The recurrence score (RS) based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low. There is little information from prospective clinical trials, however, regarding outcomes for patients with a high RS treated with chemotherapy regimens including taxanes and/or anthracyclines.
Women with hormone-receptor-positive, HER2-negative, axillary-node-negative breast cancer and a high RS of 26-100 were assigned to receive endocrine therapy plus a chemotherapy regimen selected by the treating physician.
Among the 9719 eligible women, 1389 (14%) had a RS of 26-100.The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-FU in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). The estimated rates of freedom from recurrence of breast cancer at a distant site were 93.0% (standard error [SE]+0.8%) at 5 years and 86.8% (SE + 1.7%) at 9 years. In contrast, the projected rates of freedom from distant recurrence in this population if treated with endocrine therapy alone was estimated to be 78.8% (SE ± 14.0%) at 5 years and 65.4% (SE ± 10.4%) at 9 years when estimating outcomes based on the treatment effect of chemotherapy noted in the HER2-negative cohort of the B20 trial. Five-year rates of freedom from distant recurrence ranged from 92.3% to 95.5% for all chemotherapy regimens with the exception of CMF (88.5%).
The estimated rate of freedom from distant recurrence in women with a RS of 26-100 treated with a variety of adjuvant taxane and/or anthracycline-containing chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population.
NCT00310180.
ECOG-ACRIN Cancer Research Group.
USA National Cancer Institute, Genomic Health.
All authors have declared no conflicts of interest.
We analyzed KATHERINE trial (NCT01772472) data to assess TCP, PN and CNS recurrence, key considerations in anti-HER2 treatment of BC pts.
Pts received 14 cycles of post-neoadjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w). Safety (per NCI CTCAE v4.0; all pts receiving ≥1 dose of study drug) and CNS recurrence (intent-to-treat population) were assessed.
Baseline (BL) neuropathy was well balanced between arms (T-DM1 22.7%; H 21.4%). In both arms, BL neuropathy was not associated with higher PN incidence (T-DM1 36.3% H 17.5% vs T-DM1 31.1% H 16.8%) however it was associated with longer median PN duration and lower resolution rate (352–337 days [d] 66–64% vs 243–232 d 81–83%). PN incidence was similar, irrespective of prior taxane (docetaxel T-DM1 32%; H 18%; paclitaxel T-DM1 32%; H 17%). In the T-DM1 arm, prior platinum was associated with higher TCP incidence (mostly grade 1–2) (36% vs 27%) while median duration and resolution rate of grade 3–4 TCP were similar regardless of prior platinum (33 d vs 29 d; 95% vs 96%). In the H arm, TCP rate was only 2.4% precluding further analysis. The numerically higher rate of CNS recurrence as first IDFS event for T-DM1 may be explained by competing risk, as observed in H adjuvant trials. T-DM1 was not associated with an increased overall risk of CNS recurrence and there was no evidence of subsequent overall survival (OS) detriment (Table). CNS recurrence analysisCNS recurrence T-DM1 (n = 743) H (n = 743) Pts with CNS recurrence, n (%) 45 (6.1) 40 (5.4) As first IDFS eventa 44 (5.9) 32 (4.3) After first IDFS eventb 1 (0.1) 8 (1.1) Pts with CNS as only eventc 36 (4.8) 21 (2.8) Median time to CNS recurrence, m 17.5 11.9 OS post CNS recurrence T-DM1 (n = 45) H (n = 40) Pts with OS event, n (%) 26 (57.8) 21 (52.5) Pts without OS event, n (%) 19 (42.2) 19 (47.5) Median time to event (95% CI), m 12.5 (8.6–26.6) 14.3 (7.6–29.8) Unstratified HR (95% CI) 1.07 (0.60–1.91) 3-year event-free rate, % (95% CI) 24.2 (5.05–43.3) 25.4 (6.81–44.0) CNS recurrence withina or afterb 61 days of first IDFS event cAny time; m, months
BL neuropathy may impact duration and resolution of PN with T-DM1 or H, but PN incidence was not affected by BL neuropathy or type of prior taxane. Prior platinum was associated with higher TCP incidence in the T-DM1 arm. The numerical difference in CNS recurrence as first IDFS event for T-DM1 vs H may be explained by competing risk and had no detrimental effect on OS.
NCT01772472.
Medical writing support was provided by Ify Sargeant of Twist Medical LLC and funded by F. Hoffmann-La Roche.
F. Hoffmann-La Roche.
F. Hoffmann-La Roche.
M. Untch: Honoraria (institution), Non-remunerated activity/ies: AbbVie; Honoraria (institution), Non-remunerated activity/ies: Amgen GmbH; Honoraria (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution), Non-remunerated activity/ies: BMS; Honoraria (institution), Non-remunerated activity/ies: Celgene GmbH; Honoraria (institution), Non-remunerated activity/ies: Daiji Sankyo; Honoraria (institution), Non-remunerated activity/ies: Eisai GmbH; Honoraria (institution), Non-remunerated activity/ies: Janssen Cilag/ J&J; Honoraria (institution), Non-remunerated activity/ies: Lilly Deutschland/ Lilly Int.; Honoraria (institution), Non-remunerated activity/ies: MSD Merck; Honoraria (institution), Non-remunerated activity/ies: Mundipharma; Honoraria (institution), Non-remunerated activity/ies: Myriad Genentics; Honoraria (self), Non-remunerated activity/ies: Odonate; Honoraria (institution), Non-remunerated activity/ies: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), Non-remunerated activity/ies: Riemser; Honoraria (institution), Non-remunerated activity/ies: Roche Pharma AG; Honoraria (institution), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (institution), Non-remunerated activity/ies: Sividon Diagnostics; Honoraria (institution), Non-remunerated activity/ies, Same disclosures for Novartis: TEVA Pharmaceuticals Ind Ltd. C.E. Geyer: Research grant / Funding (institution), Travel / Accommodation / Expenses, Medical writing support, travel/hotel expenses for non-compensated advisory board attendance: Genentech/Roche; Travel / Accommodation / Expenses, Travel/hotel expenses for Steering Committee activities: AstraZeneca; Non-remunerated activity/ies, Non-financial support, medical writing support : AbbVie; Advisory / Consultancy, Advisory Board: Celgene. C. Huang: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony: Novartis; Honoraria (self): EirGenix; Honoraria (self): OBI Pharma; Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Daiichi Sankyo. S. Loibl: Honoraria (institution): Roche; Honoraria (institution): AbbVie; Honoraria (institution): Amgen; Honoraria (institution): AstraZeneca; Honoraria (institution): Celgene; Honoraria (institution): Novartis; Honoraria (institution): Pfizer; Honoraria (institution): Seattle Genetics; Honoraria (institution): Teva; Honoraria (institution): Vifor; Honoraria (institution): PRIME; Honoraria (institution): Daiichi; Licensing / Royalties: EP14153692.0 pending. M.S. Mano: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Oncologica Brasil; Honoraria (self), Advisory / Consultancy: AstraZeneca; Shareholder / Stockholder / Stock options: Hypera; Shareholder / Stockholder / Stock options: Fleury; Shareholder / Stockholder / Stock options: Biotoscana. G. von Minckwitz: Honoraria (institution): Pfizer; Honoraria (self), Honoraria (institution): Amgen; Honoraria (self), Honoraria (institution): Roche; Honoraria (institution): Celgene; Honoraria (institution): AstraZeneca; Honoraria (institution): Myriad Genetics; Honoraria (institution): AbbVie; Honoraria (self): Vifor Pharma. A. Brufsky: Advisory / Consultancy: Eisai; Advisory / Consultancy: Myriad Pharmaceuticals; Advisory / Consultancy: Merck; Advisory / Consultancy: Bioarray Therapeutics; Advisory / Consultancy: Puma Biotechnology; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: NanoString Technologies; Advisory / Consultancy: BioTheranostics; Advisory / Consultancy: Lilly; Advisory / Consultancy: Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Celgene; Advisory / Consultancy: Agendia; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Pfizer. B. Kaufman: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: AZ; Advisory / Consultancy: Novartis. T. Boulet: Research grant / Funding (institution): Genentech. H. Liu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche/Genentech. C. Song: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche/Genentech. E.P. Mamounas: Honoraria (self): Genentech/Roche; Honoraria (self): Genomic Health, Inc.; Honoraria (self): Biotheranostics; Honoraria (self): Merck; Honoraria (self): Daiichi Sankyo. All other authors have declared no conflicts of interest.
Although tumor-infiltrating lymphocytes density is associated with increased response and improved outcomes in HER2+ breast cancer, BCR clonal diversity repertoire could provide a more informative measure of an individual’s immune-mediated anti-tumor response. In this study, we focus on the specific role of B-cell gene-expression signatures and BCR repertoire as predictive and prognostic biomarkers in CALGB 40601, a neoadjuvant study of single vs. dual (trastuzumab + lapatinib) HER2 targeting with paclitaxel.
Gene expression profiling by mRNA sequencing was performed on 265 pre-treatment samples and signature scores were calculated by determining the median expression of all genes in a signature. BCR repertoire analysis using V’DJer was assessed on 256 of the samples. The predictive and prognostic value of clinical parameters, signature scores and BCR diversity metrics was tested in a univariate analysis for pathologic complete response (pCR) and event-free survival (EFS).
Of the >600 expression signatures tested, 10 were significantly associated with both pCR and EFS. Five immune-related signatures were associated with higher pCR and better outcome: a T-helper signature (OR = 5.1, HR = 0.22, both p < 0.05), 2 IgG signatures (OR = 2.2 and 1.72, HR = 0.61 and 0.70 respectively, all p < 0.05) and 2 B-cell signatures (OR = 1.63 and 1.27, HR = 0.74 and 0.81 respectively, all p < 0.05). Patients with a high IgG-signature showed a significant higher pCR rate when treated with a trastuzumab combination regimen (58% vs. 34%, p 0.001). The Ig heavy chain γ (IGHG) was the most abundant isotype (median counts = 4,800). Patients without assembled IGHG or a high evenness showed a significantly lower pCR rate (27% vs. 54%, p < 0.001 and 12% vs. 59%, p < 0.001, respectively). Patients with high IGHG counts also showed a significant EFS benefit at 5 years (log rank 0.03).
B-cell gene expression signatures have a relevant predictive and prognostic value in CALGB 40601. The clinical implementation of these biomarkers could help us to design new neoadjuvant treatment strategies for HER2+ breast cancer.
NCT007708.
Alliance of Clinical Trials.
U10CA180821, U10CA180882, U24CA196171, P50-CA58223, GSK, SPORE, BCRF and SEOM.
C.M. Perou: Advisory / Consultancy, Shareholder / Stockholder / Stock options: BioClassifier LLC; Licensing / Royalties, Inventor on patent applications: Breast PAM50. All other authors have declared no conflicts of interest.
Stromal tumor-infiltrating lymphocytes (sTILs) have been shown to be a strong prognostic factor in early-stage triple negative breast cancer (TNBC). There is limited data on their prognostic value in TNBC patients in the absence of adjuvant chemotherapy.
We performed a pooled analysis of TNBC patient series not treated with chemotherapy. The percentage infiltration of sTILs was retrospectively evaluated in the most representative tumoral block of surgical specimens. Cox proportional hazards regression models stratified by series were used for invasive disease-free survival (iDFS), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.
We collected individual data from 518 patients from four series. Average age was 64 years (range, 24 to 96 years), and 83% of patients were node-negative. The median size was 1.6 cm (Q1-Q3: 1.6-2.5), and 82.7% of the cases were node-negative. Tumours were grade 1, 2 and 3 in 12%, 38% and 50% of the cases. The median level of sTILs was 10% (Q1-Q3, 4-30%). Higher grade was associated with larger amount of sTILs (p < 10-3). During follow-up, a total of 173 iDFS, 118 D-DFS events and 107 deaths were observed. In the multivariable model which included the number of lymph nodes, tumour size, age, tumour grade and radiotherapy treatment, sTILs added significant independent prognostic information for all endpoints (likelihood ratio chi2= 7.14 for iDFS; p < 10-2; chi2= 9.63 for D-DFS, p < 10-2; chi2= 5.96 for OS, p = 0.015). Each 10% increment in sTILs corresponded to a hazard ratio of 0.90 (95% CI, 0.82 to 0.97) for iDFS, 0.86 (95% CI, 0.77 to 0.95) for D-DFS, and 0.88 (95% CI, 0.79 to 0.98) for OS. In patients with stage I tumors with sTILs≥30% (n = 74), 5-year iDFS was 91% (95% CI, 84% to 98%), D-DFS was 97% (95% CI, 93% to 100%), and OS was 98% (95% CI, 95% to 100%).
sTILs provide important prognostic information in systemically untreated early stage TNBC patients. sTILs may be used to identify stage I TNBC patients with excellent prognosis in whom chemotherapy may be withheld.
The authors.
ANR and CGI (RHU MyPROBE, ANR-17-RHUS-0008).
M.V. Dieci: Advisory / Consultancy: Lily, Celgene, Genomic Health. C. Criscitiello: Honoraria (self), for speaker engagements and consultancy roles: Pfizer; Honoraria (self), for speaker engagements and consultancy roles: Roche; Honoraria (self), for speaker engagements and consultancy roles: Lily; Honoraria (self), for speaker engagements and consultancy roles: Novartis. R.F. Salgado: Travel / Accommodation / Expenses, travel support: Roche, Merck, AstraZeneca; Travel / Accommodation / Expenses, congress support: Roche, Merck; Research grant / Funding (self), Data and safety monitoring member: Roche, Merk, Puma; Advisory / Consultancy, Advisory board: Roche, BMS. S. Loi: Research grant / Funding (institution): Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology ,Pfizer and Eli Lilly; Advisory / Consultancy, but not compensated: Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech. S. Kim: Research grant / Funding (institution): Novartis, Sanofi-Genzyme, Dongkook Inc. G. Curigliano: Honoraria (institution), institutional fees from them: Merck, Roche, SEAGEN, Daichi Sankyo, Novartis, Pfizer. F. André: Research grant / Funding (institution): Pfizer, AstraZeneca, Novartis, Lilly, Roche, daiichi; Advisory / Consultancy: Pfizer, AstraZeneca, Novartis, Lilly, Roche, daiichi. S. Michiels: Advisory / Consultancy, punctual statistical advice: IDDI, Belgium; Advisory / Consultancy, advice on surrogacy: Janssen Cilag France; Advisory / Consultancy, Data and safety monitoring member: Hexal, J&J, Ipsen, Neovacs, Genticel, Mabxience, Steba, IQVIA, Roche, Sensorion, Biophytis. All other authors have declared no conflicts of interest.