancer survivors.Figure 1.: A. Endoscopic view of transverse colon demonstrating erythematous friable mucosa with ulceration. Ulcer measures three centimeters wide. B. Hematoxylin and Eosin stain: Ulcerated mucosa with underlying dense infiltrate of poorly differentiated neoplastic cells in the lamina propria. Of note, non-neoplastic colonic mucosa with unremarkable colonic glands/crypts are seen on the left of the dotted red line (arrow). C. Immunohistochemistry for CDX2. The neoplastic cells are negative for CDX-2, ruling out the possibility of adenocarcinoma of the GI tract. D. Immunohistochemistry for GATA 3. The neoplastic cells are positive for GATA3, suggesting breast origin of these neoplastic cells.

Abstract C033: Racial differences in the associations between luminal master regulator transcription factor expression and breast cancer survival

Abstract Purpose: Women of African ancestry in the United States are more likely to die from breast cancer than their European counterparts. While prior studies suggest differences in the frequency of hormone receptor-negative disease as an underlying cause, recent studies report higher race-based mortality rates in patients with hormone receptor-positive, luminal breast cancer. Here we explore biologic factors that may underly this disparity by comparing racial differences in the level, functional activity, and prognostic significance of 3 master transcriptional regulators of mammary luminal differentiation. Patients and Methods: Medical records and tissues from 555 patients (293 European and 262 African ancestry) diagnosed with Stage 0 to IV breast cancer, from 2001 to 2010 at a major medical center in East North Carolina, were analyzed for the expression of functional biomarkers of luminal differentiation including estrogen receptor (ESR1), and pioneer transcription factors FOXA1 and GATA3. Differential comparison of protein expression was integrated with network-level gene expression analysis (22% of cohort) to define predictive correlations with race and survival. Results: Univariate and multivariate odds ratios combined with area under the curve receiver operator characteristics show significant differences in predictive activity of these functional biomarkers based on race and survival—ESR1 (EA OR= 0.47, p = 5e-04; AA OR= 0.77, p = 0.22), FOXA1 (EA OR= 0.38, p= 1.4e-04; AA OR = 0.53, p = 1.3e-02), and GATA3 (EA OR= 0.36, p= 3.7e-06, AA OR= 0.57, p= 0.51)—and uncover genes in the downstream regulons of these biomarkers that strongly correlate either with genetic ancestry or overall survival. Conclusion: Transcriptional regulatory networks linked to mammary luminal differentiation reveal race-specific differences in master regulatory activity that may underlie tumor characteristics contributing to racial disparities in outcome. These biomarkers and their downstream regulons represent important targets to explore intrinsic mechanisms that drive breast cancer survival disparities. Citation Format: Jung S. Byun, Sandeep K. Singhal, Sam Park, Dae Ik Yi, Tingfen Yan, Ambar Caban, Alana Jones, Partha Mukhopadhyay, Sara Gil Hernandez, Stephen Hewitt, Lisa A. Newman, Melissa Davis, Jorge Sepulveda, Adrianna De Siervi, Anna Napoles, Nasreen Vohra, Kevin Gardner. Racial differences in the associations between luminal master regulator transcription factor expression and breast cancer survival [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C033.

Adding pertuzumab to adjuvant therapy for high-risk HER2-positive early breast cancer in APHINITY: a GRADE analysis

Aim: Adding pertuzumab to standard trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (IDFS) in the APHINITY trial. However, the magnitude of benefit was marginal in the overall population. Methods: We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) analysis on data from APHINITY to build summary-of-findings tables to evaluate the efficacy, safety and quality of evidence of predefined clinical outcomes for the addition of pertuzumab to trastuzumab-based adjuvant therapy in patients with high-risk HER2-positive early breast cancer. Results: Pertuzumab significantly improved 3-year, event-free, absolute benefit in disease-free survival, IDFS and distant relapse-free interval (DFRI) in patients with node-positive or hormone receptor-negative disease. The analysis provides strength of evidence supporting the addition of pertuzumab in this patient population.

Abstract GS1-04: Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer

Abstract Background: The APHINITY trial demonstrated that pertuzumab, when added to adjuvant trastuzumab and chemotherapy, modestly but statistically significantly improved invasive disease-free survival (IDFS) among patients with HER2-positive, operable breast cancer. From November 2011 until August 2013, 2400 patients were randomly assigned to receive pertuzumab and 2405 to receive placebo. The clinical cut off-date for the primary analysis was 19 Dec 2016 after a median follow-up of 45.4 months. In the intent-to-treat (ITT) population, the estimates of the 3-year rates of IDFS were 94.1% in the pertuzumab group and 93.2% in the placebo group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The benefit appeared more pronounced in patients with node-positive disease, with a HR of 0.77 (95% CI 0.62-0.96), and in those with hormone receptor-negative disease, where the HR was 0.76 (95% CI 0.56-1.04). Based on these results, pertuzumab in combination with trastuzumab was approved for high risk early HER2-positive breast cancer patients. The first interim analysis of OS took place at that same time. A total of 169 patients had died, with no significant treatment effect with regards to mortality found at that time. Diarrhea, grade 3 or higher, was more frequent within the pertuzumab group (9.8%) compared with the placebo group (3.7%). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Results: At 74.1 months of median follow-up (clinical cut-off date June 19, 2019), we now report results of the pre-planned, calendar-driven second interim OS analysis which requires a p-value of 0.0012 to reach statistical significance. Updated descriptive analyses of IDFS and cardiac safety were also performed. Fewer deaths were observed in the pertuzumab (P) arm [125 (5.2%) vs 147 (6.1%)], however statistical significance was not reached at this interim analysis. The hazard ratio for OS is 0.85 [95% CI 0.67-1.07 (p=0.17)]; 6-year OS percents are 94.8% vs 93.9% (0.9% difference).Updated IDFS results based on 508 events in the ITT population are: hazard ratio 0.76 [95% CI 0.64-0.91]; 6-year IDFS percents are 90.6% vs 87.8% (2.8% difference). Of note, the difference was due mainly to the reduction in distant (5.9% vs 7.7%) and loco-regional (1.2% vs 2.0%) BC relapses. The node-positive cohort continues to derive clear benefit from the addition of P: hazard ratio 0.72 (95% CI 0.59-0.87). The benefit in terms of 6-year IDFS percent is 4.5% [87.9% vs 83.4%].In the node-negative cohort, the IDFS hazard ratio is 1.02 (95% CI; 0.69-1.53) with 95% of patients being event-free in both arms at 6 years.With longer follow up, a treatment benefit of P is also seen in the hormone receptor (HR) positive cohort: IDFS hazard ratio for HR positive is 0.73 (95% CI 0.59 -0.92). IDFS hazard ratio for HR negative is 0.83 (95% CI 0.63 -1.10). No new cardiac safety concerns emerged. One additional primary cardiac event (heart failure) was reported in the P arm and 1 additional patient in each arm had a secondary cardiac event resulting to 18 and 8 for primary cardiac events and 65 and 68 for secondary cardiac events in the P and placebo arms, respectively. The benefit of P in HER2+ early BC is maintained, with the greatest benefit continuing to be observed in the node positive population. With longer follow-up, the benefit of P no longer appears to depend on HR status. Continued follow up of patients is very important to determine possible benefit for OS. A calendar-driven third interim OS analysis is planned in 2.5 years, and the event-driven final OS analysis is planned when 640 deaths have occurred. Citation Format: Martine Piccart, Marion Procter, Debora Fumagalli, Evandro de Azambuja, Emma Clark, Michael S. Ewer, Eleonora Restuccia, Guy Jerusalem, Susan Dent, Linda Reaby, Hervé Bonnefoi, Ian Krop, Tsang-Wu Liu, Tadeusz Pieńkowski, Masakazu Toi, Nicolas Wilcken, Michael Andersson, Young-Hyuck Im, Ling-Ming Tseng, Hans-Joachim Lueck, Marco Colleoni, Estefania Monturus, Mihaela Sicoe, Sébastien Guillaume, José Bines, Richard Gelber, Giuseppe Viale, Christoph Thomssen. Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-04.

PCN344 ADDITION OF PERTUZUMAB TO TRASTUZUMAB-BASED ADJUVANT THERAPY IN HIGH-RISK HER2-POSITIVE EARLY BREAST CANCER: A GRADE-BASED ANALYSIS FROM THE PHASE III APHINITY TRIAL

Although anti-HER2 (human epidermal growth factor receptor 2) therapies have dramatically improved the prognosis of patients with HER2-positive early breast cancer, some patients relapse despite receiving optimal treatment. In the large phase III APHINITY trial, the addition of 1 year of adjuvant pertuzumab to standard trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival. However, the magnitude of benefit was arguably marginal in the overall patient population. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach on data from APHINITY to build Summary of Findings tables to evaluate the efficacy and safety effects and quality of evidence of predefined clinical outcomes for the addition of pertuzumab to trastuzumab-based adjuvant therapy in patients with high-risk HER2-positive early breast cancer. The addition of pertuzumab was associated with a clinically significant better 3-year, event-free, absolute benefit in disease-free survival, invasive disease-free survival, and distant relapse-free interval in patients with node-positive or hormone receptor-negative disease. There was a more than 20% relative improvement in all relapse-related endpoints, with an absolute benefit of approximately 3 relapse-events fewer/100 patients treated. Although data from APHINITY are not yet mature, there were indications of an absolute benefit in mortality, compared with placebo (standard adjuvant chemotherapy plus trastuzumab), which should be confirmed when the overall survival analysis is conducted. The overall quality of evidence for this GRADE analysis is MODERATE. A good safety profile was confirmed. The application of the GRADE methodology to the APHINITY study provides a strength of evidence in support of the addition of pertuzumab in the adjuvant treatment of HER2-positive early breast cancer patients at higher risk of recurrence because of nodes involvement or hormone receptor-negativity. This data can be useful to guide therapeutic decisions in daily clinical practice.

De Novo Versus Recurrent HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from the SystHERs Registry.

BackgroundLimited data exist describing real‐world treatment of de novo and recurrent HER2‐positive metastatic breast cancer (MBC).Materials and MethodsThe Systemic Therapies for HER2‐Positive Metastatic Breast Cancer Study (SystHERs) was a fully enrolled (2012–2016), observational, prospective registry of patients with HER2‐positive MBC. Patients aged ≥18 years and ≤6 months from HER2‐positive MBC diagnosis were treated and assessed per their physician's standard practice. The primary endpoint was to characterize treatment patterns by de novo versus recurrent MBC status, compared descriptively. Secondary endpoints included patient characteristics, progression‐free and overall survival (PFS and OS, by Kaplan‐Meier method; hazard ratio [HR] and 95% confidence interval [CI] by Cox regression), and patient‐reported outcomes.ResultsAmong 977 eligible patients, 49.8% (n = 487) had de novo and 50.2% (n = 490) had recurrent disease. A higher proportion of de novo patients had hormone receptor–negative disease (34.9% vs. 24.9%), bone metastasis (57.1% vs. 45.9%), and/or liver metastasis (41.9% vs. 33.1%), and a lower proportion had central nervous system metastasis (4.3% vs. 13.5%). De novo patients received first‐line regimens containing chemotherapy (89.7%), trastuzumab (95.7%), and pertuzumab (77.8%) more commonly than recurrent patients (80.0%, 85.9%, and 68.6%, respectively). De novo patients had longer median PFS (17.7 vs. 11.9 months; HR, 0.69; 95% CI, 0.59–0.80; p < .0001) and OS (not estimable vs. 44.5 months; HR, 0.55; 95% CI, 0.44–0.69; p < .0001).ConclusionPatients with de novo versus recurrent HER2‐positive MBC exhibit different disease characteristics and survival durations, suggesting these groups have distinct outcomes. These differences may affect future clinical trial design. Clinical trial identification number. NCT01615068 (http://clinicaltrials.gov).Implications for PracticeSystHERs was an observational registry of patients with HER2‐positive metastatic breast cancer (MBC), which is a large, modern, real‐world data set for this population and, thereby, provides a unique opportunity to study patients with de novo and recurrent HER2‐positive MBC. In SystHERs, patients with de novo disease had different baseline demographics and disease characteristics, had superior clinical outcomes, and more commonly received first‐line chemotherapy and/or trastuzumab versus those with recurrent disease. Data from this and other studies suggest that de novo and recurrent MBC have distinct outcomes, which may have implications for disease management strategies and future clinical study design.

Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial.

Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician's choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer-specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor-negative patients (HR, 0.66; P = .02), but not among hormone receptor-positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor-negative disease. Competing risks in this older population dilute overall survival benefits.

Prognostic Impact of Pregnancy in Korean Patients with Breast Cancer.

Pregnancy concurrent with, shortly before, or after breast cancer poses unique challenges because hormonal changes in pregnancy potentially interact with breast cancer outcomes. We studied a cohort of 3,687 female patients of reproductive age (<50 years) with breast cancer, linking a large institutional database and the nationwide claims database to comprehensively capture exposure status and tumor characteristics. Exposures included breast cancer during pregnancy, postpartum breast cancer (<12 months after delivery), and pregnancy after breast cancer. Forty-five patients with postpartum breast cancer were significantly more likely to have advanced stage, hormone receptor-negative tumor and to be younger than 35 years at diagnosis than those without postpartum breast cancer. This trend was not observed with 18 patients with breast cancer during pregnancy. The unadjusted 5-year survival rates were 77% versus 96% for patients with postpartum breast cancer versus their counterparts, 89% versus 96% for patients with breast cancer during pregnancy versus their counterparts, and 98% versus 96% for patients with pregnancy after breast cancer versus their counterparts, respectively. In the multivariable analyses, postpartum breast cancer exhibited hazard ratios for death of 1.57 (95% confidence interval [CI], 0.82-2.99), whereas those for breast cancer during pregnancy and pregnancy after breast cancer were 1.09 (95% CI, 0.15-7.91) and 0.86 (95% CI, 0.26-2.83), respectively. Postpartum breast cancer, but not breast cancer during pregnancy, was associated with advanced stage, younger age at diagnosis (<35 years), hormone receptor-negative disease, and poorer survival. Pregnancy after breast cancer did not compromise overall survival. Although pregnancy around the time of diagnosis of breast cancer is expected to become increasingly common with maternal age at first childbirth on the rise, data on the prognostic impact of pregnancy have been inconsistent and rare from Asian populations. In this investigation of a Korean patient cohort with breast cancer, pregnancy-associated breast cancer was associated with advanced stage, younger age at diagnosis (<35 years), hormone receptor-negative disease, and poorer survival. This adverse impact of pregnancy on the prognosis was apparent with postpartum breast cancer but not observed with breast cancer during pregnancy. Pregnancy after breast cancer did not compromise overall survival.

Survival outcomes by hormone receptor expression in early-stage HER2-positive breast cancer.

e12050 Background: The clinical heterogeneity seen in HER 2 positive breast cancer (BC), mostly related to hormone receptor (HR) expression has been suggested to underlie the variability of response not only to endocrine treatments, but also to anti-HER-2 therapies. Herein, we describe our single institution experience with clinical outcomes by HR expression in early HER 2 positive BC. Methods: An IRB-approved single-institution retrospective analysis was performed for 400 consecutive patients with non-metastatic HER 2 + BC treated at the Ohio State University Comprehensive Cancer Center from 2005-2015. Medical records were reviewed for clinic-pathologic, treatment, and survival information. Disease Free Survival (DFS) was defined as time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary BC or death. Overall survival (OS) was defined as time from diagnosis to death or last known follow up. OS and DFS estimates were generated using Kaplan Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate univariate and multivariate hazard ratios for OS and DFS. Results: a total of 180/400(45%) patients were diagnosed with HR positive disease. The mean age was 54.1y and patients were predominately white (267, 84%), post-menopausal (190, 60%) and presented with invasive ductal cancer (293, 92%). HR negative disease was significantly associated with high tumor grade (72% vs. 52%, p &lt;0.0001) and lower BMI (27.6 vs 30.1, p 0.0218) compared to HR + tumors. The frequency of CNS metastases was not significantly different between both groups (8 (4%) in HR + vs. 8(6%) in HR –, p 0.9909). 173(96%) of HR + patients received anti-estrogen therapy with median duration of therapy of 40.9 months and 22(13%) received adjuvant ovarian suppression. There was no significant difference between the DFS and OS by hormone receptor expression (P= 0.7459 and 0.6518 respectively). However, higher number of HR negative patients undergoing neoadjuvant therapy achieved a complete pathologic response (pCR, 64% vs 44%, p 0.0092). pCR was prognostic for both DFS(p 0.0002) and OS (p 0.0008) in HR negative subgroup and not in HR + subgroup. Conclusions: The triple positive phenotype represents a distinct clinical subtype of HER 2 positive breast cancer associated with low tumor grade and lower frequency of pCR. Consistent with other studies, pCR was not prognostic of long term survival in triple positive disease. Future trials investigating the ER/ HER 2 cross talk are needed for this patient population.

Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs.

Patients with HER2-positive metastatic breast cancer (MBC) with central nervous system (CNS) metastasis have a poor prognosis. We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs). SystHERs (NCT01615068) was a prospective, U.S.-based, observational registry of patients with newly diagnosed HER2-positive MBC. Study endpoints included treatment patterns, clinical outcomes, and patient-reported outcomes (PRO). Among 977 eligible patients enrolled (2012-2016), CNS metastasis was observed in 87 (8.9%) at initial MBC diagnosis and 212 (21.7%) after diagnosis, and was not observed in 678 (69.4%) patients. White and younger patients, and those with recurrent MBC and hormone receptor-negative disease, had higher risk of CNS metastasis. Patients with CNS metastasis at diagnosis received first-line lapatinib more commonly (23.0% vs. 2.5%), and trastuzumab less commonly (70.1% vs. 92.8%), than patients without CNS metastasis at diagnosis. Risk of death was higher with CNS metastasis observed at or after diagnosis [median overall survival (OS) 30.2 and 38.3 months from MBC diagnosis, respectively] versus no CNS metastasis [median OS not estimable: HR 2.86; 95% confidence interval (CI), 2.05-4.00 and HR 1.94; 95% CI, 1.52-2.49]. Patients with versus without CNS metastasis at diagnosis had lower quality of life at enrollment. Despite advances in HER2-targeted treatments, patients with CNS metastasis continue to have a poor prognosis and impaired quality of life. Observation of CNS metastasis appears to influence HER2-targeted treatment choice.

Clinicopathological Features of Young Versus Older Patients With Breast Cancer at a Single Pakistani Institution and a Comparison With a National US Database.

PURPOSEThe age at which women present with breast cancer varies widely among nations, and breast cancer may behave differently in younger women. Differences in clinicopathological characteristics based on age have not been well characterized in Pakistani patients with breast cancer.METHODSWe conducted a retrospective review of patients with symptoms of breast cancer presenting to Aga Khan University Hospital (AKUH), a large tertiary care center in Pakistan, between 2001 and 2010; we compared young (≤ 40 years) versus older (> 40 years) patients in terms of their clinicopathological characteristics. We also compared this Pakistani cohort with the US population using data from the National Cancer Database (NCDB).RESULTSA total of 1,334 patients with breast cancer presented to our center over the 10-year review period. The median age at diagnosis was 50 years, compared with 60 years for patients in the NCDB. In the AKUH cohort, younger patients were significantly more likely than their older counterparts to present with metastatic disease (13.1% v 10.8%; P < .01). They also were more likely to present with higher-grade tumors (grade 3: 40.1% v 28.3%; P < .001), have triple hormone receptor–negative phenotype (25.4% v 14.1%, P < .001), and have positive axillary lymph node involvement (70.9% v 57.5%; P < .001) compared with older women. Younger and older patients in the AKUH cohort tended to present with higher-stage disease (P < .001) and were more likely to have triple hormone receptor–negative disease (P < .001), compared with all patients in the NCDB and with those of Indo-Pakistani origin.CONCLUSIONYoung Pakistani women, similar to their Western counterparts, present with more advanced disease and more aggressive tumor biology than their older counterparts.

Survivorship care visits in a high-risk population of breast cancer survivors.

Breast cancer survivors face numerous challenges after diagnosis and treatment. Several models have been developed to attempt to improve quality of care. Here, we describe characteristics and outcomes of patients who participated in survivorship visits (SV) at Johns Hopkins (JH). We retrospectively reviewed charts of breast cancer patients who participated in an optional SV 1-3months after completing locoregional therapy and initial systemic therapy. We report patient demographics, comorbidities, tumor characteristics, treatments, and responses to symptom questionnaires. We compared the characteristics of SV participants to stage I-III analytical cases in the 2010-2015 JH Cancer Registry (JHCR). We identified 87 women with stage I-III breast cancer who participated in SVs from 2010 to 2016. Compared to patients in the JHCR (n = 2942), SV participants were younger, more likely to be African American and more likely to have a higher TNM stage, hormone receptor-negative disease, and HER2-positive disease. They were more likely to have received chemotherapy and radiation therapy. They also have similar recurrence rates despite the SV cohort's shorter median follow-up time. Among SV participants, the prevalence of comorbidities including peripheral neuropathy, anemia, lymphedema, anxiety, deep vein thrombosis, and depression increased significantly from time of diagnosis to most recent follow-up. Compared to the JHCR cohort, SV participants had higher risk cancers and a high frequency of comorbidities potentially associated with breast cancer and therapy. These high-risk patients may benefit most from specific interventions targeting survivorship care, and their experiences may help improve care delivery models.

Immediate Breast Reconstruction in De Novo Metastatic Breast Cancer: An Analysis of 563 Cases Based on the SEER Database

BackgroundControversy exists regarding the appropriateness of immediate breast reconstruction (IBR) in patients with metastatic breast cancer (MBC). Patients and MethodsBy using the Surveillance, Epidemiology, and End Results (SEER) database, data of patients with de novo MBC undergoing mastectomy with or without IBR were assessed. The trend of IBR in de novo MBC was explored. Comparisons of the distribution of clinicopathologic characteristics were evaluated by chi-square and Fisher exact tests. The predictors of IBR in de novo MBC were evaluated by multivariate logistic regression. The survival outcomes were compared by Cox hazards models adjusting for known clinicopathologic variables in both the entire population and in the matched cohorts. ResultsBetween 1998 and 2015, 5.2% of patients with de novo MBC undergoing mastectomy received IBR. The rate of IBR increased significantly, from 6.3% in 1998 to 16.8% in 2015. Patients undergoing IBR were younger and had smaller tumor size, fewer positive lymph nodes, lower proportion of hormone receptor–negative disease and lung metastasis, and better economic status. They were also more likely to receive radiotherapy and chemotherapy. Although IBR was an independent favorable prognostic factor for breast cancer–specific survival and overall survival in the whole population, there were no statistically significant differences between IBR and mastectomy for breast cancer–specific survival (P = .892) and overall survival (P = .708) in the well-matched analysis. ConclusionIBR in selected de novo MBC could be an acceptable practice when balancing quality of life, underlying health care burden, and oncologic risks.

Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor–Positive Breast Cancer

Late recurrence 5 or more years after diagnosis accounts for at least one-half of all cases of recurrent hormone receptor-positive breast cancer. To determine whether the presence of circulating tumor cells (CTCs) in a peripheral blood sample obtained approximately 5 years after diagnosis was associated with late clinical recurrence of operable human epidermal growth factor receptor 2-negative breast cancer. This per-protocol secondary analysis of the Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer enrolled patients from 2007 to 2011 who were without clinical evidence of recurrence between 4.5 and 7.5 years after primary surgical treatment of human epidermal growth factor receptor 2-negative stage II-III breast cancer followed by adjuvant systemic therapy. Patients were enrolled in a subprotocol for secondary analysis from February 25, 2013, to July 29, 2016, after signing consent for the subprotocol. The analysis was performed in April 2018. A blood sample was obtained for identification and enumeration of CTCs. The association between a positive CTC assay result (at least 1 CTC per 7.5 mL of blood) and clinical recurrence. Among 547 women included in this analysis, the results of the CTC assay were positive for 18 of 353 with hormone receptor-positive disease (5.1% [95% CI, 3.0%-7.9%]); 23 of 353 patients (6.5% [95% CI, 4.2%-9.6%]) had a clinical recurrence. The recurrence rates per person-year of follow-up in the CTC-positive and CTC-negative groups were 21.4% (7 recurrences per 32.7 person-years) and 2.0% (16 recurrences per 796.3 person-years), respectively. In multivariate models including clinical covariates, a positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (hazard ratio point estimate, 13.1; 95% CI, 4.7-36.3). Seven of 23 patients (30.4% [95% CI, 13.2%-52.9%]) with recurrence had a positive CTC assay result at a median of 2.8 years (range, 0.1-2.8 years) before clinical recurrence. The CTC assay result was also positive for 8 of 193 patients (4.1% [95% CI, 1.8%-8.0%]) with hormone receptor-negative disease, although only 1 patient (0.5% [95% CI, 0%-2.9%]) experienced disease recurrence (this patient was CTC negative). A single positive CTC assay result 5 years after diagnosis of hormone receptor-positive breast cancer provided independent prognostic information for late clinical recurrence, which provides proof of concept that liquid-based biomarkers may be used to risk stratify for late recurrence and guide therapy. ClinicalTrials.gov identifier: NCT00433511.