Background: Patients with clinically HER2−positive (clinHer2+) tumors often receive trastuzumab in combination with chemotherapy as their standard of care. This study sought to determine the predictive value of the HER2−enriched (HER2−E) molecular subtype for sensitivity to neoadjuvant anthracycline/taxane containing chemotherapy and a trastuzumab plus taxane-based regimen within clinHer2+ disease. Materials and methods: Gene expression data on pre-treatment fresh-frozen tumor tissues were collected from a combined cohort of MDACC/I-SPY trial (GSE25055/65), and the XeNA trial (GSE22358). Patients from MDACC/I-SPY were treated with doxorubicin/cyclophosphamide (AC) or 5-fluorouracil/epirubicin or doxorubicin/C (FEC or FAC) sequentially with paclitaxel. All patients from XeNA received capecitabine/docetaxel (and trastuzumab if clinHer2+). Intrinsic subtypes were determined using PAM50. Chisquare test and multivariable logistic regression analysis were used to test significance of association between subtype and pathological complete response (pCR or residual cancer burden [RCB] 0/1) and residual disease (RD or RCB2/3) adjusted with pre-treatment tumor size. Kaplan Meier was used for distant relapse-free survival (DRFS) estimates. Results: For the MDACC/I-SPY cohort (n=595), pCR rates for intrinsic subtypes were 3% (5/168) for LumA, 16% (14/90) for LumB, 33% (23/69) for HER2−E and 37% (76/208) for Basal-like. Tumors achieving RCB0/1 were significantly associated with better DFRS compared to those tumors with RCB 2/3, even within each intrinsic subtype. The 5-year DFRS for HER2−E with RCB0/1 and RCB2/3 was 100% and 31% (p=0.007), respectively. ClinHer2+ status was also significantly associated with pCR (34% vs. 19%, p=0.016). Strikingly, among the clinHer2+ tumors (n=47), 75% (12/16) of the responders were classified as HER2−E (Table 1A) and those tumors that were clinHer2+/HER2−E had 6 times odds to achieve pCR when compared to clinHer2+/non-HER2−E. In the XeNA trial (n=122), the HER2−E subtype was significantly associated with response, composing 85% (7/8) of the clinHer2+ who achieved a pCR. Finally, clinHer2+/HER2−E tumors were 34 times more likely to achieve pCR than clinHer2+/non-HER2−E tumors (Table1B). Conclusion: The sensitivity of clinHer2+ tumors to neoadjuvant anthracycline/taxane-based regimens, and trastuzumab-based chemotherapy is mainly contained within tumors of the HER2−E subtype. Given that this molecular subtype cannot simply be recapitulated using clinical ER and HER2 status, our results highlight the importance of identifying patients with HER2−E tumors as this appears to greatly enrich for responsiveness and treatment benefit. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-2.
LBA515 Background: I-SPY is a multi-center trial designed to identify predictive markers of pathological complete response (pCR) and survival of women with locally advanced breast cancers (3cm or greater). Women received neoadjuvant doxorubicin and cyclophosphamide then paclitaxel. Methods: 237 women enrolled, 216 completed serial imaging and core biopsies. Pre-treatment assays include: Agilent expression arrays, MIP aCGH, p53 gene chip and sequencing, IHC and reverse phase protein arrays (RPMA). Response to therapy was measured by serial MRI, pCR and residual cancer burden (RCB). Associations among molecular markers, pCR, RCB and survival were evaluated using chi-square test, Kaplan-Meier curves and log-rank test. Results: Median tumor size was 6cm, % pCR and RCB 0/1 was 27% and 36% for the entire study; % pCR rate for the 144 Agilent arrays was 25%. Distribution, rates of pCR and RCB 0/1 are shown in the Table for molecular and IHC markers. DFS and OS will be presented. Several molecular subtypes, including NKI 70 gene low, luminal A, 21 gene set low and IHC HR+, define 15–28% of patients with 3–10% pCR, yet excellent early survival. Wound healing, most discriminatory for prognosis, is not predictive of chemotherapy response. By RPMA, patients with pCR had increased phosphorylation of 4EBP1, eNOS, cAbl, STAT5, EGFR, AKT (p<0.05). In ER+ patients with poor MR response, pIRS, pIGFR, p706S were activated (p<0.05). RCB is a more refined way to measure pCR and was more predictive of DFS and OS (p=0.01) than pCR alone with a mean follow up of 3.9 years. MR volume is highly predictive of pCR and RCB. For specific subtypes, e.g. basal, RCB is predictive of DFS (p<0.00001). Conclusions: LABC have aggressive biology. Response to therapy and outcome can be predicted by many biomarkers. The I-SPY data set provides a platform to compare, contrast and combine marker signatures to tailor therapy and demonstrates the power of the neoadjuvant setting. Support: ACRIN U01 CA079778 ; CALGB CA31964, CA33601; NCI SPORE CA58207. [Table: see text] [Table: see text]
Background TNT previously reported that patients(pts) with advanced triple negative breast cancer(TNBC) and germline BRCA1/2(gBRCA+) mutations are more likely to respond to carboplatin(C) than to docetaxel(D), and have longer progression-free survival with C. Here, we report results from a pre-planned biological analysis to test whether BRCA silencing or methylation status confer sensitivity to platinum. Methods Pts eligible for TNT had ER-, PgR-, HER2- BC or were known gBRCA+(any ER/PgR/HER2). Pts were randomized to C(AUC 6 q3wk) or D(100mg/m2 q3wk) for 6-8 cycles or until disease progression if sooner, with crossover possible on progression. Blood and archival tissue samples were requested for BRCA1/2 genotyping, central analysis of TN and DNA repair deficiency biomarkers. Primary endpoint was intention-to-treat objective response rate(ORR) up to cycle 6. BRCA1 mRNA level was estimated from whole-genome total RNA sequencing(RNA-Seq). BRCA1 methylation analysis was quantified by bisulfite sequencing. A methylation score for the sample was computed as percentage of methylated reads relative to total number of reads that were either methylated or not methylated for CpG sites. A sample with a score >10% was considered methylated(BRCA1meth)? a BRCA1 mRNA level "silenced" subgroup(BRCA1 silencing) was defined as value of log2(mRNA)<8.4, based on bimodal distribution. Results 212 and 191 pts' samples were assessed for BRCA1 methylation and mRNA levels. 33 pts (15.6%) were found to be BRCA1meth. Pts with BRCA1meth had a better response to D (42%, 95%CI: 20, 64) than C (21%, 95%CI: -0.1, 43)? absolute difference (C-D) -21% (95%CI: -52, 10)? p=0.28), but not statistically significant. There was no evidence of a difference when gBRCA+ tumours were excluded. 31 pts (16%) had BRCA1 silencing. Concordant with BRCA1meth, pts with BRCA1 silencing had a better response to D (65%, 95%CI: 42, 87) than C (29%, 95%CI: 4.9, 52)? absolute difference (C-D) -36% (95%CI: -69, -3.3)? p=0.07), with an odds ratio 0.22 (95%CI: 0.035, 1.2) in favor of D, interaction with treatment not significant (p=0.066). 19 pts with BRCA1meth and BRCA1 silencing had a better response to D (60%, 95%CI: 30, 90) than C (22%, 95%CI: -5.0, 49)? absolute difference (C-D) -38% (95%CI: -79, 2.9) in favor of D (p=0.17), and the interaction was not significant (p=0.15). Further exploratory analyses examining any relationship between a response to C and new cutpoints for BRCA1meth or BRCA1 mRNA level did not suggest any evidence of a signal. Conclusion Our data did not support a priori hypotheses that BRCA1 methylation or silencing would be associated with a greater response to C than D, which is consistent with other reports in ovarian cancer. As BRCA1 methylation will not always lead to significant silencing or be the only cause of low BRCA1 gene expression, exploratory analysis is investigating the interaction of BRCA silenced group with D sensitivity. RNA-seq is ongoing and results from the final database will be presented. Citation Format: Tutt A, Cheang MCU, Kilburn L, Tovey H, Gillett C, Pinder S, Lanchbury J, Abraham J, Barrett S, Barrett-Lee P, Chan S, Gazinska P, Grigoriadis A, Kernaghan S, Hoadley K, Gutin A, Harper-Wynne C, Hatton M, Owen J, Parker P, Roylance R, Shaw A, Smith I, Thompson R, Timms K, Wardley A, Wilson G, Harries M, Ellis P, Ashworth A, Perou C, Bliss J, Rahman N, Brown R, On Behalf of the TNT Trial Management Group and Investigators. BRCA1 methylation status, silencing and treatment effect in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-01.
Background: Intrinsic breast cancer subtypes determined by the PAM50 assay are reported to be prognostic independent of standard clinicopathological variables. The CALGB (Alliance) 9741 adjuvant trial randomized treatment in a 2×2 factorial design to (i) 2-wk (dose dense; DD) vs 3-wk therapy and (ii) sequential vs concurrent doxorubicin, cyclophosphamide, paclitaxel (A>T>C vs AC>T). DD therapy improved disease-free survival and overall survival (OS) (Citron et al. JCO 2003.). A significant interaction between intrinsic breast cancer subtypes and the use of DD therapy was hypothesized. Methods: C9741 was conducted in collaboration with ECOG, NCCTG, and SWOG. Biospecimens were collected from 1652 of 2005 subjects. Multiplexed gene expression profiling (NanoString Technologies, Inc) generated PAM50 subtype calls (luminal A, luminal B, HER2-enriched, basal-like), risk of relapse (ROR) score, and proliferation score for 1321 cases (80%). Excluded samples were due to insufficient tumor (n = 181) or RNA (n = 150). The primary endpoint was relapse-free survival (RFS). The primary analysis to determine if the clinical benefit of DD therapy is dependent on intrinsic subtype was conducted as a test of interaction in a Cox proportional hazards model (3 degrees of freedom, df; alpha=0.05). Similar analyses were performed for ROR score and proliferation score as continuous measures of risk (1 df). PAM50 subtype, ROR score, and proliferation score were evaluated in separate multivariate models adjusting for number of positive nodes, menopausal status, dose density, and sequence of therapy. Results: Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete dataset (HR = 1.20; 95%CI 0.99–1.44) with a median follow-up of 12.3 yrs. Subtype analysis identified 32% luminal A (n = 417), 26% luminal B (n = 341), 20% HER2-enriched (n = 267), and 22% basal-like (n = 296). Intrinsic subtypes were prognostic of RFS (p < 0.0001) irrespective of treatment assignment with HRs relative to the luminal A subgroup of 1.50 (luminal B), 1.70 (HER2-enriched) and 1.66 (basal-like). No subtype specific treatment effect on RFS was identified (p = 0.44). ROR scores (range 0–100, median 60) were also prognostic of RFS (HR = 1.12 for a 10-unit change; 95% CI 1.07–1.18; p < 0.0001), but no association with DD therapy benefit was seen (p = 0.58). Similar results were obtained for the proliferation score, for OS as a secondary endpoint, and from multivariate models with clinical covariates. Conclusion: The prognostic value of PAM50 subtype, ROR score, and proliferation score remains highly significant in patients treated with contemporary adjuvant anthracycline and taxane based chemotherapy. Intrinsic subtype did not predict for improved survival with the 2-wk DD vs 3-wk treatment schedule; we hypothesize that this is because the prognostic differences by subtype outweighed the modest but significant clinical benefit of DD chemotherapy administration for the overall population. Planned clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize systemic therapy regimens based on the expected risk of distant recurrence. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-01.
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