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Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor–positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared with invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in preclinical models and clinical samples showed that, compared with IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1–estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1–ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the autoinduction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1–ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype. Significance: A unique FOXA1–ER axis in invasive lobular breast cancer promotes disease progression and tamoxifen resistance, highlighting a potential therapeutic avenue for clinical investigations dedicated to this disease. See related commentary by Blawski and Toska, p. 3668

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). 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 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 Conclusions: In the ALTTO trial, HER2-positive early breast cancer patients who experienced shorter TFI (i.e. 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.

Background: Survival for metastatic breast cancer (MBC) patients (pts) has modestly improved over time. Until the early 2000's, incidence rates for invasive lobular carcinoma (ILC) had steadily risen, in contrast to the stable rates observed for invasive ductal carcinoma (IDC). Historically, ILC was deemed to have a more favorable prognosis than IDC. Nevertheless, data on recent time trends in incidence and survival of lobular vs. ductal histology among newly diagnosed MBC pts are limited. Pts and Methods: Using the Surveillance, Epidemiology, and End Results (SEER) 9 registries, we included 10,767 pts diagnosed with de novo lobular or ductal MBC from 1990-2011, and followed through 2012. Time trends in annual age-adjusted incidence rates were analyzed, stratified by histology. Multivariable Cox regression models were fit to investigate the association of year of diagnosis and overall survival (OS) by stratum, adjusting for features presented in Table 1. We examined interactions between year of diagnosis and histology. In sensitivity analyses, we modeled year of diagnosis as categorical, and restricted the cohort to hormone-receptor positive pts. Table 1IDC N= 9,376 (87%)ILC N= 1,391 (13%)Cohort characteristics%Age, yearsƚ Results: 9,376 (87%) pts had IDC and 1,391 (13%) had ILC. Overall, we found a 1.4 fold increase in incidence rates for de novo MBC over the study period, (with a 1.3- and 2.6-fold increase for IDC and ILC, respectively). OS improved over the study period for the overall cohort (Hazard ratio (HR) of death=0.99; 95% confidence interval (CI)=0.98-0.99; 1% decrease/year; 5% decrease/5 years; p=.0059 for the interaction year of diagnosis-histology on OS). ILC pts had better outcomes than IDC pts (median OS=28 vs. 21 months; adjusted HR of death= 0.93; 95%CI=0.87-0.99). For IDC pts, we found a statistically significant improvement in OS over time (HR of death=0.98; 95%CI=0.98-0.99; 2% decrease/year; 6% decrease/5 years). However, we observed no significant change in survival outcomes for ILC pts (HR of death=1.01; 95%CI=0.99-1.02) (Table 1). Results from sensitivity analyses were similar. Conclusions: From 1990-2011, incidence rates for de novo MBC increased. In this cohort, ILC pts had a better prognosis than IDC pts. Nevertheless, although we found an expected overall improvement in OS for MBC pts, this effect was restricted to IDC pts, with no significant improvement among ILC pts. Dedicated studies are warranted to understand whether our results can be confirmed in other datasets and to investigate the reasons driving this discrepancy, such as the impact of patterns of care, new drug approvals, and tumor molecular subtype. Citation Format: Di Meglio A, Freedman RA, Lin NU, Barry WT, Metzger-Filho O, Keating NL, Winer EP, Vaz-Luis I. Time trends in incidence rates and survival for women with de novo metastatic lobular vs. ductal carcinoma, a population-based study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-08.

Background: Recent consensus guideline on margins for breast conserving surgery recommends the use of no ink on tumor as the standard for an adequate margin. Current recommendation extends to invasive lobular carcinoma (ILC), however the data in this subset is limited by small numbers. In the present analysis we sought to evaluate the influence of margin status on outcomes in ILC and mixed tumors. Methods: We performed retrospective cohort study and reviewed 809 eligible patients diagnosed with ILC (337 with pure ILC; 472 with mixed ILC) with Stage I –III treated at Dana Farber/Brigham and Women’s Cancer Center (DFBWCC) between May 1997 and Dec 2007. Clinico-pathologic data was extracted following the Clinical Research Information Systems (CRIS) Database procedures and manually reviewed to confirm inclusion and details of margin status. Margin status was defined using the last ASCO/ASTRO/SSA consensus guidelines criteria. Analysis results were considered to be statistically significant when the two-tailed p-value was Results: Breast conservation was performed in 399 patients (49%). Margin status at the initial attempt for breast conservation was defined as follows: 180 (45%) negative, 64 (16%) positive, 71 (18%) ≤ 1mm margin, and 84 (21%) close margins (> 1 and < 3 mm). Following initial lumpectomy, 102 (25%) patients underwent additional surgery (96 re-excisions and 6 mastectomies) and residual invasive disease was found in 40 patients. Whole-breast radiation therapy was performed in 376 patients (96%). In multivariate models adjusted for classic clinico-pathologic factors, tumor size (HR= 1.8 95% CI 1.0 to 3.3, p=0.05), multifocality (HR= 2.0 95% CI 1.1 to 3.6, p= 0.02) and ILC subtype (HR= 2.0 95% CI 1.0 to 3.7, p=0.04) were correlated with positive margins, while year of diagnosis, age and pre-surgical MRI findings were not statistically significant. With 72 months median follow-up, 12 ipsilateral breast cancers (3.1%), 5 other locoregional (1.2%) and 15 distant (3.8%) recurrences were observed after definitive breast conserving therapy. The incidence of locoregional recurrence (LRR) was 4.3% and similar for ILC and mixed ILC (p=0.76). In univariate analysis positive surgical margin was associated with LRR (HR=5.1, p= 0.03) and disease-free survival (DFS) (HR=8.9, p≤ .001), but due to limited number of cases and events this could not be adjusted for other clinico-pathologic prognostic factors in a mulitvariate model. Close surgical margins, margins within 1mm and multifocality were not associated with increased LRR or worse DFS. Re-excision did not impact on DFS for patients with close margin (p= 0.57) and within 1 mm margin (p= 0.85). By contrast, significant improvement of DFS following re-excision was observed in patients with positive margin (p= 0.01). Conclusions: Following lumpectomy, local recurrence rates for ILC patients with close surgical margin and ≤ 1mm margin are low and equivalent to those in patients with negative margins. This study supports the validity of using no ink on tumor as the standard for an adequate margin for patients diagnosed with pure or mixed ILC treated with multimodality therapy. Citation Format: Yasuaki Sagara, William T Barry, Ines Vaz-Luis, Fatih Aydogan, Jane E Brock, Eric P Winer, Mehra Golshan, Otto Metzger-Filho. Effect of margin width on local recurrence in invasive lobular carcinoma treated with multimodality therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-16-01.

Background: Invasive lobular carcinoma (ILC) represents the second most common breast cancer (BC) subtype and is usually characterized as hormone-receptor positive, low-to-intermediate histologic grade, and human epidermal growth factor receptor (HER) 2-negative. In the early-stage setting, ILCs are associated with lower rates of pathological response to preoperative chemotherapy compared with invasive ductal carcinoma (IDC). This exploratory analysis investigated the magnitude of benefit of single-agent eribulin for the treatment of advanced ILC using data from three clinical trials in women with advanced BC. We also describe the patterns of response and survival outcomes compared with IDC. Methods: Individual patient (pt) data from the experimental arms of two phase III studies (305 and 301) and a single-arm, phase II study were pooled for the present analysis. Study 305 (EMBRACE) randomized pts treated with ≥2 lines of chemotherapy for advanced BC to receive eribulin or treatment of physician's choice. In study 301, pts treated with ≤2 lines of chemotherapy for advanced BC were randomized to receive eribulin or capecitabine. In the phase II study, pts who had received ≥3 lines of chemotherapy were treated with eribulin. Overall survival (OS) and progression-free survival (PFS) analyses were adjusted by study, estrogen receptor (ER) and HER2 status, and number of lines of therapy for advanced disease. Results: The three studies included 1353 eribulin-treated pts. Of the 1152 pts included in the present analysis, 118 were classified as ILC and 1034 as IDC. Median age of ILC and IDC pts was 58 years and 55 years, respectively. ER and/or progesterone receptor (PgR) positivity was more common in ILC (ER = 69%, PgR = 55%) than IDC (ER = 60%, PgR = 48%), while HER2 positivity was less frequent in ILC than IDC (9% vs 16%). A total of 52.5% of ILC and 61.4% of IDC pts received ≥3 lines of chemotherapy (for any stage BC) prior to eribulin. Pts with ILC and IDC had similar median OS (13.4 vs 13.5 months; hazard ratio [HR] = 1.10; 95% confidence intervals [CIs] 0.87, 1.38) and PFS (4.1 vs 3.6 months; HR = 0.91; 95% CIs 0.72, 1.14). Investigator-evaluated tumor response rates are shown in the table. Table: Best overall tumor responses (by investigator review)Response, %Invasive lobular carcinoma, n = 110Invasive ductal carcinoma, n = 985Objective response rate: CR + PR (95% CIs)15.5 (9.3, 23.6)14.8 (12.7, 17.2)Complete response (CR)00.4Partial response (PR)15.514.4Stable disease (SD)53.652.7Progressive disease (PD)26.428.9Clinical benefit rate: CR + PR + SD ≥6 months (95% CIs)29.1 (20.8, 38.5)28.6 (25.8, 31.6)Not evaluable4.53.6 Conclusions: In this exploratory, pooled analysis, magnitude of benefit from single-agent eribulin did not differ between the ILC and IDC cohorts. While there was a limited numbers of pts with ILC, response rates, PFS, and OS were similar for the two pt groups. The results with eribulin for advanced ILC contrast with data for other agents in early-stage settings, where ILC is generally less responsive to chemotherapy than IDC. These findings may, however, underline changes in the disease biology after exposure to previous therapies or changes inherent to disease progression. Citation Format: Javier Cortés, José Pérez, Yi He, Otto Metzger-Filho. Efficacy of eribulin in patients with invasive lobular carcinoma of the breast: data from a pooled analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-06.

BACKGROUND: PIK3CA mutations (mt) represent one of the most common gene aberrations occurring in breast cancer (BC). Despite their high prevalence, the mechanisms underlying prognosis in PIK3CA mutated BC remain largely unknown. METHODS: Seven datasets of primary BC patients were compiled comprising 1030 patients with available PIK3CA genotype and whole genome gene expression data. Overall survival data were available for 669 patients, 502 were ER-positive patients. We evaluated whether genes of interest (ESR1, HER2, MET, MYC, TP53, FGFR1) and previously published gene signatures (GS) of proliferation (AURKA, CIN70, GGI, Gene70), stroma (PLAU, DCN), and kinase signalling pathways (IGF1, SRC, PTEN, RAS, MAPK), were associated with PIK3CA genotype using ROC curve and t-tests as well as clinicopathologic parameters using chi-square and Mann-Whitney test. Survival and interactions with genotype was evaluated using Cox regression analyses, stratified by dataset. RESULTS: A total of 1030 cases were pooled for analysis. PIK3CA mt were found in 30.4% (314/1030) of cases in our cohort. PIK3CA mutations were significantly associated with positive ER status (p CONCLUSIONS: This is the largest analysis to combine gene expression and PIK3CA genotype. PIK3CA genotype was not significantly associated with survival in this cohort. There was no interaction between known prognostic GS reflecting proliferation and genomic instability and genotype implying that additional hits are necessary for PIK3CA mutated tumors to develop an aggressive, proliferative phenotype. In contrast, upregulation of MET was associated with a poor prognosis in only PIK3CA-mutated tumours suggesting a possible biomarker and rationale combination with PI3K inhibitors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-02.

Background: 1-year of adjuvant trastuzumab (T) is the standard of care in managing patients (pts) with early HER2−positive breast cancer (BC). As T is not known to alter fertility, pts with childbearing potential could become pregnant during or following treatment with T. Cases of oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus have been reported in women receiving T during pregnancy (preg). Here we report the outcome of preg in all pts enrolled in the HERA trial. Methods: Pregnancies in the HERA trial are reported on a distinct “pregnancy form” for up to 10 years following T completion. The form includes information on approximate date of conception, preg course & outcome, fetal measurements at birth, and congenital anomalies. Any missing data were retrieved from the study site, if available. For this analysis, pts were grouped into 3 groups: 1) preg during and up to 3 months after T, 2) preg > 3 months of last T dose, and 3) preg with no prior exposure to T. Results: By March 2010, 70 preg were reported in 58 out of 5102 pts randomized. Five, 30 and 7 completed preg were reported in groups 1, 2 & 3 respectively. As per protocol, all pts on T were required to use adequate contraceptive measures, yet 16 pts became pregnant during the course of T and up to 3 months thereafter. The percentage of completed preg was lowest in group 1, with 4 spontaneous and 7 induced abortions. In group 2, preg occurred at a mean of 29 months following completion of T, with 6 spontaneous and 4 induced abortions. In group 3, abortion was induced in 3 pts and no spontaneous abortions reported. Across all 3 groups, all but 1 spontaneous abortion occurred during the 1st trimester. Two congenital anomalies were reported; a Down's syndrome in a 43 year old pt >5 years after completing T for which abortion was induced, and one with partial fusion of the 2nd and 3rd toe born to a pt in group 3. Conclusions: Unintentional exposure to T during preg may be associated with spontaneous abortion, yet the numbers remain low to draw firm conclusions (spontaneous abortion rate in general population is up to 20%). No oligohydramnios or anomalies were observed in group 1. While an increased risk of oligohydramnios has been reported when T is administered after the 1st trimester, T administered to Cynomolgus monkeys during organogenesis did not cause fetal harm (Pentsuk et al; 2009). Nevertheless, women of childbearing potential should be advised to use effective contraception during and up to 6 months after treatment with T. On the other hand, prior exposure to T did not appear to affect the preg course or outcome. We are planning to collect information from the other T adjuvant trials to confirm our findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-01.