Distant Relapse-free Interval Research Articles

Abstract PO3-11-07: Dose-response association between post-diagnosis exercise and clinical outcomes among survivors of breast cancer (BC)

Abstract Background: Higher levels of pre and post-diagnosis physical exercise lead to reduced risk of death among survivors of BC. However, the effect of exercise on recurrence remains unclear. Furthermore, previous studies assumed a linear relationship between exercise and clinical outcomes, used discrete classifications of exercise and did not report results according to BC subtype. The aim of this study was to investigate the dose–response relationship of exercise and clinical outcomes among survivors of BC and by BC subtypes. Methods: We included pts diagnosed with stage I-III BC from the CANTO cohort (NCT01993498). CANTO collects longitudinal data, including self-reported exercise exposure using the Global Physical Activity Questionnaire (GPAQ-16), at diagnosis (dx), 1 (T1), 2 (T2) and 4 (T3) years after dx. Exercise exposure in travel and leisure time was calculated according to GPAQ16 guidelines to derive a total MET-hours per week (MET-h/w) at dx and T1 and absolute change in exercise was computed between these timepoints. Outcome of interest was distant relapse-free interval (DRFI) according to STEEP criteria. Restricted cubic splines from unadjusted Cox models assessed the dose-response relationship between exercise and DRFI in the overall cohort and by BC subtype. Kaplan-Meier estimator, log-rank test and multivariate Cox models assessed the prognostic role of exercise. Results: In the overall cohort with available data on exercise at dx (N=10,359) mean (SD) age and BMI were 56.3 (11.2) years and 25.9 (5.4) kg/m2, 38.7% of pts were premenopausal, 52.9% received chemotherapy and 81.9% hormonal therapy, 57.1% were meeting WHO exercise recommendations at dx. At a median (IQR) follow-up of 5.5 (3.9-6.5) years, 541 DRFI events were observed. In the overall cohort, the spline showed a significant non-linear relationship between exercise at dx and DRFI: exposure greater than ≈5 MET-h/w was associated with an inverse linear risk reduction up to ≈25 MET-h/w. A similar relationship was observed in the HR+/HER2- and HR-/HER2- cohorts. On this basis, exercise was categorized as ‘no exercise’ (0 MET-h/w) and ‘exercise’ (≥ 5 MET-h/w). Pts reporting exercise ≥ 5 MET-h/w had longer DRFI compared to those reporting no exercise in the overall (log-rank p< 0.0001), HR+/HER2- (log-rank p< 0.0113) and HR-/HER2- (log-rank p< 0.0001) cohorts. In multivariate analyses, reporting exercise ≥ 5 MET-h/w was associated with a significant lower risk of DRFI events in the overall (HR 0.75, 95%CI 0.62-0.90) and HR-/HER2- cohorts (HR 0.54, 95%CI 0.37-0.80). Absolute change in exercise exposure from dx to T1 was available in 8,516 pts: 34.2% increased exercise (≥ 5 MET-h/w), 25.9% decreased exercise (≤ -5 MET-h/w) and 39.8% maintained exercise ( > –5 and < +5 MET-h/w). The spline showed a non-significant relationship between change in exercise and risk of DRFI events and change in exercise was not significantly associated with risk of DRFI events in multivariate analyses. Conclusions: In this large, prospective cohort of survivors of BC, higher exercise at diagnosis was associated with reduced risk of DRFI events. The relationship between exercise dose and clinical outcomes appears non-linear and to differ based on subtype. Change in exercise after breast cancer diagnosis does not appear to impact on clinical outcomes. Future studies should aim at validating these findings in independent cohorts. XX XX Citation Format: Davide Soldato, Ines Vaz Luis, Julie Havas, Antonio Di Meglio, Neil Iyengar, Barbara Pistilli, Paul Cottu, Florence Lerebours, Charles Coutant, Aurélie Bertaut, Olivier Trédan, Laurence Vanlemmens, Christelle Jouannaud, Ioana Hrab, Sibille Everhard, Anne-Laure Martin, Fabrice André, Lee Jones. Dose-response association between post-diagnosis exercise and clinical outcomes among survivors of breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-11-07.

Abstract PO4-15-07: ESR1 mutations emerging during neoadjuvant endocrine therapy in postmenopausal ER+/HER2- early breast cancer patients: prevalence and prognostic impact

Abstract Background Neoadjuvant endocrine therapy (NET) is currently used in several clinical trials to select patients for chemotherapy de-escalation. However, exposure to NET may induce/select endocrine-resistant tumor cell clones harboring ESR1 mutations (ESR1mut), which are well known to confer poor prognosis and ET resistance to aromatase inhibitors in the metastatic setting. In this study, we sought to determine the frequency and prognostic significance of ESR1mut after NET in postmenopausal patients with HR+/HER2- early breast cancer. Materials and methods We conducted a retrospective study in postmenopausal patients with ER+/HER2-early breast cancer diagnosed between 2000 and 2012 and treated with NET for at least three months at Institut Curie Hospitals (Paris and Saint Cloud, France). Exclusion criteria were: stage IV breast cancer, no surgery of the primary tumor, neoadjuvant radiation therapy, chemotherapy or targeted therapies. DNA from post-NET surgical samples was extracted using the phenol-chloroform DNA isolation method. ESR1mut were detected with multiplex drop-off ddPCR assay previously used in the PADA-1 trial (targeting clustered hotspot mutations in exon 8 and 5, using a BioRad QX100 system and analyzed with QuantaSoft v.1.7.4 software). Associations between ESR1mut detection and patient outcomes, distant relapse-free interval (DRFI) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results N=143 patients treated with NET were eligible for this study, of whom N=136 had interpretable ESR1mut detection results. Median age at NET initiation was 75.4 (IQR 66.6-81.3) years. The median duration of NET was 6.6 months (IQR 5.8 – 7.6). Most patients were treated with aromatase inhibitors (n=107, 75.9%), while 24.1% (n=34) received tamoxifen. The median time between diagnosis and surgery was 7.6 (IQR 6.4 – 8.7) months. ESR1mut were detected in post-NET surgical samples in N=7 patients (5.2%). Baseline clinicopathological characteristics were not associated with post-NET ESR1mut detection status. The median follow-up for DRFI and OS was 11.0 (IQR 7.7 – 13.8) and 18.7 (IQR 13.3 – 18.7) years, respectively. The median DRFI was 6.7 (95%CI [4.9-NR]) vs 14.0 [10.7-NR] years in ESR1mut and ESR1wt patients, respectively (HR=1.9 [0.6-6.2], p=0.29). Similarly, median OS was numerically shorter in patients with post-NET ESR1mut (6.8 [3.7-NR] vs 9.8 [8.5-NR]; HR=2.0 [0.9-4.7], p=0.09). Conclusions Post-NET tumors are enriched in ESR1mut subclones, which represent a potentially lethal threat in the context of aromatase inhibitor-based adjuvant endocrine therapy. Although the limited sample size of our study did not allow reaching statistical significance, our results suggest, for the first time, worse survival outcomes for patients with a ESR1mut detected in post-NET primary tumors. The role of next-generation oral SERDs as neoadjuvant or adjuvant endocrine therapy to prevent ESR1mut-related relapses remains to be determined. Citation Format: José Luis Sandoval, Helene Salaun, Shufang Renault, Marcela Carausu, Aurore Rampanou, Caroline Hego, Matthieu Carton, Luc Cabel, Jean-Yves Pierga, Romain Geiss, Francois-Clement Bidard, Florence Lerebours. ESR1 mutations emerging during neoadjuvant endocrine therapy in postmenopausal ER+/HER2- early breast cancer patients: prevalence and prognostic impact [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-07.

Comparison of SP142 and 22C3 PD-L1 assays in a population-based cohort of triple-negative breast cancer patients in the context of their clinically established scoring algorithms

BackgroundImmunohistochemical (IHC) PD-L1 expression is commonly employed as predictive biomarker for checkpoint inhibitors in triple-negative breast cancer (TNBC). However, IHC evaluation methods are non-uniform and further studies are needed to optimize clinical utility.MethodsWe compared the concordance, prognostic value and gene expression between PD-L1 IHC expression by SP142 immune cell (IC) score and 22C3 combined positive score (CPS; companion IHC diagnostic assays for atezolizumab and pembrolizumab, respectively) in a population-based cohort of 232 early-stage TNBC patients.ResultsThe expression rates of PD-L1 for SP142 IC ≥ 1%, 22C3 CPS ≥ 10, 22C3 CPS ≥ 1 and 22C3 IC ≥ 1% were 50.9%, 27.2%, 53.9% and 41.8%, respectively. The analytical concordance (kappa values) between SP142 IC+ and these three different 22C3 scorings were 73.7% (0.48, weak agreement), 81.5% (0.63) and 86.6% (0.73), respectively. The SP142 assay was better at identifying 22C3 positive tumors than the 22C3 assay was at detecting SP142 positive tumors. PD-L1 (CD274) gene expression (mRNA) showed a strong positive association with all two-categorical IHC scorings of the PD-L1 expression, irrespective of antibody and cut-off (Spearman Rho ranged from 0.59 to 0.62; all p-values < 0.001). PD-L1 IHC positivity and abundance of tumor infiltrating lymphocytes were of positive prognostic value in univariable regression analyses in patients treated with (neo)adjuvant chemotherapy, where it was strongest for 22C3 CPS ≥ 10 and distant relapse-free interval (HR = 0.18, p = 0.019). However, PD-L1 status was not independently prognostic when adjusting for abundance of tumor infiltrating lymphocytes in multivariable analyses.ConclusionOur findings support that the SP142 and 22C3 IHC assays, with their respective clinically applied scoring algorithms, are not analytically equivalent where they identify partially non-overlapping subpopulations of TNBC patients and cannot be substituted with one another regarding PD-L1 detection.Trial registration The Swedish Cancerome Analysis Network - Breast (SCAN-B) study, retrospectively registered 2nd Dec 2014 at ClinicalTrials.gov; ID NCT02306096.

The usefulness of CanAssist Breast over Ki67 in breast cancer recurrence risk assessment.

Assessment of Ki67 by immunohistochemistry (IHC) has limited utility in clinical practice owing to analytical validity issues. According to International Ki67 Working Group (IKWG) guidelines, treatment should be guided by a prognostic test in patients expressing intermediate Ki67 range, >5%-<30%. The objective of the study is to compare the prognostic performance of CanAssist Breast (CAB) with that of Ki67 across various Ki67 prognostic groups. The cohort had 1701 patients. Various risk groups were compared for the distant relapse-free interval (DRFi) derived from Kaplan-Meier survival analysis. As per IKWG, patients are categorized into three risk groups: low-risk (<5%), intermediate risk (>5%-<30%), and high-risk (>30%). CAB generates two risk groups, low and high risk based on a predefined cutoff. In the total cohort, 76% of the patients were low risk (LR) by CAB as against 46% by Ki67 with a similar DRFi of 94%. In the node-negative sub-cohort, 87% were LR by CAB with a DRFi of 97% against 49% by Ki67 with a DRFi of 96%. In subgroups of patients with T1 or N1 or G2 tumors, Ki67-based risk stratification was not significant while it was significant by CAB. In the intermediate Ki67 (>5%-<30%) category up to 89% (N0 sub-cohort) were LR by CAB and the percentage of LR patients was 25% (p < 0.0001) higher compared to NPI or mAOL. In the low Ki67 (≤5%) group, up to 19% were segregated as high-risk by CAB with 86% DRFi suggesting the requirement of chemotherapy in these low Ki67 patients. CAB provided superior prognostic information in various Ki67 subgroups, especially in the intermediate Ki67 group.

Abstract P3-05-28: Impact of increased adiposity on extended aromatase inhibitor treatment in postmenopausal patients with estrogen receptor positive (ER+) breast cancer: a retrospective analysis of the SOLE trial

Abstract Background: The risk of late distant recurrence (≥ 5 years) in post-menopausal patients with ER+ BC remains significant even after standard adjuvant endocrine therapy (ET). Obesity, which has reached high proportions in Western Countries, is one of the modifiable factors that can contribute to BC recurrences. While body mass index (BMI) is an easily available surrogate measure of adiposity, it might not reflect accurately patient adiposity, especially in post-menopausal patients. We therefore hypothesize that mammary adipocyte measurements might better capture the adiposity of the patient. In this study, we retrospectively evaluated the prognostic role of both BMI and adipocyte measurements in the SOLE trial. Patients &amp; Methods: The SOLE trial (NCT00553410) consisted of 4,884 postmenopausal women with hormone receptor positive, lymph node-positive BC treated with 5 years of letrozole after having completed 4-6 years of adjuvant ET. BMI was available for 3,606 patients with ER+/HER2- BC and categorized according to the WHO classification (underweight: &amp;lt; 18.5, normal weight 18.5 – 24.9, overweight 25 – 29.9, obesity ≥ 30 kg/m2). Considering the small sample size, patients with underweight (n=35) were grouped together with patients with normal weight for the subsequent analyses. We evaluated the association between clinico-pathological characteristics and BMI using Fisher exact test and Kruskal-Wallis test. Given the previously reported association of BMI with distant recurrences (PMID: 21115856), we considered distant-relapse free interval (DRFI) as the main study endpoint. Cox regression analyses were adjusted for histology, chemotherapy (yes/no), type of local therapy, in addition to previously reported clinico-pathological variables (PMID: 29158011). Then, we conducted a stratified case-cohort study consisting of 311 patients (97 with distant relapse-cases) with successful digital assessment of adipocytes on normal mammary adipose tissue sample collected at surgery, as previously described (PMID: 33120083). Stratification factors were treatment arm and type of prior ET. Weighted Cox regression models (PMID: 17554753, 18712477) were used to evaluate prognostic association with adipocyte size (area in µm²) categorized in quartile of the 75th percentile (Q4 vs Q1-3), as done previously (PMID: 33753731). Results: 1392 (39%) patients were normal weight, 1315 (36%) were overweight and 899 (25%) were obese. Older age at diagnosis, lymph node involvement (≥4), large tumor size and menopausal status were associated with overweight and obesity. After a median follow-up of 84 months, no associations were found between DRFI and BMI in the univariable and multivariable analysis (adjusted HR overweight vs normal=0.99, 95%CI: 0.76 – 1.29, p=0.977 and HR obese vs normal=1.11, 95%CI: 0.84 - 1.47, p=0.425). In the case-cohort study, patients with larger adipocytes had an increased hazard of distant recurrence in the univariable and multivariable analysis (see table 1). Conclusion: In this study, we did not detect any association between BMI and survival outcomes. We however found that larger mammary adipocytes were independently associated with an increased hazard of distant recurrence. These results suggest that mammary adipocytes, which can be easily evaluated on H&amp;E slides using digital pathology, should be considered as a novel marker to evaluate the risk of late recurrence in patients with breast cancer. Citation Format: Edoardo Isnaldi, François Richard, Giuseppe Marano, Patrizia Boracchi, Marion Maetens, Giuseppe Floris, Guy Jerusalem, Andrea Gombos, Alastair M. Thompson, Erika Hitre, Stefan Aebi, Marco Colleoni, Patrizia Dell’Orto, Roswitha Kammler, Patrick Neven, Giuseppe Viale, Meredith Regan, Elia Biganzoli, Christine Desmedt. Impact of increased adiposity on extended aromatase inhibitor treatment in postmenopausal patients with estrogen receptor positive (ER+) breast cancer: a retrospective analysis of the SOLE trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-28.

Abstract P1-02-04: Real world adjuvant endocrine treatment in premenopausal breast cancer patients compared with the proposed algorithm using the Regan Composite Risk Score

Abstract Background The Regan Composite Risk Score (RCRS) is a web-based prognostic and predictive calculator to guide the use of adjuvant exemestane plus ovarian function suppression (AI + OFS) versus tamoxifen plus ovarian function suppression (TAM + OFS) or tamoxifen alone (TAM) for premenopausal women with hormone receptor-positive HER2-negative early breast cancer (HR+/HER2- EBC). We compared our adjuvant endocrine therapy policy based on the tumor board with the treatment guided by the RCRS during 2 time periods, one before and one after the acquaintance of the Tamoxifen and Exemestane Trial (TEXT) and Suppression and Ovarian Function Trial (SOFT) data. This allowed us to see a possible evolution in therapy policy. Methods A retrospective cohort study of 563 premenopausal patients with HR+/HER2- and HER2+ EBC diagnosed at the University Hospital of Leuven during 2 periods, 2010-2012 (cohort 1) and 2015-2017 (cohort 2), was conducted. For each patient with HER2- EBC, the RCRS was calculated by entering the requested characteristics in the online available tool. The primary outcome was to investigate how frequent our therapy differed from the therapy guided by the RCRS based on the estimated 8-yr distant relapse free interval (DRFI) with an arbitrary cut-off set at 3 %. If the received therapy was ≥ 3 % less efficient in 8-year DRFI compared to the optimal therapy according to RCRS, the patient was considered undertreated. If the received therapy differed by less than 3 % in 8-year DRFI compared to the optimal therapy according to RCRS and yet the most intensive therapy (AI + OFS &amp;gt; TAM + OFS &amp;gt; TAM) was administered, the patient was considered overtreated. In the other cases, the patient was considered to have been treated concordant with the RCRS. Secondarily, nonadherence of the HER2- and HER2+ patients towards the endocrine treatments leading to therapy switch because of intolerance was recorded at 6, 12, 24 and 36 months. Analyses were performed using SAS software and the comparison of both cohorts was performed by the chi-squared test for categorical variables. Results According to the RCRS, 43.2 % (89/206) of the HER2-negative patients of cohort 1 were undertreated compared to 22.1 % (43/194) in cohort 2 (chi- squared test, p-value &amp;lt; 0.001). The number of overtreated patients also differed significantly between the two cohorts (chi-squared test, p-value = 0.003) with 2.9 % (6/206) in the first cohort and 10.3 % (20/194) in the second cohort. Finally, the number of patients treated concordant with the guidance derived from the RCRS was 53.9 % (111/206) in cohort 1 and 67.5 % (131/194) in cohort 2 (chi-squared test, p-value = 0.005). Treatment intolerance and switch was observed in 34.8 %, 16.7 % and 12.4 % of the patients receiving AI + OFS, TAM + OFS or TAM as initial therapy respectively; this was numerically higher for all treatments in cohort 2 vs cohort 1, although the observed difference was only significant for TAM. Conclusion In our center, a recent cohort of premenopausal women was more likely to be treated with the adjuvant endocrine treatment concordant with the guidance derived from the RCRS when using an arbitrary cut-off of 3 % to define a relevant improvement in outcome. Citation Format: Charlotte Berteloot, Patrick Neven, Maja Vangoitsenhoven, Annouschka Laenen, Hans Wildiers, Kevin Punie, Ann Smeets, Ines Nevelsteen, Sileny Han, Thaïs Baert, Hilde Janssen, Eva Oldenburger, Adinda Baten, Patrick Berteloot, Rani Vanhoudt, Anne Deblander, Chantal Remmeriev, Christine Desmedt. Real world adjuvant endocrine treatment in premenopausal breast cancer patients compared with the proposed algorithm using the Regan Composite Risk Score [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-04.

Effect of mevalonate pathway inhibitors on outcomes of patients (pts) with HER2-positive early breast cancer (BC) in the ALTTO trial.

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 &lt; 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 &lt;.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 &lt;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]

Trends in Adjuvant Chemotherapy Use in Endocrine-Sensitive, HER-2 Negative Breast Cancer, With 1 to 3 Positive Nodes: A Single-Centre Study

Background: There is a tendency to decrease the intensity of breast cancer treatments, e.g. omitting adjuvant chemotherapy in endocrine-sensitive and HER-2 negative patients. The purpose of this study was to analyse changes in the frequency of the indication of adjuvant chemotherapy and the differences in survival over time for this subtype of breast cancer, with 1–3 positive nodes.Methods: The study was based on descriptive, observational, retrospective, single-institution research between 2004–10 and 2011–18, on endocrine-sensitive, HER-2 negative breast cancer, stage pN1 (1–3 nodes). The analytical tests carried out for a comparison of the frequency of chemotherapy use the chi-square test with Fisher's exact test. Survival data in both periods are presented.Results: A total of 236 patients were included, 66 for the period 2004–10, and 170 for 2011–18. More patients were treated with hormone therapy alone in 2011–18: hormone therapy alone 10/66 (15.20%) for 2004–10, and 83/169 (49.10%) for 2011–18; chemotherapy-hormone therapy 56/66 (84.80%) for 2004–10, and 86/169 (50.90%) for 2011–18 (P = 0.0001). For 2004–10, the 5-year overall survival probability was 100%. For 2011–18 it was 98.20% (95% CI 95.65–100). For 2004-10, 5-year disease free survival (DFS) was 96.9% (95% CI 92.7–101). For 2011–18 it was 87.7% (95% CI 81.8–93.5) (P=0,040). For 2004–10 the 5 year distant relapse free interval was 96.9% (95% CI 92.5–101.2). For 2011–18 it was 93% (95% CI 88.1–97.9) (P=0.312).Conclusion: A decrease in the indication of adjuvant chemotherapy according to the clinical risk is confirmed in endocrine-sensitive, HER-2 negative breast cancer, with 1-3 positive nodes, over the period 2011–18 compared to 2004–10. Based on the results, 5-year DFS is slightly worse in the 2011–18 period.

Chemotherapy or endocrine therapy, first-line treatment for patients with hormone receptor-positive HER2-negative metastatic breast cancer in China: a real-world study.

BackgroundAlthough endocrine therapy (ET) is the preferred option for hormone receptor-positive HER2-negative metastatic breast cancer (HR+/HER2– MBC), chemotherapy (CT) is still commonly used. The objective of this real-world study was to present the actual choice of first-line treatment for patients with HR+/HER2– MBC and evaluate the consistency with guidelines in China.MethodsPatients with HR+/HER2– MBC between 1996 and September 2018 were identified from of the database of Chinese Society of Clinical Oncology Breast Cancer (CSCO BC). The statistical description was conducted to present the first-line treatment. Factors influencing the prescription of ET or CT were obtained using univariate and multivariate analysis. The consistency of the actual treatment with the guideline of Chinese Society of Clinical Oncology Breast Cancer (CSCO BC guideline) was evaluated.ResultsOf 1,877 patients, 662 (35.3%) received ET, and 1,215 (64.7%) received CT. ET proportion was only 25.4% in 1996–2005 and gradually increased to 44.6% in 2016–2018. Aromatase inhibitors (69% of ET) and taxane-based regimens (66% of CT) were the most commonly used ET and CT, respectively. Univariate and multivariate analysis showed that patients with age ≥60, distant relapse-free interval (DRFI) ≥24 months, ER+/PR+, bone metastasis only, or progression on (neo)adjuvant ET were preferably chosen for ET as first-line treatment. Factors associated with preferring CT were de novo stage IV, liver or lung metastasis. 17.2% of patients (322 cases) who had neither visceral metastasis nor progression on (neo)adjuvant ET wrongly received CT instead of ET, which is inconsistent with CSCO BC guideline. More than half of patients receiving CT discontinued their initial treatment due to adverse events and other non-disease progression reasons.ConclusionsAlthough high proportion of HR+/HER2– MBC patients received CT as first-line treatment in China, it is gratifying to see that the proportion of patients receiving ET has gradually increased. Our study revealed that 17.2% of patients were over-treated according to CSCO BC guideline, which may provide data to promote guideline adherence. The clinical application for ET should be appropriately expanded in first-line treatment, especially for patients without visceral disease and proof of endocrine resistance.

Abstract P3-08-31: Clinical and pathological features of invasive micropapillary carcinoma of the breast and correlation with prognosis

Abstract Background and objective: Invasive micropapillary carcinoma (IMPC) of the breast is a special variant of breast carcinoma with a unique morphology. Data about long-term outcome are conflicting and reports on stromal tumor infiltrating lymphocytes (sTILs) and their correlation with prognosis are scarce. In this retrospective cohort study we aimed to describe clinical and pathological features of IMPC, including sTILs assessment and immunohistochemistry studies, and their correlation with long-term outcome. Materials and methods: Patients with stage I-III IMPC (pure and mixed forms) who underwent upfront surgery at our institution between 2000 and 2016 were included. All patients signed informed consent. Standard clinico-pathological features and follow-up data to calculate distant relapse-free interval and breast cancer-specific survival were obtained from clinical records. Pathologic review of representative H&amp;E-slides of the resection specimens included evaluation of sTILs and assessment of the micropapillary component. Surrogate molecular subtypes were based on receptor-status and histological grade. Using tissue microarrays we assessed by immunohistochemistry the pattern of staining of P53, and scored semi-qualitatively the expression of Bcl2, PAX8 and WT1. The association between predictors and outcome is analyzed using the Fine and Gray model, accounting for other-cause death as competing event. All tests are two-sided, assuming a 5% significance level. The sample size did not allow multivariate analysis. Results: We included 111 patients (median age 61,5 years; range 33-88). Luminal surrogate subtypes were most prevalent with 51 luminal A-like, 41 luminal B-like, 12 luminal HER2+, 5 HER2+ and 2 triple negative IMPC. 89% of patients had a T1 or T2 tumor and 50% of IMPC were poorly differentiated. Lymph node involvement was present in 59% and lymphovascular invasion in 44% of cases. Adjuvant chemotherapy, radiotherapy and endocrine therapy was administered in 47%, 87% and 90% of patients, respectively. Of all cases 59% were pure IMPC. Standard clinico-pathological features were comparable between pure and non-pure IMPC. sTILs were classified as low (&amp;lt;30%), intermediate (30-50%) and high (&amp;gt;50%) in 78%, 14% and 8% of specimens respectively. Comparison between surrogate subtypes showed higher sTILs (p=0.025) and a higher likelihood of aberrant P53 expression (p&amp;lt;0.001) in HER2+ compared to luminal A-like subtype. Immunohistochemistry studies performed on 105 samples with enough material showed aberrant P53 expression in 10% and WT1 nuclear expression in 7% of cases. Pax8-staining was negative in all IMPC in this cohort. Bcl-2 expression was strongly related to all luminal subtypes (p&amp;lt;0.03). After a median follow-up of 100 months, we observed 8 distant relapses (7,2%) and 3 breast cancer-related deaths (2,7%). All events occurred in non-pure IMPC. Surrogate subtypes for patients with distant relapses where luminal A-like in 4 patients while the other subtypes where each observed in 1 patient. Five out of eight patients with distant relapse had received prior adjuvant chemotherapy. Six had lymph node involvement. Higher median sTILs was correlated with worse distant relapse-free interval (HR=1.55; p=0.0172) and breast cancer-specific survival (HR=2.10; p&amp;lt;0.001). Conclusions: Standard clinico-pathological features were similar in pure and non-pure IMPC. Despite high proportion of grade 3 differentiation and lymph node involvement, we observed a low rate of distant metastasis and within the pure IMPC (59% of patients), no distant relapses occurred. These findings could be explained by the high proportion of luminal-A like tumors in our cohort and need confirmation. Higher sTILs was associated with worse outcome in this IMPC cohort, confirming previously published observations. Citation Format: Kevin Punie, Frederik Deman, Annouschka Laenen, Timothy Faes, Hans Wildiers, Ann Smeets, Ines Nevelsteen, Chantal Van Ongeval, Adinda Baten, Melissa Christiaens, Eva Oldenburger, Hilde Janssen, Caroline Weltens, Tatjana Geukens, Nynke Willers, Jan Ardui, Hava Izci, Laurence Slembrouck, Patrick Neven, Christine Desmedt, Giuseppe Floris. Clinical and pathological features of invasive micropapillary carcinoma of the breast and correlation with prognosis [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 P3-08-31.

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.

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.

Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study.

SummaryWhole genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore clinical value of WGS, we sequenced 254 triple negative breast cancers (TNBC) with associated treatment and outcome data collected between 2010-2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have Homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (Hazard Ratio, HR=0.42, 95% confidence interval, CI=0.2-0.87), and distant relapse-free interval (HR=0.31, CI=0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient - another targetable defect, not typically sought; and was enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.

Prognostic value of a new clinical-genomic model to predict 10-year risk of recurrence in patients with operable breast cancer.

530 Background: Searching for a specific biomarker to predict long-term risk of recurrence for all breast cancer subtypes is challenging. DGM-CM6 (Distant Genetic Model-Clinical variable Model 6) is a new clinical-genomic prognostic model developed from the 18-gene panel which was reported previously. This study aims to validate the long-term prognostic value of this new model in all subtypes of operable breast cancer patients. Methods: We included 752 operable breast cancer patients with stage I-III in all subtypes treated in a Cancer Center from 2005 to 2014 as the internal validation (IV) cohort. The median follow-up was 94.1 months. Meanwhile, Affymetrix U133P2 (n = 1139) data obtained from GEO (GSE9195/16391/17907/19615/20711/21653/42568, EMTAB365) were collected as the external validation (EV) dataset. The prognostic effect of DGM-CM6 was then evaluated by uni- and multivariate analyses. The low- and high-risk patients ( &lt; 33 or ≥ 33 as cut-off value) classified by DGM-CM6 were evaluated by the 10-year distant relapse-free interval (DRFI), relapse-free interval (RFI), relapse-free survival (RFS) and distant relapse-free survival (DRFS), respectively. We further compared the predictive performance between DGM-CM6/DGM and PAM50-ROR score in our IV dataset. Results: In the IV dataset, DGM-CM6 was proved to be an independent prognostic factor by multivariate analysis with hazard ratios of 3.1 (1.6-6.0) for RFS (P = 0.0009) and 3.2 (1.6-6.3) for DRFS (P = 0.0009). Significant differences were observed between low- and high-risk groups with 10-year RFI (94.0% vs. 83.5%, P &lt; 0.0001), RFS (90.0% vs. 80.5%, P = 0.0003), DRFI (94.1% vs. 85.0%, P &lt; 0.0001), and DRFS (90.1% vs. 81.9%, P = 0.0004), respectively. The prognostic value of RFS was convinced in the EV dataset (HR = 1.34, P = 0.00052) by the DGM only. According to C-index estimate analysis, DGM appeared to have better performance comparing with PAM50 ROR score in prediction of long-term DR, DRFS, RFI, and RFS in N0 patients (C index for distant recurrence: 0.582 by DGM, 0.528 by ROR). Conclusions: DGM-CM6 could be a new long-term prognostic model to be applied in all subtypes of operable breast cancer patients. Further validation in a large scale of clinical trials is needed.

Abstract GS4-07: Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial

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 (&amp;gt;2 cm vs. &amp;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 (&amp;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&amp;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.

A metastasis biomarker (MetaSite Breast\u2122 Score) is associated with distant recurrence in hormone receptor-positive, HER2-negative early-stage breast cancer

Metastasis is the primary cause of death in early-stage breast cancer. We evaluated the association between a metastasis biomarker, which we call “Tumor Microenviroment of Metastasis” (TMEM), and risk of recurrence. TMEM are microanatomic structures where invasive tumor cells are in direct contact with endothelial cells and macrophages, and which serve as intravasation sites for tumor cells into the circulation. We evaluated primary tumors from 600 patients with Stage I–III breast cancer treated with adjuvant chemotherapy in trial E2197 (NCT00003519), plus endocrine therapy for hormone receptor (HR)+ disease. TMEM were identified and enumerated using an analytically validated, fully automated digital pathology/image analysis method (MetaSite Breast™), hereafter referred to as MetaSite Score (MS). The objectives were to determine the association between MS and distant relapse free interval (DRFI) and relapse free interval (RFI). MS was not associated with tumor size or nodal status, and correlated poorly with Oncotype DX Recurrence Score (r = 0.29) in 297 patients with HR+/HER2- disease. Proportional hazards models revealed a significant positive association between continuous MS and DRFI (p = 0.001) and RFI (p = 0.00006) in HR+/HER2- disease in years 0–5, and by MS tertiles for DRFI (p = 0.04) and RFI (p = 0.01), but not after year 5 or in triple negative or HER2+ disease. Multivariate models in HR+/HER- disease including continuous MS, clinical covariates, and categorical Recurrence Score (<18, 18–30, > 30) showed MS is an independent predictor for 5-year RFI (p = 0.05). MetaSite Score provides prognostic information for early recurrence complementary to clinicopathologic features and Recurrence Score.

Abstract S4-04: Tumor microenvironment of metastasis (TMEM) score is associated with early distant recurrence in hormone receptor (HR) positive, HER2-negative early stage breast cancer (ESBC)

Abstract Background: Metastasis is the primary cause of death in ESBC. We have shown in mouse models that a subpopulation of tumor cells expressing invasive Mena isoforms stream, form microanatomic structures (“TMEM”) with endothelial cells and macrophages, intravasate into the circulation at TMEM sites, and metastasize (Harney et al. Cancer Discovery, 2015). Further, TMEM sites (“MetaSites”) are identifiable in human ESBC, and “MetaSite score” [MS] is positively associated with distant recurrence in HR+/HER2- ESBC independent of clinicopathologic features, including IHC4 (Rohan et al. JNCI 2014). Here we determined the association between MS and recurrence in an independent ESBC cohort (E2197; NCT00003519). Methods: We evaluated primary tumors from 600 patients (median followup 14.8 years) with ESBC (weighted % = 50% T1, 54% N0, 46% N1) treated with surgery and 4 cycles of adjuvant chemotherapy (AC or AT) and endocrine therapy. Grade, ER, PR, and HER2, and Oncotype DX Recurrence Score (RS) were evaluated in central labs (Badve et al. JCO 2008), and MS was determined in a CLIA-certified lab using an analytically validated, fully automated digital pathology/image analysis method that identifies Mena expressing tumor cells in direct contact with CD68+ macrophages and CD31+ endothelial cells (ie, “TMEMs”, or “MetaSites”). The objectives were to determine the association between MS and distant relapse free interval (DRFI) and relapse free interval (RFI). Kaplan-Meier survival curves were used to estimate time-to-event distributions. Cox proportional hazards models were used to assess hazard ratio associated with MS while controlling for covariates, and allowing time-varying association with MS. Both Kaplan-Meier and Cox regression methods addressed stratified sampling by incorporating proper weights. All analyses were performed in R 3.2.3. Results: MS ranged from 0-199; the weighted mean MS was lower in HR+/HER2- than TN (16.1 vs. 23.8, p=0.001) and HER2+ disease (26.2, p=0.003). MS was not associated with T or N status, and correlated poorly with RS (r=0.29). Proportional hazards models revealed a significant positive association between continuous MS and DRFI (p=0.001) and RFI (p=0.00006) in HR+/HER2- disease in years 0-5 (and by MS tertiles for DRFI [p=0.04] and RFI [p=0.01]), but not after year 5 or in TN or HER2+ disease. Proportional hazards models including clinical covariates (N0 vs. N1; T1 vs. T2; high vs. int. vs. low grade) also revealed significant positive associations for continuous MS with RFI (p=0.04), and borderline association with DRFI (p=0.08). Similar findings for MS (RFI p=0.05;DRFI p=0.10) were noted in a joint model including categorical RS (&amp;lt;18,18-30, &amp;gt;30). Conclusions: MS, a novel metastasis biomarker reflecting interaction between streaming and metastasizing tumor cells and microenvironment, provides prognostic information complementary to classical clinicopathologic features and RS in HR+/HER2- ESBC. Further evaluation is warranted in order to identify patients at highest risk of recurrence within 5 years most likely to benefit from adjuvant chemotherapy or novel therapies. (Supported by BCRF and NCI CA21115, CA180794, CA23318, CA66636, CA180820). Citation Format: Sparano JA, Gray R, Oktay MH, Entenberg D, Rohan T, Xue X, Donovan M, Peterson M, Shuber A, Hamilton D, D'Alfonso T, Goldstein LJ, Gerlter F, Davidson N, Condeelis J, Jones J. Tumor microenvironment of metastasis (TMEM) score is associated with early distant recurrence in hormone receptor (HR) positive, HER2-negative early stage breast cancer (ESBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S4-04.

Correlation between severe infection and breast cancer metastases in the EORTC 10994/BIG 1-00 trial: Investigating innate immunity as a tumour suppressor in breast cancer

BackgroundBreast cancer cells which express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced metastatic potential. Infections can induce interferon signalling and may activate an anti-tumour immune response. We investigated whether ‘severe infection’ can be a clinical surrogate of this phenomenon and/or the presence of high levels of the IRF7 signature at diagnosis before neo-adjuvant chemotherapy (NACT) is associated with a reduced distant relapse risk, specifically in bones. MethodsClinical data of the European Organisation for Research and Treatment of Cancer 10994/BIG 1-00 phase III trial which randomised 1856 patients treated with NACT between 2001 and 2006, were used. Severe infection was febrile neutropenia or any other grade III–IV infective adverse event during NACT. The IRF7 signature was calculated from gene expression data available for 160 patients on a pre-NACT biopsy. Cox models for distant relapse-free interval (DRFI) investigated the effect of the severe infection and IRF7. Fine and Gray models studied the occurrence of bone metastases as first distant relapse. ResultsMedian follow-up was 4.8 years. No association between severe infection and DFRI was observed in the entire population (n = 1615 eligible patients) hazard ratio [(HR] = 0.99, 90% CI, confidence interval [CI] = 0.81–1.20). For IRF7 (N = 160), a trend towards an association with DRFI was observed (HR = 0.89 for a 50 unit increase, 90% CI = 0.78–1.02, p = 0.081). Higher levels of the IRF7 signature were significantly associated with a decreased bone metastases risk: (HR = 0.76 for a 50 unit increase, 95% CI, 0.62–0.94, p = 0.012). ConclusionsIn this study it was shown that severe infection during NACT was not associated with decreased DRFI while high expression of the IRF7 gene signature was significantly associated with reduced bone relapse. This result may be useful for future adjuvant bisphosphonate/denosumab use.

256P - Correlation between severe infection and breast cancer metastases in the EORTC 10994/BIG 1-00 trial: Investigating innate immunity as a tumor suppressor in breast cancer

Breast cancer cells that express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced bone metastatic capacity (Bidwell et al, Nat Med 2012). However, viral or bacterial infections can restore this IFN signature and activate an anti-tumor immune response. Objectives of the study were to evaluate if the occurrence of “severe infection” could be a clinical surrogate of this phenomenon and/or if the presence of high levels of an IRF7 signature during neoadjuvant chemotherapy (NACT) was associated with a reduced distant relapse risk, specifically of bony metastases. Clinical data of the EORTC 10994/BIG 1-00 phase III trial were used which evaluated NACT in 1856 early-stage breast cancers. “Severe infection” was defined as febrile neutropenia or other infective adverse events (grade 3-4) during NACT. The IRF7 signature was calculated from gene expression data available for 160 patients. Cox models for distant relapse free interval (DRFI) investigated the effect of the severe infection (landmark approach) and IRF7. Fine & Gray models studied the secondary endpoint of bone metastases as first distant relapse. No major associations were observed between the occurrence of a severe infection during NACT and baseline patient and tumor characteristics. Median follow-up was 4.8 years. No significant association between severe infection and DFRI was observed (HR = 0.99, 90% CI = 0.81-1.20, N = 1615). For IRF7 (N = 160), a trend towards an association with DRFI was observed (HR = 0.89 for a 50-unit increase, 90% CI = 0.78-1.02, 1-sided p = 0.081). However higher levels of the IRF7 signature were significantly associated with a decreased bone metastases risk: HR = 0.76 for a 50-unit increase, (95% CI, 0.62-0.94, p = 0.012). The occurrence of a severe infection during NACT was not associated with decreased DRFI. High expression of the IRF7 signature was significantly associated with reduced risk of bone relapse supporting preclinical evidence that tumor intrinsic innate immunity is crucial for bone metastases prevention. This may be useful for guiding future adjuvant bisphosphonate/denosumab use.

Abstract P2-08-01: Prospective trial of endocrine therapy alone in patients with estrogen receptor positive, HER2-negative, node-negative breast cancer: Results of the TAILORx low risk registry

Abstract Background: The Trial Assigning Individualized Options for Treatment (TAILORx) is a prospective trial evaluating the role of endocrine therapy or chemoendocrine therapy in patients 18-75 years of age with estrogen receptor (ER)-positive, HER2-negative breast cancer, a primary tumor between 0.6-5.0 cm, and negative axillary nodes, a population for whom chemotherapy is typically recommended or least considered based on National Comprehensive Cancer Center Network (NCCN) guidelines. Methods: The trial was designed to demonstrate non-inferiority of endocrine therapy compared with chemoendocrine therapy in the randomized group with an Oncotype DX Recurrence Score (RS) of 11-25. Patients with a low RS &amp;lt; 11 were assigned to endocrine therapy alone and with a high RS &amp;gt; 25 assigned to chemoendocrine therapy, and both groups were followed in a prospective registry. The definition of an intermediate RS differed in this trial (RS 11-25) from the original reports (RS 18-30) in order to reduce the risk of chemotherapy undertreatment in patients with a mid-range or low RS (Sparano &amp; Paik. J Clin Oncol 2008; 26:721-728). Results: The trial enrolled 10,273 patients between April 2006 and October 2010, of whom 6907 patients (67.2%) had a mid-range RS of 11-25, 1737 (16.9%) had a high RS &amp;gt; 25, and 1639 (15.9%) had a low RS of &amp;lt; 11. At the fourth planned interim analysis, the ECOG-ACRIN data monitoring committee recommended that the study continue as planned for the randomized group with a RS 11-25, and that the results be released to the investigators for the low risk group with a RS &amp;lt;11. The characteristics of the low risk registry population are as follows: age 50 or less (27%), 51-60 (35%), &amp;gt; 60 (39%); tumor size &amp;lt; 1 cm (8%), 1-2 cm (61%), &amp;gt; 2 cm (31%); histologic grade low (34%), intermediate (59%), high (7%); breast conservation (68%) or mastectomy (32%). Initial endocrine therapy included tamoxifen in 35%, aromatase inhibitors in 59%, ovarian function suppression in 3%, and unspecified therapy in 3%; 5 patients received adjuvant chemotherapy (1 of whom relapsed). Five-year rates (and 95% confidence intervals [CI]) for low RS group were 99.2% (98.5, 99.6%) for distant relapse free interval, 98.5% (97.7, 99.1%) for relapse-free interval, 93.7% (92.2, 94.9%) for invasive disease free survival, and 98.2% (97.3, 98.7%) for overall survival. Information regarding ER, PR, and HER2 RNA expression will be presented. Conclusions: Despite meeting guidelines for recommending or at least considering adjuvant chemotherapy based on classical clinicopathologic features, the risk of recurrence was very low at 5 years in patients with ER-positive, HER2-negative, axillary node-negative breast cancer and a low RS of &amp;lt; 11 treated with endocrine therapy alone without chemotherapy. Citation Format: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer Jr CE, Dees EC, Perez EA, Olson Jr JA, Zujweski J, Keane MM, Gomez Moreno HL, Reddi RP, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Atkins JN, Berenberg JL, Sledge Jr GW. Prospective trial of endocrine therapy alone in patients with estrogen receptor positive, HER2-negative, node-negative breast cancer: Results of the TAILORx low risk registry. [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 P2-08-01.