Background

In the phase III KEYNOTE-522 study (NCT03036488), neoadjuvant (neoadj) pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo followed by adjuvant (adj) pembro vs pbo in patients (pts) with early-stage TNBC showed a statistically significant improvement in pCR (ypT0/Tis ypN0) and EFS (dual primary endpoints). We present PRO endpoint results from KEYNOTE-522.

Methods

Pts with previously untreated, nonmetastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to neoadj pembro 200 mg Q3W or pbo, both given with 4 cycles of paclitaxel + carboplatin then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, pts received adj pembro or pbo for up to 9 cycles. PROs measured with EORTC QLQ-30 and QLQ-BR23 were prespecified secondary objectives, and with EQ-5D VAS were exploratory objectives. PROs were assessed during the neoadj and adj treatment phases and analyzed for pts who received at least 1 study treatment and completed ≥1 PRO assessment within the neoadj and adj treatment phases. Between-group differences in LS mean change from baseline to the latest time point with ≥60%/80% completion/compliance were assessed using a longitudinal model (no alpha assigned). A threshold of 10 points has been published as a meaningful change.

Results

PRO analyses for QLQ-C30 included 1145 pts in the neoadj phase (pembro + chemo; n = 762; pbo + chemo, n = 383) and 847 in the adj phase (n = 539; n = 308). Completion/compliance rates at wk 21 in neoadj phase and wk 24 in adj phase were ≥80% in both pembro and pbo groups. There were no meaningful differences between treatment group in PRO results (Table). Table: 135MO

Between-group difference in LS mean change from baseline to Wk 21 (Neoadj) or Wk 24 (Adj) in PRO endpoints in all pts with TNBC

Conclusions

Neoadj pembro + chemo followed by adj pembro did not have a negative meaningful impact on HRQoL vs pbo control in pts with previously untreated early-stage TNBC, reinforcing the clinical benefit seen with this regimen.

Clinical trial identification

NCT03036488.

Editorial acknowledgement

Writing support was provided by Christabel Wilson, MSc, of ICON plc (Blue Bell, PA, USA), funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

R.A. Dent: Financial Interests, Personal, Other, Advisory/Consultancy: AstraZeneca, Novartis; Financial Interests, Personal, Other, Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai, Merck, Pfizer, Roche. J. Cortés: Financial Interests, Personal, Advisory Role, Consultancy; Travel/Accomodation/Expenses; Honoraria: Roche; Financial Interests, Institutional, Research Grant, Research Grant Funding: Roche; Financial Interests, Personal, Other, Travel/Accomodation/Expenses; Honoraria: Novartis; Financial Interests, Personal, Advisory Role, Consultancy; Honoraria: Celgene, Lilly, Merck; Financial Interests, Personal and Institutional, Other, Travel/Accomodation/Expenses; Honoraria, Research Grant Funding: Eisai, Pfizer; Financial Interests, Personal, Other, Honoraria: Samsung Bioepis; Financial Interests, Institutional, Research Grant: Merk; Financial Interests, Personal, Advisory Role, Consultancy: Cellestia, Biothera, Merus, Seattle Genetics, Erytech, Athenex, Polyphor, Servier, AstraZeneca; Financial Interests, Institutional, Invited Speaker, Research Grant Funding: AstraZeneca; Financial Interests, Personal, Advisory Role, Consultancy; Travel/Accomodation/Expenses: Daiichi Sankyo; Financial Interests, Institutional, Research Grant, Funding: Ariad, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Guardian Health, Piqur, Puma C, Queen Mary University of London, Seagen; Financial Interests, Personal, Stocks/Shares: MedSIR. L. Pusztai: Financial Interests, Personal, Advisory Role, Consultancy; Travel/Accomodation/Expenses: Merck, AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Research Grant, Funding: Merck, AstraZeneca, Seattle Genetics; Financial Interests, Personal, Advisory Role, Consultancy; Travel/Accomodation/Expenses; Honoraria: Novartis, Genentech, Eisai, Pieris, Immunomedics, Almac, Syndax. H.L. McArthur: Financial Interests, Personal, Invited Speaker, Consultancy; Travel/Accomodation/Expenses: Merck, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Funding: Merck, Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Consultancy; Travel/Accomodation/Expenses: Spectrum Pharm, Lilly, Amgen, Immunomedics, Pfizer, Genentech, AstraZeneca; Financial Interests, Personal, Other, Travel/Accomodation/Expenses: Puma Biotechnology. S. Kuemmel: Financial Interests, Personal, Other, Consulting Fees: Roche, Genomic Health, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, Merck, Pfizer; PFM Medical, Lilly, Sonoscape; Financial Interests, Personal, Ownership Interest: WSG Study Group; Financial Interests, Personal, Other, Travel/Accomodation/Expenses: Roche, Daiichi, Sankyo, Sonoscape. J. Bergh: Financial Interests, Institutional, Research Grant, Funding: Amgen, AstraZeneca, Bayer, Merck, Roche, Pfizer, Sanofi Aventis; Financial Interests, Institutional, Other, Honoraria from UpToDate: Asklepios Medicin Hb. C. Denkert: Financial Interests, Personal, Other, Honoraria: Teva, Novartis, Pfizer, Roche; Financial Interests, Personal, Advisory Role, Consultancy, Honoraria: Amgen; Financial Interests, Personal, Advisory Role, Consultancy: MSD, Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Sividon (Myriad); Financial Interests, Personal, Licensing Fees, Royalties: VmScope. Y.H. Park: Financial Interests, Institutional, Advisory Board: AstraZeneca, Pfizer, Eisai, Roche, Novartis; Financial Interests, Personal, Other, Consultancy: AstraZeneca, Pfizer, Eisai, Roche, Novartis; Financial Interests, Institutional, Funding: AstraZeneca, Merck, Pfizer, Novartis, Alteogen, Roche. R. Hui: Financial Interests, Personal, Other, Advisory Board/Personal fees for advisory boards: MSD, AstraZeneca, BMS, Eli Lilly, Merck, Novartis, Oncosec, Pfizer, Roche, Seagen; Financial Interests, Personal, Other, Speaker honoraria: MSD, Novartis, Roche; Financial Interests, Institutional, Funding, Study funding: MSD, AstraZeneca, BMS, Corvus, Eli Lilly, Janssen, Novartis, Olema, Oncosec, Roche, Seagen. N. Harbeck: Financial Interests, Personal, Stocks/Shares, Ownership Interest: West German Study Group; Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Zodiac Pharma; Financial Interests, Personal, Other, Advisory Role/Consultancy: Agendia, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, Seattle Genetics, West German Study Group (I); Financial Interests, Institutional, Funding: Lilly, Merck, Novartis, Pfizer, Roche/Genentech. M. Takahashi: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Pfizer, Lilly, Eisai; Financial Interests, Institutional, Research Grant, Research funding: Eisai, Taiho, Kyowa-Hakko Kirin, Nippon Kayaku. M. Untch: Financial Interests, Personal, Other, Consulting Fees: Amgen, Pfizer, Mundipharma, Roche, Lilly, Celgene, MSD, Novartis, AbbVie, Daiichi Sankyo, Pierre Fabre, Mylan, Myriad, GSK, AstraZeneca, Gilead, Molecular Health; Financial Interests, Personal, Other, Contracted research: German Breast Group, BMS, MSD, Polyphor, Daiichi Sanyko, Merck. P.A. Fasching: Financial Interests, Personal, Other, Consulting Fees: Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, MSD, Lilly, Pierre Fabre, Seagen, Roche, Hexal, Agendia; Financial Interests, Personal, Other, Fees for Non-CME services received directly from commercial interest or their agents: Novartis, Daiichi Sankyo, Lilly, Seagen. Research grant; Author; Biontech, Cepheid. F. Cardoso: Financial Interests, Personal, Other, Advisory Role/Consultancy: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanof. A. Haiderali, L. Jia, A.M. Nguyen, W. Pan: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. J. O'Shaughnessy: Financial Interests, Personal, Other, Consulting fees: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bayer, BMS, Celgene, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Gilead Sciences, GRAIL, Halozyme, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myri. P. Schmid: Financial Interests, Personal, Other, Consultancy, Honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Eisai, Celgene; Financial Interests, Institutional, Other, Research Grant/Funding: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation; Financial Interests, Personal, Other, Spouse is an employee: Roche.

Background

Triple-negative breast cancer (TNBC) is a heterogeneous disease with at least five molecular subtypes characterized by distinct gene expression, genomic and tumor microenvironment (TME) profiles. The phase III adjuvant IBCSG 22-00 trial evaluating low-dose cyclophosphamide and methotrexate (CM) chemotherapy did not show a clinical benefit in unselected TNBC patients. Here, we aimed to explore whether specific TNBC molecular subtypes and TME features could predict benefit to low-dose CM maintenance chemotherapy in the IBCSG 22-00 study.

Methods

RNA sequencing was performed on a selection of 347 TNBC FFPE tumor samples matched in a 1:3 relapse cases and non-relapse controls ratio. TNBC subtypes were computed applying the methodology described by Bareche et al. and Burstein et al. GDSC database was used to analyze the resistance of methotrexate across TNBC cell lines.

Results

Immunomodulatory (IM) and basal-like/immune activated (BLIA) molecular subtypes showed a significant survival benefit when treated with low-dose CM compared to those who were not (DFS: HR = 0.5; 95% CI, 0.28 to 0.89; p interaction = 0.018 and HR = 0.49; 95% CI, 0.27 to 0.9; p interaction = 0.021). Of interest, high expression of regulatory T-cell immune signature was also associated with better prognosis in the CM arm highlighting the potential antitumor T-cell response of cyclophosphamide. In contrast, we observed worse outcome in mesenchymal (M) subtype when treated with low-dose CM (DFS: HR = 1.9; 95% CI, 1.2 to 3; p interaction = 0.0044) suggesting potential intrinsic resistance of M tumors with embryonic stem cell characteristics to methotrexate. These results were further substantiated in TNBC cell lines experiments where tumor cells with a mesenchymal phenotype showed resistance to methotrexate (t value = 2.22; p = 0.037).

Conclusions

Our results showed a differential benefit of low-dose CM maintenance therapy among TNBC subtypes highlighting a substantial TNBC heterogeneity regarding treatment response. Low-dose CM maintenance therapy could be considered as a potential immunomodulatory strategy for TNBC tumors with IM phenotype in the adjuvant setting. Further validation of these findings is warranted.

Clinical trial identification

NIH: NCT00022516 Release date: January 27, 2003.

Legal entity responsible for the study

The authors.

Funding

Breast Cancer Research Foundation (BCRF).

Disclosure

M.A. Colleoni: Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Co-Chair Scientific Committee IBCSG: IBCSG. S. Loi: Financial Interests, Institutional, Funding, Research: Novartis, BMS, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech, Seattle Genetics; Non-Financial Interests, Other, Consultant: Seattle Genetics, Novartis, BMS, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, Roche-Genentech; Financial Interests, Institutional, Other, Consultant: Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Puma Biotechnology, Pfizer, Gilead Therapeutics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, BMS; Financial Interests, Personal, Other, Consultant: Seattle Genetics. G. Viale: Financial Interests, Personal, Other, Honoraria: MSD Oncology, Pfizer, Daiichi Sankyo Europe GmbH; Financial Interests, Personal, Advisory Role: Dako, Roche/Genentech, Novartis, Bayer, Daiichi Sankyo, MSD Oncology, Menarini; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech; Financial Interests, Personal, Funding: Roche/Genentech; Financial Interests, Institutional, Funding: Ventana Medical Systems, Dako/Agilent Technologies, Cepheid; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Roche. M.M. Regan: Financial Interests, Personal, Advisory Board, Also invited speaker: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Includes consulting.: Tolmar Pharmaceuticals; Financial Interests, Personal, Invited Speaker: WebMD; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb, Bayer; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial supported by company: Novartis; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported by company: Pfizer, Ipsen, TerSera; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial drug supply from company: Roche; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported or drug supply from company: AstraZeneca; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials with funding from company: Debiopharm; Non-Financial Interests, Advisory Role: Bristol-Myers Squibb. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, AMGEN, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.

Background

Preventing initiation of micro metastases from early breast cancer by peri-operative intervention has not been explored adequately. Local anaesthesia blocks voltage gated sodium channels which prevents activation of pro-metastatic pathways. A Cochrane review of using local anaesthesia before surgery for breast cancer concluded inadequate data on its efficacy. We conducted a multi-centre randomized trial to test the impact of peri-tumoral infiltration of local anaesthesia before surgery on survival in women with early breast cancer.

Methods

Women with early breast cancer were randomized, to receive peri-tumoral injection of 0.5% lidocaine, 5-10 minutes before surgery (LA arm) or surgery without lidocaine(No-LA arm). Randomisation was stratified by menopausal status and tumour size. Women on neo-adjuvant chemotherapy were not included in the study. Participants underwent breast conservation or modified radical mastectomy and received standard post-operative adjuvant radiotherapy and systemic therapy. The primary endpoint was disease-free survival(DFS) and the secondary endpoint was overall survival(OS).

Results

The study included 1600 patients randomized to LA(N=796) and No-LA(N=804) arms, of whom 1583 were included in the analysis. At 72 months there were 255 DFS events (109 LA arm, 146 No-LA arm). At 6-year DFS were 86.1% and 81.7% in LA and No-LA arms, respectively (HR 0.74, 95% CI 0.58-0.95, p=0.017) and OS were 89.9% and 86.2%, respectively (HR 0.71, 95% CI 0.53-0.94, p=0.019). The impact of LA was similar in subgroups defined by menopausal status, tumour size, lymph node metastases, hormone receptor and HER2neu status. In the LA and no-LA arm, the loco-regional DFS were 94.8% and 92.3%, respectively (HR=0.67, 95%CI 0.45-0.99, p=0.04) and distant DFS were 89.2% and 85.1%, respectively (HR=0.70, 95%CI 0.53 – 0.94, p=0.013). There were no adverse events due to lidocaine injection.

Conclusions

Peri-tumoral injection of lidocaine before surgery is a simple implementable intervention that can reduce 1 of 4 recurrences and 3 of 10 deaths in women with early breast cancer. Altering events at the time of surgery can prevent metastases in women with early breast cancer(CTRI/2014/11/005228).

Legal entity responsible for the study

Tata Memorial Centre, Mumbai, India.

Funding

Department of Atomic Energy, Government of India.

Disclosure

All authors have declared no conflicts of interest.

Background

Several tumor and microenvironment features impact HER2-positive breast cancer progression, portraying its heterogeneity. Here, we aimed to identify subgroups associated with prognosis in patients receiving adjuvant trastuzumab in the phase III ALTTO trial.

Methods

A case-control approach (1:2) was used to select from the trastuzumab arm 134 and 268 patients with and without a distant relapse, matched for clinicopathological characteristics. RNA was obtained from FFPE tumor cores from surgical samples. PAM50 subtypes were computed using Absolute Intrinsic Molecular Subtyping (AIMS). Uni- and multivariable (controlling for clinicopathological characteristics and PAM50 HER2-enriched [HER2-E] vs others) Cox proportional hazard models and Kaplan-Meier curves were used for distant relapse-free survival (DRFS) analysis. Clusters were identified using non-negative matrix factorization (NMF) and k-means clustering, and characterized with gene signatures.

Results

The case-control cohort includes higher proportions of >2cm, node positive and G3 tumors compared to the whole trastuzumab arm. RNA sequencing data were generated for 386/402 patients. Genes associated with DRFS (false discovery rate < 0.05, multivariable analysis) were selected for NMF to extract 4 factors. K-means clustering identified 4 groups with distinct prognosis: immune-enriched (N = 69; 91% 5-year DRFS), metabolic-enriched (N = 87; 51% 5-year DRFS), stroma-enriched (N = 76; 58% 5-year DRFS), and hormone receptor positive-enriched (N = 154; 78% 5-year DRFS) which could be divided into HER2-E and non-HER2-E (mainly Luminal A/B) tumors (N = 91 and 63; 72% and 87% 5-year DRFS, respectively). The robustness and prognostic value of the clusters were assessed via cross-validation of gene selection, NMF and k-means clustering.

Conclusions

A supervised top-down approach identified 4 biologically-driven clusters in HER2-positive breast cancer which can be integrated with PAM50. Our findings support the evaluation of de-escalation approaches in luminal and immune-enriched subgroups, presenting excellent prognosis with adjuvant trastuzumab alone in a high-risk population. Further validation is required.

Clinical trial identification

NCT00490139. First Posted: June 22, 2007.

Legal entity responsible for the study

Novartis and NCI.

Funding

The conduct of the ALTTO study was funded by GSK and later Novartis. The RNA sequencing on which the analyses described in this abstract are based was funded by Breast Cancer Research Foundation (BCRF) and Fondation contre le Cancer.

Disclosure

S. El-Abed: Financial Interests, Personal, Other, Grant within the submitted work: Novartis; Financial Interests, Personal, Other, Grant outside the submitted work: Roche/Genentech, Pfizer. M.C. Liu: Financial Interests, Institutional, Other, Research support: 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. S. Di Cosimo: Financial Interests, Personal, Other, Consulting fees: Pierre-Fabre, IQVIA, AstraZeneca; Financial Interests, Personal, Other, Grant reviewer compensations: Swiss Cancer League, Ellipses; Financial Interests, Personal, Other, Medical advisor fees: MEDSIR; Financial Interests, Institutional, Research Grant: Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC); Non-Financial Interests, Personal, Other, Member of the steering committee: Neo-/ALTTO, Neo-Phoebe, Neo-Erubilin, NSABP-FB7, Parsifal, PHERGain; Non-Financial Interests, Personal, Member: ESMO EU Policy Committee, Regional Board of Associazione Italiana di Oncologia Medica, DIGICORE. M. Piccart: Financial Interests, Personal, Invited Speaker: Astra-Zeneca, Lilly, MSD, Novartis, Pfizer; Financial Interests, Personal, Other, Consultant: Camel-IDS/Precirix; Financial Interests, Personal, Advisory Board: Immunomedics, Menarini, Odonate, Seattle Genetics, Immutep, SeaGen, Gilead, NBE Therapeutics, Frame Therapeutics; Financial Interests, Personal, Advisory Board, Consultant and invited speaker: Roche-Genentech; Financial Interests, Personal, Invited Speaker, Scientific Board: Oncolytics; Financial Interests, Institutional, Research Grant: Astra-Zeneca, Immunomedics, Lilly; Financial Interests, Institutional, Funding: Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. L. Pusztai: Financial Interests, Personal, Other, consulting fees and honoraria: Seagen, Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb, Genentech, Eisai, Pieris, Immunomedics, Clovis, Syndax, H3Bio, Radius Health, Personalis, Daiichi, Natera; Financial Interests, Institutional, Other, research funding: Seagen, AstraZeneca, Merck; Financial Interests, Institutional, Other, research: Pfizer, Bristol-Myers Squibb. S. Loi: Financial Interests, Institutional, Other, research funding: Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech, Seattle Genetics; Non-Financial Interests, Personal, Other, consultant: Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, Roche-Genentech; Financial Interests, Institutional, Other, consultant: Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, Bristol Meyers Squibb. R.F. Salgado: Non-Financial Interests, Personal, Other, non-financial support: Merck, Bristol Myers Squibb (BMS); Financial Interests, Personal, Other, research support: Merck, Puma Biotechnology, Roche; Financial Interests, Personal, Other, advisory board: Roche, Bristol Myers Squibb (BMS), Exact Sciences. G. Viale: Financial Interests, Personal, Other, Honoraria: MSD Oncology, Pfizer, Daiichi Sankyo Europe GmbH; Financial Interests, Personal, Advisory Role: Dako, Roche/Genentech, Novartis, Bayer, Daiichi Sankyo, MSD Oncology, Menarini; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech; Financial Interests, Personal, Other, Research Funding: Roche/Genentech; Financial Interests, Institutional, Other, Research Funding: Ventana Medical Systems, Dako/Agilent Technologies, Cepheid; Financial Interests, Personal, Invited Speaker, Travel, Accommodations, Expenses: Roche. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, AMGEN, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.

Background

HER2DX is a prognostic and predictive assay in early-stage HER2+ BC based on clinical data and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon), including ERBB2 levels. Here, we evaluated the ability of HER2DX to predict efficacy of a de-escalated, chemotherapy (CT)-free neoadjuvant regimen in HER2+/HR+ BC.

Methods

HER2DX was evaluated on pre-treatment FFPE tumor samples from the PerELISA phase II study for postmenopausal patients (pts) with operable HR+/HER2+ BC. Pts received 2-week (wk) letrozole (L), and then underwent re-biopsy for Ki67 evaluation. Patients with endocrine therapy sensitive tumors (EST) (i.e., >20% Ki67 relative reduction at wk 2) continued L and 5 cycles of trastuzumab T+P. Primary aim was to test the ability of HER2DX risk-score, HER2DX pCR score and HER2DX ERBB2 score (as continuous variables and group categories) to predict pathological complete response (pCR) in patients with EST. Logistic regression and receiver-operator curve (ROC) analysis assessed associations of HER2DX scores with 1) pCR and 2) EST.

Results

HER2DX was evaluated in 55 pts (86%) enrolled in PerELISA and 40 pts (73%) had EST. The pCR rate in pts with EST was 22.5% (9/40). In this group, HER2DX pCR score, but not HER2DX risk-score, was significantly associated with pCR (p=0.012; Area under ROC [AUC]=0.80). The pCR rate in low, medium, and high HER2DX pCR score groups was 8.0% (2/25), 43.0% (6/14) and 100.0% (1/1), respectively. HER2DX ERBB2 score was significantly associated with pCR (p=0.004; AUC=0.88) and independently of HER2 levels (2+ vs 3+). The pCR rate in low, medium, and high HER2DX ERBB2 score groups was 0.0% (0/12), 8.3% (1/12) and 50.0% (8/16), respectively. HER2DX pCR score was also significantly associated with Ki-67 response following 2-wk L (p=0.004; AUC=0.77). The rate of EST in low, medium, and high HER2DX pCR score groups was 89.3% (25/28), 66.7% (14/21) and 16.7% (1/6), respectively.

Conclusions

HER2DX predicts endocrine sensitivity and pCR following neoadjuvant T+P+letrozole in pts with early-stage HER2+/HR+ BC. HER2DX could help tailor systemic therapy in this context.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

V. Guarneri: Financial Interests, Personal, Advisory Board: Roche, EliLilly, Novartis, MSD, Gilead; Financial Interests, Personal, Invited Speaker: EliLilly, Novartis; Financial Interests, Institutional, Invited Speaker: EliLilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck. M.V. Dieci: Financial Interests, Personal, Invited Speaker: Eli Lilly, Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Eli lilly, Seagen, Exact Science; Financial Interests, Personal, Other, Consultancy: Pfizer; Financial Interests, Institutional, Research Grant: Veneto Institute of Oncology IOV-IRCCS, Italian Ministry of health, University of Padova. G. Griguolo: Financial Interests, Personal, Invited Speaker: Novartis, Eli Lilly; Other, Travel Support: Novartis, Amgen, Daiichi Sankyo; Other, Trave Support: Pfizer. L. Pare Brunet, M. Marin: Financial Interests, Full or part-time Employment: Reveal Genomics. F. Miglietta: Financial Interests, Invited Speaker: Roche. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Meyers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Meyers Squibb, Roche, Incyte. P. Villagrasa Gonzalez: Financial Interests, Stocks/Shares: Reveal Genomics. J. Parker: Financial Interests, Stocks/Shares: Reveal Genomics. C.M. Perou: Financial Interests, Stocks/Shares: Reveal Genomics. 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

Early-stage HR+ breast cancer patients face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) and BCIN+ prognostic models are significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence (DR) in N0 and N1 breast cancer, respectively. Here, the prognostic performance of BCI and BCIN+ was evaluated in a cohort of HR+ postmenopausal women from the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial.

Methods

BCI testing was performed blinded to clinical outcome with BCI/BCIN+ risk groups calculated based on pre-specified cut-points. Kaplan-Meier analysis and log-rank test were used to assess the prognostic significance of BCI/BCIN+ risk groups based on DR. Cox proportional hazard models with and without clinical covariates were used to estimate hazard ratios (HRs) and the associated 95% confidence intervals (CIs).

Results

1520 HR+ N0 and 2249 N1 patients were included. For overall 10y DR, BCI stratified 1197 N0 patients who did not receive chemotherapy into three prognostic groups: 47% low-, 29% intermediate- and 24% high-risk. BCIN+ stratified 1319 N1 patients into two groups: 23% low- and 77% high-risk. In the 3053 patients who were DR-free for 5 years, the 10-year late DR rates for low- and high-risk were 5.4% (95%CI: 3.0%-7.8%) and 9.3% (95%CI: 6.7%-11.8%) in the N0 cohort (N= 1285) and 5.5% (95%CI: 2.9%-8.0%) and 12.2% (95%CI: 10.2%-14.1%) in the N1 cohort (N= 1768). Similarly, significant prognostic results were observed in the multivariate analysis adjusting for age, tumor size, grade, treatment as well as in HER2- patients (Table). Table: 138MO

Conclusions

BCI and BCIN+ are significantly prognostic for risk of overall DR (0-10y) and late DR (5-10y) for N0 and N1 patients, respectively. These results provide further validation of BCI clinical utility as an aid in the decision-making for adjuvant therapies for HR+ breast cancer.

Legal entity responsible for the study

Biotheranostics, Inc., a Hologic Company.

Funding

Biotheranostics, Inc., a Hologic Company.

Disclosure

J.M. Bartlett: Financial Interests, Personal, Other, Honoraria: Nanostring Technologies, Inc., Oncology Education, Biotheranostics, A Hologic Company, MedcomXchange, Communications Inc; Financial Interests, Personal, Advisory Role: Insight Genetics, Inc., BioNTech AG, Biotheranostics, A Hologic Company, Pfizer, Rna Diagnostics Inc, oncoXchange/MedcomXchange Communications Inc., Herbert Smith French Solicitors, OncoCyte Corporation; Financial Interests, Personal, Funding: Thermo Fisher Scientific, Genoptix, Agendia, NanoString Technologies, Inc., Stratifyer GmbH, Biotheranostics, A Hologic Company; Financial Interests, Personal, Other, Patents - Jan 2017: Methods and Devices for Predicting Anthracycline Treatment Efficacy, US utility – 15/325,472; EPO – 15822898.1; Canada – not yet assigned Jan 2017: Systems, Devices and Methods for Constructing and Using a Biomarker, US utility – 15/328,108; EPO – 15824751.0; Canada – not yet assigned Oct 2016: Histone gene module predicts anthracycline benefit, PCT/CA2016/000247 Dec 2016: 95-Gene Signature of Residual Risk Following Endocrine Treatment, PCT/CA2016/000304 Dec 2016: Immune Gene Signature Predicts Anthracycline Benefit, PCT/CA2016/000305 June 2020: Use of Molecular Classifiers to Diagnose, Treat and Prognose Prostate Cancer, US Provisional 63/040.692, Disclosure Name: A Molecular Classifier for Personalized Risk Stratification for Patients with Prostate Cancer, Date: 21/08/2019: Other - Patents; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Biotheranostics, A Hologic Company, NanoString Technologies, Inc., Breast Cancer Society of Canada. J. Wong: Financial Interests, Personal, Full or part-time Employment: Biotheranostics, A Hologic Company; Financial Interests, Personal, Stocks/Shares: Biotheranostics, A Hologic Company; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Biotheranostics, A Hologic Company. G. Pond: Financial Interests, Personal, Other, Honoraria: Astra-Zeneca, Takeda; Financial Interests, Personal, Advisory Role: Merck, Profound Medical; Financial Interests, Personal, Stocks/Shares: Roche Ltd. Y. Zhang: Financial Interests, Personal, Full or part-time Employment: Biotheranostics, A Hologic Company; Financial Interests, Personal, Stocks/Shares: Biotheranostics, A Hologic Company; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Biotheranostics, A Hologic Company; Financial Interests, Personal, Other, Patents: Predicting likelihood of response to combination therapy, Registered United States of America Application no: 14/724,732 Application date: 5/28/2015 Registration No: 10,253,369 Registration date: 4/9/2019; Integration of tumor characteristics with breast cancer index, pending united States of America Application no: 15/349,915 Application date: 11/11/2016; Predicting breast cancer recurrence; Pending United States of America Application no: 14/483,108 Application date: 9/10/2014; Post-treatment breast cancer prognosis, Pending United States of America Application no: 15/298,128 Application date: 10/19/2016; Neuroendocrine tumors, Pending United States of America Application no: 15/656,998 Application date: 7/21/2017: Biotheranostics, A Hologic Company. R. Salunga: Financial Interests, Personal, Full or part-time Employment: Biotheranostics, A Hologic Company; Financial Interests, Personal, Stocks/Shares: Biotheranostics, A Hologic Company; Financial Interests, Institutional, Funding: Biotheranostics, A Hologic Company. C. Markopoulos: Financial Interests, Personal, Advisory Role: Exact Sciences. D. Rea: Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche; Financial Interests, Personal, Advisory Role: Genomic Health, MSD Oncology; Financial Interests, Institutional, Funding: Celgene, Roche, Biotheranostics, A Hologic Company; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Daiichi Sankyo, Eisai, Novartis, Pfizer. C.A. Schnabel: Financial Interests, Personal, Full or part-time Employment: Biotheranostics, A Hologic Company; Financial Interests, Personal, Stocks/Shares: Biotheranostics, A Hologic Company; Financial Interests, Personal, Officer: Biotheranostics, A Hologic Company; Financial Interests, Personal, Other, Patents: Predicting likelihood of response to combination therapy, Registered United States of America Application no: 14/724,732 Application date: 5/28/2015 Registration No: 10,253,369 Registration date: 4/9/2019; Integration of tumor characteristics with breast cancer index, Pending United States of America Application no: 15/349,915 Application date: 11/11/2016; Predicting breast cancer recurrence; pending united states of america application no: 14/483,108 Application date: 9/10/2014; Post-treatment breast cancer prognosis, pending united states of america application no: 15/298,128 Application date: 10/19/2016; Neuroendocrine tumors, Pending United States of America Application no: 15/656,998 Application date: 7/21/2017: Biotheranostics, A Hologic Company; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Biotheranostics, A Hologic Company. K. Treuner: Financial Interests, Personal, Full or part-time Employment: Biotheranostics, A Hologic Company; Financial Interests, Personal, Stocks/Shares: Biotheranostics, A Hologic Company; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Biotheranostics, A Hologic Company; Financial Interests, Personal, Leadership Role: Biotheranostics, A Hologic Company. J. Bayani: Financial Interests, Personal, Other, Honoraria: Thermo Fisher Scientific, NanoString Technologies; Financial Interests, Personal and Institutional, Research Grant: Thermo Fisher Scientific. All other authors have declared no conflicts of interest.

Background

The identification of predictive biomarkers of response to neoadjuvant chemotherapy (NACT) is an unmet need in early-stage TNBC. Transcriptomic classification according to TNBCtype-4 classifier has shown predictive value, and we aimed to validate our previous results (Echavarria I et al, CCR 2018) in terms of response and long-term outcomes in a larger cohort.

Methods

Stage I-III TNBC patients were enrolled across 10 hospitals in a prospective cohort and were treated with neoadjuvant carboplatin and docetaxel for 6 cycles (NCT01560663). RNAseq was performed from FFPE core biopsies and TNBCtype-4 classification was done on the TNBCtype online tool. Response was categorized based on the Symmans residual cancer burden score.

Results

RNAseq and TNCBtype4 classification was available for 235 patients. Median age was 53 years, median tumor size 29.5 mm and 46.0% of the patients were clinically node negative. 14 patients were not evaluable for response due to incomplete axillary evaluation after NACT. Among the 221 remaining patients, the pCR rate was 47.5% (n=105). 71 (30.2%) of the patients were classified as BL1, 48 (20.4%) as BL2, 40 (17.0%) as LAR and 57 (24.3%) as M. 19 additional patients (8.1%) were considered estrogen receptor-positive (ER+) according to the TNBCtype4 classifier. pCR rate differed significantly according to TNBCtype subtyping (p=0.001), with BL1 achieving a pCR rate of 60.6%, followed by BL2 (52.1%), and M and LAR with a pCR rate of 33.3% and 32.5% respectively. Patients classified as ER+ had a pCR rate of 26.3%. This significant association was maintained in the multivariate analysis including clinicopathological factors and TILs. Although different rates of distant relapse were observed across subgroups, they did not reach statistical significance with the current follow-up (p=0.09). With a median follow-up of 53 months, 3 year-distant disease-free survival (dDFS) was 89.4% for BL1, 82.3% for BL2, 83.9% for M and 73.2% for LAR (p=0.13).

Conclusions

TNCBtype-4 classifier significantly predicts pCR rate to NACT in operable TNBC patients. A non-significant trend towards different dDFS was observed, although longer follow-up is needed.

Clinical trial identification

NCT01560663.

Legal entity responsible for the study

Hospital General Universitario Gregorio Marañon.

Funding

Instituto de Salud Carlos III PI12/02684, PI15/00117, PI18/01775 Fondo Europeo de Desarrollo Regional.

Disclosure

J.Á. García Saenz: Financial Interests, Personal, Invited Speaker: Novartis, Celgene, Eli Lilly, Eisai; AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, travel support: Novartis, Roche, Pfizer. All other authors have declared no conflicts of interest.