Background

Despite recent improvements in MBC management, sensitivity to treatment and disease outcomes remain heterogeneous. We developed a deep learning and user-friendly model to predict individual outcomes and select the most adequate treatments according to the course of the disease.

Methods

We used data from the Unicancer large national multicenter real-world Epidemiological Strategy and Medical Economics (ESME) database (NCT03275311) that included 27,855 women diagnosed between 2008 and 2020 with MBC. The primary outcome was overall survival (OS). To measure this outcome and follow the disease, treatment line (TL) initiation dates were used as essential time points, allowing us to build a dynamic deep learning survival model. The main structure of this model is the extension of a Long-Short Term Memory cell, a recurrent neural network designed to handle sequential data with irregular timing. The time-dependent concordance index (C-index) and the Integrated Brier Score (IBS) allowed the selection of the best models.

Results

The cohort included 4,857 patients with triple-negative (TN), 5,027 with HER2+ and 17,971 with hormonal receptor positive (HR+)/HER2- MBC. Median follow-up was 65.1 months (95%CI 63.8, 66.4). The areas under the receiving operator characteristics (AUCs) for 6-month and 1-year OS prediction, the sensitivity at 90% specificity for 6-month OS prediction, as well as the global C-index and IBS of the model per subtype, averaged across 5-fold cross-validation cohorts, are reported in the table for the three first TLs. Table: 193MO

Average metrics for our model per subtype for the three first TLs

Conclusions

Our models showed promising results in predicting OS for MBC patients of each subtype at different time points. The ability to anticipate early failure and death despite adjusted standard treatment is important for identifying patients requiring a more innovative investigation. The strong prognostic capacity of our deep learning survival model could inform treatment selection for MBC patients.

Clinical trial identification

NCT03275311.

Legal entity responsible for the study

Unicancer.

Funding

The used database is the ESME MBC database, which receives financial support from an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai, and Daiichi Sankyo). Data collection, analysis, and publication are managed entirely by Unicancer independently of the industrial consortium. The first author received fundings by the doctoral school Interfaces of the Université Paris-Saclay.

Disclosure

W. Jacot: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Novartis, Roche, Pfizer, Eli Lilly, MSD, BMS, Chugai, Seagen, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo; Financial Interests, Invited Speaker: Roche, Novartis, Daiichi Sankyo, Daiichi Sankyo. J. Frenel: Financial Interests, Personal, Advisory Board: Pfizer, Novocure, Pierre Fabre, Eisai, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: GSK, Amgen; Financial Interests, Institutional, Advisory Board: Exactscience, Lilly, Daiichi Sankyo, AstraZeneca, Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Novartis, MSD; Financial Interests, Invited Speaker: AstraZeneca, Seagen, MSD, Daiichi; Non-Financial Interests, Principal Investigator: Novartis, Lilly, AstraZeneca, Pfizer, Daiichi, MSD. E.G.C. Brain: Financial Interests, Personal, Invited Speaker, Webinars, optimized endocrine therapy for older breast cancer patients: Eli Lilly; Financial Interests, Personal, Advisory Board, Palbociclib and older breast cancer patients: Pfizer; Financial Interests, Personal, Invited Speaker, Symposium HER2+ MAO conference 03/21: Seagen; Financial Interests, Personal, Invited Speaker, ELEVATE 10/2021 and ABC 11/2021 meeetings: Pfizer; Financial Interests, Personal, Other, IDMC DESTINY 05: DAIICHI; Financial Interests, Personal, Advisory Board, GCSF and FN in older patients: Sandoz; Financial Interests, Personal, Advisory Board, Underserved Patients Populations with breast cancer, advisory board: Pfizer; Financial Interests, Personal, Invited Speaker, Management of older patients with cancer, series of seminars in Canada for HCP: Pfizer; Financial Interests, Institutional, Invited Speaker, APPALACHES study EORTC 1745: Pfizer; Financial Interests, Institutional, Invited Speaker, TOUCH study (IBCSG 55/GERICO study): Pfizer; Financial Interests, Institutional, Invited Speaker, DEESTINY 09: DAIICHI; Financial Interests, Institutional, Invited Speaker, DESTINY 06: DAIICHI; Financial Interests, Institutional, Invited Speaker, SERENA 06: AstraZeneca; Financial Interests, Institutional, Invited Speaker, AMEERA 6: Sanofi. V.C. Dieras: Financial Interests, Personal, Advisory Board, National advisory board: Pierre Fabre Oncologie; Financial Interests, Personal, Advisory Board, Steering Committee, consultant, Symposium, travel expenses: Roche Genentech; Financial Interests, Personal, Advisory Board, + Symposia and travel expenses: Novartis; Financial Interests, Personal, Advisory Board, Advisory boards, symposia, travel expenses: Pfizer; Financial Interests, Personal, Advisory Board, Symposia, travel expenses: Lilly, AstraZeneca, MSD; Financial Interests, Personal, Advisory Board, Symposia,travel expenses: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, symposia,travel expenses: Seagen, Gilead; Financial Interests, Personal, Advisory Board, Steering Committee: AbbVie; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Other, IDMC: Sanofi; Financial Interests, Personal and Institutional, Other, IDMC: Sanofi; Financial Interests, Institutional, Invited Speaker: Roche Genentech, AstraZeneca; Financial Interests, Institutional, Invited Speaker, Steering Committee: Lilly; Financial Interests, Institutional, Invited Speaker, + IDMC: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, PI: Seagen. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca. A. Mailliez: Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD, Novartis, Roche; Financial Interests, Personal, Invited Speaker: Pierre Fabre, Oseus, Seagen, Pfizer, Daiichi Sankyo; Financial Interests, Personal, Expert Testimony: GSK. F. Dalenc: Non-Financial Interests, Principal Investigator: Roche, AstraZeneca, Gilead, Novartis. P.H. Cottu: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer, Lilly; Financial Interests, Personal, Expert Testimony: Roche; Financial Interests, Institutional, Invited Speaker: Daiichi, Lilly, Gilead; Financial Interests, Institutional, Funding: Novartis. A. Antoine: Financial Interests, Personal, Research Grant: Roche. M. Chevrot: Financial Interests, Institutional, Funding: Roche, Pfizer, AstraZeneca, MSD, Eisai, Daiichi Sankyo. D. Perol: Financial Interests, Personal, Training: Roche, AstraZeneca, Bayer, Boehringher-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Ipsen, Novartis, Merck sharp and Dohme, Pfizer; Financial Interests, Personal, Advisory Role: Takeda. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Pierre Fabre, Orion, Sanofi, Rappta, Cellectis, Isis/servier; Financial Interests, Institutional, Invited Speaker: Exact Sciences, Pfizer, Seagen, Lilly, AstraZeneca, MSD, Roche Genentech, BMS, Puma, AstraZeneca, Orion, Sanofi, Pfizer; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Invited Speaker, ESMO symposium: Gilead; Financial Interests, Institutional, Advisory Board, scientific board: Elsan; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho; Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM; Non-Financial Interests, Principal Investigator, H2020 funding: European Commission. All other authors have declared no conflicts of interest.

Background

HER3-DXd and trastuzumab deruxtecan (T-DXd) are antibody-drug-conjugates (ADCs) directed against HER3 and HER2, respectively. Both drugs have shown efficacy in patients (pt) with HR+/HER2- BC. Baseline HER3 protein or mRNA levels do not predict efficacy from HER3-DXd. Here, we aimed to evaluate the association of early response to HER3-DXd with HER2 levels.

Methods

TOT-HER3 (NCT04610528), a window-of-opportunity trial, evaluated a single dose of HER3-DXd in 77 pts with untreated HR+/HER2- early BC in Part A (6.4 mg/kg) and 17 in Part B (5.6 mg/kg). Primary objective was CelTIL score [a surrogate of response that combines tumor cellularity and tumor-infiltrating lymphocytes] variation between baseline and day 21 tumor samples. Here, CelTIL response was defined as an absolute increase of 20 at day 21. HER2 expression was determined by immunohistochemistry (IHC). RNA and DNA were purified from baseline FFPE tumor samples and analyzed using the nCounter and the VHIO-300 NGS platforms, respectively. Logistic regression models and area under the ROC Curve (AUC) estimated the performance of HER2 IHC, mRNA or copy-number (CN) levels with CelTIL response.

Results

In TOT-HER3 Part A, HER2 IHC status was 32% HER2 0, 38% HER2 1+ and 30% HER2 2+. Distribution of high CelTIL responders was 40% in HER2 0, 45% in HER2 1+ and 13% in HER2 2+ (p=0.034). High ERBB2 mRNA and RNA-based HER2 amplicon signatures were significantly associated with low CelTIL response (ERBB2: Odds Ratio [OR]=0.34, p<0.001, AUC=0.71; and HER2 amplicon: OR=0.20, p=0.005, AUC=0.74). The association of ERBB2 mRNA with CelTIL response was independent of HER2 IHC expression (p=0.002), PAM50 subtype (p=0.001) or proliferation (p=0.003). High HER2 CN signal was found associated with low CelTIL response (p=0.005). The association of HER2 IHC and ERBB2 mRNA with CelTIL response will be independently validated in TOT-HER3 Part B.

Conclusions

Low HER2 IHC, mRNA or CN levels in early-stage HR+/HER2- BC are associated with high response to HER3-DXd. HER3-DXd might be highly active in HR+ BC with very low HER2 levels, thereby offering a new therapeutic paradigm to this subset of patients.

Legal entity responsible for the study

SOLTI.

Funding

Has not received any funding.

Disclosure

F. Brasó-Maristany: Financial Interests, Personal, Licensing Fees: Reveal Genomics. M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo/AstraZeneca, Gilead, Pierre Fabre, Roche, Seagen, iTEOS, Relay Therapeutics; Financial Interests, Personal, Invited Speaker: Gilead, MSD, Novartis, Pfizer, Roche, Seattle Genetics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. P. Tolosa Ortega: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Lilly, Seagen, AstraZeneca, Daiichi Sankyo and MSD; Financial Interests, Personal, Advisory Board: Novartis, Adamed, Seagen and Daiichi Sankyo; Financial Interests, Personal, Full or part-time Employment, Medical Advisor and Madical Monitor: SOLTI. M. Margeli Vila: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Novartis, MSD, Gilead, Lilly, Pierre Fabre; Financial Interests, Personal, Other, Travel expences: Gylead; Financial Interests, Institutional, Invited Speaker, I have received research funding for my institution from Pfizer: Pfizer. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: PharmaMar, Roche, Lilly, Pfizer, Novartis, Gilead, AstraZeneca, Daiichi, Seagen, GSK, bayer; Financial Interests, Personal, Invited Speaker: PharmaMar, Roche, Lilly, Pfizer, Novartis, Eisai, Gilead, AstraZeneca, Daiichi, Seagen, Esteve, Roche. J.M. Cejalvo: Financial Interests, Institutional, Invited Speaker: Pfizer, Novartis. S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: Astra-Zeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. S. Esker: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P. Fan: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. A. Santhanagopal: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. R. Sanchez Bayona: Financial Interests, Personal, Invited Speaker: Novartis, Lilly Oncology, GSK Oncology, AstraZeneca, Seagen, Clovis Oncology; Financial Interests, Personal, Other, Travel and accommodation: Pfizer; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: SOLTI; Financial Interests, Personal, Other, Medical Monitor in HARMONIA Trial: Novartis. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.

Background

In the phase III DESTINY-Breast04 trial (NCT03734029), T-DXd significantly improved progression-free survival (PFS) and overall survival (OS) vs TPC in pts with HER2-low mBC regardless of hormone receptor expression. Breast cancers with low ER expression (IHC 1-10%) represent a subset of pts that may mimic the clinical behavior of triple-negative breast cancer. Here, we report analyses of pts with ER IHC 0% and 1-10%.

Methods

Pts with HER2-low (HER2 IHC 1+ or IHC 2+/ISH−) mBC who had been previously treated with 1 or 2 lines of chemotherapy were randomly assigned (2:1) to either T-DXd or TPC (physician’s choice of chemotherapy). Exploratory analyses of efficacy and safety, using the primary analysis data cutoff (Jan 11, 2022), were conducted for pts with ER IHC 0-10%.

Results

110 pts were included (ER IHC 0% n = 58; ER IHC 1-10% n = 52). Efficacy results are shown in the table. Pts with ER IHC 1-10% treated with T-DXd had longer PFS (median PFS, 8.4 months with T-DXd vs 2.6 months with TPC; hazard ratio, 0.24 [95% CI, 0.12-0.48]) and OS (hazard ratio, 0.35 [95% CI, 0.16-0.75]) vs TPC. In ER IHC 0-10% pts, the most common any-grade treatment-emergent adverse events (TEAEs; ≥20% of pts in either arm) were nausea, vomiting, fatigue, decreased appetite, alopecia, constipation, anemia, diarrhea, transaminases increased, white blood cell count decreased, and neutrophil count decreased. 40 (53.3%) and 24 (75.0%) pts in the T-DXd and TPC groups, respectively, experienced grade ≥3 TEAEs.

Table: 192MO

Efficacy in ER IHC 0% and ER 1-10% subgroups

Conclusions

Efficacy, including survival, of T-DXd over TPC in pts with HER2-low ER 1-10% mBC was consistent with the outcomes observed in pts with HER2-low ER 0% mBC. T-DXd safety in the ER IHC 0-10% subgroup was manageable and consistent with the primary analysis.

Clinical trial identification

NCT03734029.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Katie Henderson, PhD, and Rachel Hood, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc., and AstraZeneca.

Funding

Daiichi Sankyo, Inc., and AstraZeneca.

Disclosure

D.A.A. Cameron: Financial Interests, Personal, Advisory Role, Consultancy: Seagen, Daiichi Sankyo, AstraZeneca, Synthon, Novartis, GSK. W. Jacot: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Novartis, Roche, Pfizer, Eli Lilly, MSD, BMS, Chugai, Seagen, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo; Financial Interests, Invited Speaker: Roche, Novartis, Daiichi Sankyo, Daiichi Sankyo. T. Yamashita: Financial Interests, Personal, Invited Speaker, Honoraria: Chugai, Taiho, Nippon Kayaku, Kyowa Kirin, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, Novartis, Eli Lilly; Financial Interests, Institutional, Research Grant: Chugai, Taiho, Nippon Kayaku, Kyowa Karin. P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation; Other, Spouse - Employee: Roche. F. Zagouri: Financial Interests, Personal, Invited Speaker, Honoraria: AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, Roche; Financial Interests, Personal, Advisory Role, Consultancy: AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, Roche. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. N. Harbeck: Financial Interests, Personal, Invited Speaker, Honoraria: Seagen, Roche, Pfizer, Pierre-Fabre, Novartis, MSD, Lilly, Gilead, Daiichi Sankyo, AstraZeneca, Amgen; Financial Interests, Personal, Advisory Role: Gliead, Sandoz, Seagen; Non-Financial Interests, Personal, Leadership Role: West Germany Study Group. R. Yerushalmi: Financial Interests, Personal, Invited Speaker: Roche, Teva, Medison, MSD, Astra-Zeneca; Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis, Astra-Zeneca, Gilead. Y. Lu: Financial Interests, Personal, Invited Speaker, Honoraria: AstraZeneca, Daiichi Sankyo, MSD, Novartis, Roche, Eli Lilly, Pfizer, Europharma, Eisai; Non-Financial Interests, Personal, Leadership Role, Co-Chair: MONALEESA7 steering committee; Non-Financial Interests, Personal, Advisory Role, Chair: RIGHT Choice steering committee; Financial Interests, Personal, Research Grant: AstraZeneca, MSD, Novartis, Roche, Pfizer; Financial Interests, Personal, Invited Speaker, Travel Expenses: Novartis, Roche; Financial Interests, Personal, Royalties: Taiwan. A. Gombos: Financial Interests, Personal, Invited Speaker, Honoraria: Lilly, Novartis; Financial Interests, Personal, Advisory Role, Consultancy: AstraZeneca, Seagen; Financial Interests, Personal, Invited Speaker, Travel & Expenses: AstraZeneca. C.M.A. Orbegoso, F. Cheng, L. Yung, R. Rajagopalan: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. J. Tsurutani: Financial Interests, Personal, Invited Speaker, Honoraria: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Honoraria: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Travel and Expenses: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Daiichi Sankyo. S. Modi: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Genentech, AstraZeneca, Seagen, Macrogenics; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, Genentech, AstraZeneca, Seagen. All other authors have declared no conflicts of interest.

Background

The randomized phase II Neo-peaks study examined usefulness of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1+P) following docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) vs the standard TCbHP regimen. Pathological complete response (pCR) rate was numerically higher with T-DM1+P following TCbHP (Masuda N et al Breast Cancer Res Treat 2020;180:135–46).

Methods

Patients received TCbHP (6 cycles, group A), TCbHP followed by T-DM1+P (4 cycles each, group B) or T-DM1+P (4 cycles, group C). In group C, non-responders after 4 cycles were switched to an anthracycline (A)-based regimen. We evaluated 5-yr disease-free survival (DFS), distant DFS (DDFS) and overall survival (OS).

Results

From Aug 2014 to Feb 2016, 204 patients (51, 52, 101 in groups A–C, respectively) were enrolled; 129 (63.2%) had cN0, 118 (57.8%) had ER-positive disease, median age was 53 (25–70) yrs, and median diameter of the primary tumor was 26 (11–70) mm. During follow-up, 1 patient withdrew consent. The table shows 5-yr DFS, DDFS and OS rates. Of 181 patients who received A-free neoadjuvant therapy, 116 achieved pCR. Of these, 111 did not receive A after surgery and achieved 5-yr DDFS of 97.3% (91.7%–99.1%) with 3 events.

Table: 125MO

Conclusions

Patients with pCR after neoadjuvant therapy had favorable long-term prognosis, and omission of A may be a reasonable option. Treatment needs to be adjusted in case of residual disease.

Legal entity responsible for the study

Japan Breast Cancer Research Group.

Funding

The Neo-peaks study was funded by Chugai Pharmaceutical, and the present follow-up study was funded by Japan Breast Cancer Research Group.

Disclosure

K. Inoue: Financial Interests, Institutional, Research Grant: AstraZeneca, Chugai, Daiichi Sankyo, MSD, Ono, Gilead, Takeda, Eisai , Novartis, Astellas. N. Masuda: Financial Interests, Personal and Institutional, Speaker’s Bureau: AstraZeneca, Chugai, Eli Lilly, Pfizer; Financial Interests, Institutional, Research Grant: AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kyowa Kirin, MSD, Novartis, Pfizer, Ono; Non-Financial Interests, Personal, Member of the Board of Directors: Japanese Breast Cancer Society, Japan Breast Cancer Research Group Association. T. Takano: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Chugai, Eli Lilly. K. Kawaguchi: Financial Interests, Personal, Speaker’s Bureau: Chugai , Daiichi Sankyo, Takeda, Eisai; Financial Interests, Institutional, Research Grant: Eli Lilly, KBCRN. H. Yasojima: Financial Interests, Institutional, Research Grant: Chugai. H. Bando: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Eisai, Kyowa Kirin, Pfizer, Daiichi Sankyo, Eli Lilly, MSD. R. Nakamura: Financial Interests, Personal, Speaker’s Bureau: Eli Lilly, AstraZeneca, Chugai, Novartis. T. Yamanaka: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kyowa Kirin, Novartis, Pfizer. T. Argua: Financial Interests, Personal, Speaker’s Bureau: Pfizer, Chugai, AstraZeneca. E. Tokunaga: Financial Interests, Personal, Speaker’s Bureau: Eli Lilly, AstraZeneca, Daiichi Sankyo. K. Aogi: Financial Interests, Personal, Invited Speaker: Chugai, Eisai, Taiho, AstraZeneca , Daiichi Sankyo, Pfizer, Eli Lilly; Financial Interests, Personal, Advisory Board: Taiho. S. Ohno: Financial Interests, Personal, Speaker’s Bureau: Chugai, AstraZeneca, Eli Lilly, Pfizer, Eisai; Financial Interests, Institutional, Research Grant: Eisai. S. Morita: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb , Chugai, Eisai, Eli Lilly, MSD, Pfizer , Taiho. M. Toi: Financial Interests, Personal, Invited Speaker: Chugai, Takeda, Pfizer, Kyowa Kirin, Taiho, Eisai, Daiichi Sankyo, AstraZeneca, Eli Lilly, Exact Science, Novartis, Shimadzu, Yakult, Nippon Kayaku; Financial Interests, Institutional, Research Grant: Chugai, Takeda, Kyowa Kirin, Taiho, JBCRG association, Eisai, Daiichi Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI technologies, Luxonus, Shionogi, GL Science; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Personal, Advisory Board: Kyowa Kirin, Daiichi Sankyo, AstraZeneca, Eli Lilly, Konica Minolta, Bristol Myers Squibb, Athenex Oncology, Bertis, Terumo, Luxonus, Kansai Medical Net; Non-Financial Interests, Personal, Member of the Board of Directors: JBCRG association; Non-Financial Interests, Institutional, Member of the Board of Directors: KBCRN, OOTR. All other authors have declared no conflicts of interest.

Background

The optimal neoadjuvant therapy for HER2-positive breast cancer patients is subject to ongoing debate and the use of biomarkers can help to personalise treatment decision. The 27-gene HER2DX test predicts pathological complete response (pCR) following neoadjuvant trastuzumab-based chemotherapy. Here, we evaluated the value of HER2DX to predict increases in pCR rate when 1) a second anti-HER2 agent is added to trastuzumab and chemotherapy, and 2) multi-agent chemotherapy is used instead of a single agent taxane in the context of dual HER2 blockade.

Methods

We conducted a combined analysis of four neoadjuvant cohorts with HER2DX and clinical data (i.e., DAPHNe, GOM-HGUGM-2018-05, CALGB-40601 and ISPY-2). All patients were treated with neoadjuvant trastuzumab (n=568) in combination with multi-agent chemotherapy (n=282), a single taxane (n=286), pertuzumab (n=264), lapatinib (n=103) or without a second anti-HER2 drug (n=201). Interaction tests were performed to evaluate the predictive capacity of HER2DX to identify patients who benefit most from each treatment approach.

Results

HER2DX pCR as continuous score was significantly associated with pCR in all patients (odds-ratio [OR]=1.62, 95% CI 1.43-1.85; AUC=0.75), in patients treated with trastuzumab and chemotherapy (OR=1.48, 1.18-1.86) and in patients treated with dual HER2 blockade and chemotherapy (OR=1.69, 1.50-1.91). A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR=4.10, 1.85-9.07; interaction test p=0.03). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR=2.52, 1.18-5.52; interaction test p=0.01). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of type of treatment.

Conclusions

HER2DX might help identify patients with HER2-positive breast cancer who benefit from neoadjuvant dual HER2 blockade in combination with a single taxane.

Legal entity responsible for the study

The authors.

Funding

Reveal Genomics.

Disclosure

A.G. Waks: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Genentech, Macrogenics, Merck. G. Villacampa: Financial Interests, Personal, Invited Speaker: GSK, Pierre Fabre, Pfizer, MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Full or part-time Employment: Reveal Genomics. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. C. Bueno Muiño: Financial Interests, Speaker’s Bureau: Roche/Novartis/Lilly/M.S.D/AstraZeneca; Financial Interests, Research Grant: Roche/Novartis/Pfizer. I. Echavarria Diaz-Guardamino: Financial Interests, Invited Speaker: Roche/Teva/Novartis/Pfizer/Lily; Financial Interests, Advisory Board: Lilly/AstraZeneca. S. Lopez-Tarruella Cobo: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Lilly, Gilead, GSK, Roche, Pierre Fabre, Seagen, Menarini, Stemline, Gebro Pharma; Non-Financial Interests, Invited Speaker: GEICAM, SEOM. M. Marín-Aguilera: Financial Interests, Institutional, Full or part-time Employment, Product Manager: Reveal Genomics, S.L. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. A.C. Wolff: Financial Interests, Institutional, Invited Speaker, Became site PI upon departure of a previous Hopkins faculty member who was site PI for this study.: Roche; Other, Co-chair of ASCO/CAP Panel on HER2 Testing in Breast Cancer: American Society of Clinical Oncology. C.M. Perou: Financial Interests, Personal, Invited Speaker: GeneCentric Therapeutics; Financial Interests, Personal, Stocks/Shares: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics; Financial Interests, Personal, Royalties, from PAM50 licensing: Bioclassifier LLC; Financial Interests, Personal, Royalties: GeneCentric Therapeutics; Non-Financial Interests, Advisory Role: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics. L.A. Carey: Financial Interests, Personal, Royalties, immediate family member-royalty-sharing agreement, investorship interest in licensed IP to startup company, Falcon Therapeutics, that is designing neural stem cell-based therapy for glioblastoma multiforme.: Falcon Therapeutics; Financial Interests, Institutional, Funding, research funding: Syndax, Immunomedics, Novartis, Nanostring Technologies, AbbVie, Seattle Genetics, Veracyte; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, AstraZeneca/ Daiichi Sankyo, Apitude Health, Exact Sciences. E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck, BioNTech; Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Gilead provides clinical trial support to my institution for a study that I am the PI on: Gilead; Financial Interests, Personal, Invited Speaker: Roche/Genentech, BMS; Non-Financial Interests, Invited Speaker: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Invited Speaker: TRIO; Non-Financial Interests, Leadership Role: GEICAM. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. All other authors have declared no conflicts of interest.

Background

Individuals with gTP53m have nearly 24 times higher incidence of any cancer than the general population, of which breast cancer (BC) comes first. Beside prophylactic mastectomy, no preventative measures are currently available. Nothing or very little is known regarding the role of immune and inflammatory factors. We aimed to search for predictors of the development of new subsequent cancers (NSC) among inflammatory and immune cytokines, in patients (pts) with gTP53m from the prospective LIFSCREEN MRI screening trial (NCT01464086).

Methods

All pts with gTP53m who entered the LIFSCREEN trial at Gustave Roussy 11/2011 - 12/2014, with frozen serum samples available were eligible. We analysed inflammatory cytokines and chemokines on samples collected sequentially at accrual month (M) 0 and at M12 using multiplex immunoassay of serum analytes (Bio-Plex Pro™ 40-plex, Bio-Rad). Primary objective was potential associations between M0 and M12 biomarkers and the incidence of any NSC. We used Wilcoxon-Mann Whitney tests and logistic regressions.

Results

Among 107 pts, 42 had serum stored and were eligible. Median age 35.5 (7-67), 67% females. Median follow-up 100 months (95% CI 83-117). 24 pts (57%) had already had cancer before entering the study, of which 7 BC. 11 NSC were diagnosed. At M0, a Th1-like profile (high serum IL-2 (>2 pg/ml) (p=0.03; overall) and CXCL9 levels (>50 pg/ml) (p=0.01; without history of cancers)) was associated with the incidence of NSC. In logistic regression, the Th1 CXCL9 and CXCL10 chemokines were associated with a higher probability of NSC (p=0.03 and 0.04, respectively). At M12, high levels of the follicular T helper cell CXCL13 (>25 pg/ml) chemokine were protective against NSC (p=0.04). Individuals with a significant drop between M0 and M12 of neutrophil and T cell-chemoattracting factors (such as CXCL1 and IFNg/CXCL16 respectively) did not develop cancer.

Conclusions

This exploratory study identifies a disbalance between Th1 and TFH soluble markers in Li Fraumeni deemed to experience additional neoplasia among pts carrying gTP53m. These findings warrant further validation and could be actionable for cancer interception.

Legal entity responsible for the study

Gustave Roussy, Department of Cancer Medicine.

Funding

The LIFSCREEN clinical trial (NCT01464086) was funded by the French Ligue Contre le Cancer. Tarek Ben Ahmed was funded by the grant for DUERTECC (European University Diploma in Translational and Clinical Cancer Research) and by Odyssea for the conduct of the present work. Experiments were conducted as part of the ONCOBIOME consortium project, a European Commission Horizon 2020-funded project (lead Laurence Zitvogel, www.oncobiome.eu).

Disclosure

All authors have declared no conflicts of interest.

Background

Adjuvant CAPE is the standard-of-care (SoC) in eTNBC pts with incomplete response to anthracycline-based NAT. Presence of ctDNA following standard therapy in early breast cancer is associated with poor relapse-free survival (RFS). Here, we evaluated the rates of ctDNA detection before, during and after adjuvant CAPE.

Methods

Pts with residual disease after NAT receiving adjuvant CAPE for 6 months (+/- pembrolizumab) were enrolled in 2 separate, prospective ctDNA monitoring studies. Plasma samples for ctDNA detection (SignateraTM, bespoke mPCR-NGS assay) were collected before, during and after CAPE. Association between ctDNA detection and residual cancer burden (RCB) scores and pathologic stage were evaluated using chi square test. Correlation of ctDNA status with outcomes was evaluated using log-rank test.

Results

Median follow up was 19.3 months (range: 10.7-43.7). A total of 29 pts with a median age of 43 years (range: 33-78) were included. RCB scores after NAT were available for 26 pts (I:10, II:12, III:4). ctDNA positivity during CAPE was significantly higher in pts with RCB III (p=0.0082) and pN3 (p=0.0072). Detection of ctDNA was 15% (3/20) prior to and 25% (7/28) after completion of CAPE. Treatment with CAPE did not result in ctDNA clearance for any pts. Among the 7 pts who were ctDNA-positive, after CAPE, 6 (86%) subsequently experienced clinical relapse with a median of 3.85 months (range: 0.6-11). ctDNA-positivity was strongly associated with inferior RFS (ctDNA-positive: 14% vs ctDNA-negative: 100%; p=0.0001). Only one pt died, 13 months after testing ctDNA-positive prior to CAPE, resulting in an overall survival of 97%.

Conclusions

Treatment with CAPE failed to achieve ctDNA clearance in eTNBC pts who were ctDNA-positive prior to CAPE. ctDNA-positive status was associated with poor RFS in this high-risk population. ctDNA persistence on CAPE may prove useful as a biomarker to select patients for novel agents in adjuvant trials.

Clinical trial identification

NCT04768426.

Legal entity responsible for the study

The authors.

Funding

Only the ctDNA testing in our study is being covered by the company Natera (through their early adopter program). The rest of the study is not funded by the company.

Disclosure

T. Gupta: Financial Interests, Personal, Other, Support: ASCO Gianni Bonadonna Breast Cancer Research Fellowship; Financial Interests, Personal, Advisory Board: Gilead, Biotheranostics. E. Kalashnikova, A.A. Rodriguez: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. M.C. Liu: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera; Financial Interests, Institutional, Research Grant: Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Financial Interests, Institutional, Advisory Board: AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax; Financial Interests, Personal, Other, Travel reimbursement: AstraZeneca, Genomic Health, Ionis. A.J. Medford: Financial Interests, Personal, Advisory Role: Natera, Illumina. S. Isakoff: Financial Interests, Personal, Funding: AstraZeneca, Genentech, Merck, Oncopep. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lily, Foundation Medicine; Financial Interests, Institutional, Research Grant: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lily. M.L. Telli: Financial Interests, Institutional, Research Grant: AbbVie, Arvinas, Bayer, Biothera, Calithera Biosciences, EMD Serono, Genentech, GlaxoSmithKline, Hummingbird Biosciences, Medivation, Merck, Novartis, OncoSec, Pfizer, PharmaMar, Tesaro, Vertex; Financial Interests, Personal, Advisory Role: AbbVie, Aduro Biotech, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Genentech/Roche, Gilead, GlaxoSmithKline, G1 Therapeutics, Guardant, Immunomedics, Merck, Natera, Novartis, OncoSec, Pfizer, RefleXion, Replicate, Sanofi. A.Y. Ho: Financial Interests, Personal, Funding: Merck, GSK, Natera, Breast Cancer Research Foundation; Financial Interests, Personal, Research Grant, R01 CA274254: National Institutes of Health. All other authors have declared no conflicts of interest.

Background

HR deficiency (HRD) may be exploited through use of DNA-damaging chemotherapy and/or PARP inhibitors (PARPi). The current biomarker to infer HRD in breast cancer (BC) is a germline pathogenic variant (PV) in BRCA1/2 (gBRCAm). This biomarker strategy misses a significant proportion of HRD BC. We analysed the HR status of an enriched cohort of platinum-responsive aTNBC on the DORA study.

Methods

Between Feb 2019, and Dec 2020, 45 patients (pts) were enrolled to receive maintenance olaparib (O) +/- durvalumab (D). HRD testing using Pillar Biosciences oncoReveal™ HRD Panel was performed on archival tissue. This panel detects SNVs and indels in 33 HR related genes. Quantitation of BRCA1 and RAD51C promoter methylation assessed using oncoReveal™ BRCA1 & RAD51C Methylation Panel. Median progression free survival (mPFS) by HR status was compared using log-rank test.

Results

Of the 45 pts, 40 had available samples for HRD testing. gBRCAm were reported from medical history: 15 (37.5%) gBRCA unknown, 17 (42.5%) gBRCA wildtype, 8 (20%) gBRCAm. 21 (52.5%), harbored any HR alterations (HRD). OncoReveal™ panel identified 8 BRCA1 (1 FANCA co-mutation), 1 BRCA2, 2 PALB2, 1 BRIP1, 1 RAD51D PV. Mutually exclusive to BRCA PV, 9 were identified to have BRCA1 promoter hypermethylation, 5 classified as highly methylated. 1 tumor with partial BRCA1 hypermethylation had concurrent highly methylated RAD51C. 1 BRCA1 highly methylated tumor had a co-mutation with BRIP1. The mPFS of pts with HRD vs. no HRD was 7.8 months (m) (3.9 - not estimable) vs. 2.1 m (1.9 - 3.4), p=0.002. The association between mPFS and HRD did not vary by maintenance therapy. The mPFS of O pts (HRD n=9 vs. no HRD n=10) is 7.8 vs 1.9 m HR 0.3; 0.11-0.8 and of O+D pts (HRD n=12 vs. no HRD n=9) is 7.4 vs 3.3 m HR 0.34; 0.12-1.0. 11 of the 21 pts with HRD were on maintenance therapy for >6 months vs. 3 of the 19 pts without HRD.

Conclusions

BRCA1/RAD51C promoter hypermethylation and mutations are mutually exclusive with similar proportions identified in this enriched cohort of aTNBC. Current companion diagnostic for PARPi therapy underestimates the proportion of BC with HRD. Testing for BRCA1/RAD51C hypermethylation to guide therapies is worthy of further exploration.

Clinical trial identification

NCT03167619.

Legal entity responsible for the study

Duke Cancer Research Institute.

Funding

AstraZeneca.

Disclosure

T.J.Y. Tan: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Everest Medicines (Singapore) Pte Ltd., DKSH, Pfizer; Financial Interests, Personal, Invited Speaker: DKSH, AstraZeneca, Novartis, Roche, Pfizer, MSD, DHPL Malaysia SDN BHD; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, AstraZeneca, Odonate, Daiichi Sankyo, Genentech, Sanofi; Non-Financial Interests, Member: ASCO.

S. Sammons: Financial Interests, Personal, Advisory Board: Novartis, Sermonix Pharmaceuticals, Daiichi Sankyo, Foundation Medicine, Pfizer; Financial Interests, Personal, Research Grant: Lilly, AstraZeneca/MedImmune, Sermonix Pharmaceuticals, AbbVie, Bristol Myers Squibb. J.L. Fink: Financial Interests, Personal, Full or part-time Employment: Xing Technologies; Financial Interests, Personal, Stocks/Shares: Xing Technologies. P. Waring: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Advisory Role: Pillar Biosciences, Xing Technologies, ORI healthcare; Financial Interests, Personal, Funding, Travel, Accommodations, Expenses: Xing Technologies, Pillar Biosciences; Financial Interests, Personal, Stocks/Shares: Roche/Genentech, Pillar Biosciences, Xing Technologies. Y.S.J. Chan: Financial Interests, Personal, Invited Speaker: Takeda Pharmaceuticals, Novartis, MSD, Specialised Therapeutics; Financial Interests, Personal, Advisory Board: Antengene, Roche; Financial Interests, Personal, Invited Speaker, Others: Travel support: AstraZeneca; Financial Interests, Institutional, Other, Grant/Research support: SymBio Pharmaceuticals, Scinnohub Pharmaceuticals, Invitae, Miltenyi Biotec, STEMCELL Technologies, MGI Tech, Twist Biosciences; Financial Interests, Personal, Other, Travel support: Janssen, Amgen; Financial Interests, Personal, Royalties: SymBio Pharmaceuticals. A. Nixon: Financial Interests, Personal, Advisory Role: Leap Therapeutics, Promega, AdjuVolt; Financial Interests, Institutional, Funding: MedPacto, Seattle Genetics, Genentech/Roche, AstraZeneca/MedImmune, HTG Molecular Diagnostics, Promega, Genmab. T.A. Traina: Financial Interests, Personal, Advisory Role: Genentech/Roche, Pfizer, Merck, Daiichi Sankyo, Gilead Sciences, Blueprint Medicines, Ellipses Pharma, Fuji Pharma, ITeo Therapeutics, Agendia, Novartis, GlaxoSmithKline, GE Healthcare, bioTheranostics, Infinity Pharmaceuticals, Seattle Genetics, Hengrui Pharmaceuticals, G1 Therapeutics, Tersera; Financial Interests, Institutional, Funding: Pfizer, Novartis, Innocrin Pharma, Astellas Pharma, Immunomedics, Genentech/Roche, Daiichi Sankyo, Carrick Pharm, Ayala Pharmaceuticals. C. Anders: Financial Interests, Personal, Advisory Role: Genentech/Roche, Eisai, Ipsen, Seattle Genetics, Elucida Oncology, Immunomedics, Athenex, AstraZeneca; Financial Interests, Personal, Funding, Travel, Accommodations, Expenses: Eisai; Financial Interests, Personal, Royalties: Uptodate.com, Jones and Bartlett; Financial Interests, Personal, Invited Speaker: Eisai, Genentech/Roche, Ipsen, Seattle Genetics, Puma Biotechnology, Elucida Oncology, Immunomedics, Athenex, Novartis, AstraZeneca; Financial Interests, Institutional, Funding: Puma Biotechnology, Lilly, Merck, Nektar, Tesaro, Seattle Genetics, G1 Therapeutics, Pfizer, ZION, Novartis Pharmaceuticals UK Ltd., Caris Life Sciences, Elucida Oncology. S. Kim: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Lilly, DaeHwa Pharma, ISU Abx, Daiich-Sankyo, Beigene, HLB Life Science, Samsung Bioepics, OBI pharma; Financial Interests, Personal, Invited Speaker: Legochem Bioscience; Financial Interests, Personal, Ownership Interest: Genopeaks, Neogene TC; Financial Interests, Institutional, Research Grant: Novartis, Sanofi-Genzyme, DongKook Pharm Co. R.A. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Pfizer, Merck, Lilly, Eisai; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Pfizer, Merck, Lilly, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: Roche; Financial Interests, Personal and Institutional, Research Grant, Investigator Initiated Trial: AstraZeneca. All other authors have declared no conflicts of interest.