Real-World Data From a Molecular Tumor Board: Improved Outcomes in Breast and Gynecologic Cancers Patients With Precision Medicine

Abstract

Purpose: Next-generation sequencing is increasingly used in gynecologic and breast cancers. Multidisciplinary Molecular Tumor Board (MTB) may guide matched therapy; however, outcome data are limited. We evaluate the effect of the degree of matching of tumors to treatment as well as compliance to MTB recommendations on outcomes.

Methods: Overall, 164 patients with consecutive gynecologic and breast cancers presented at MTB were assessed for clinicopathologic data, next-generation sequencing results, MTB recommendations, therapy received, and outcomes. Matching score (MS), defined as percentage of alterations targeted by treatment over total pathogenic alterations, and compliance to MTB recommendations were analyzed in context of oncologic outcomes.

Results: Altogether, 113 women were evaluable for treatment after MTB; 54% received matched therapy. Patients with MS ≥ 40% had higher overall response rate (30.8% v 7.1%; P = .001), progression-free survival (PFS; hazard ratio [HR] 0.51; 95% CI, 0.31 to 0.85; P = .002), and a trend toward improved overall survival (HR 0.64; 95% CI, 0.34 to 1.25; P = .082) in univariate analysis. The PFS advantage remained significant in multivariate analysis (HR 0.5; 95% CI, 0.3 to 0.8; P = .006). Higher MTB recommendation compliance was significantly associated with improved median PFS (9.0 months for complete; 6.0 months for partial; 4.0 months for no compliance; P = .004) and overall survival (17.1 months complete; 17.8 months partial; 10.8 months none; P = .046). Completely MTB-compliant patients had higher MS (P < .001). In multivariate analysis comparing all versus none MTB compliance, overall response (HR 9.5; 95% CI, 2.6 to 35.0; P = .001) and clinical benefit (HR 8.8; 95% CI, 2.4 to 33.2; P = .001) rates were significantly improved with higher compliance.

Conclusion: Compliance to MTB recommendations resulted in higher degrees of matched therapy and correlates with improved outcomes in patients with gynecologic and breast cancers.

FIG 1.

Representative case of metastatic high-grade serous adenocarcinoma of likely gynecologic (favor tubo-ovarian) primary managed with matched targeted combination therapy approach. This is a 68-year-old woman who initially noticed enlargement of a right groin node (study ID: 4275). Biopsy was consistent with metastatic high-grade serous adenocarcinoma. CT showed multiple enlarged abdominal lymph nodes (left), with no obvious primary tumor on positron emission tomography. She was counseled on options for standard-of-care therapy with paclitaxel and carboplatin or enrollment in clinical trial. Tissue molecular profiling through Foundation Medicine showed alterations in NF1 R440*, CCND2 amplification, CCNE1 amplification, KDM5A amplification, and TP53 T231fs*9. Tumor mutation burden was low (3 mutations per megabase), microsatellite stable, and PD-L1 by immunohistochemistry showed low positivity (5%, Ventana SP142). The case was discussed at the Molecular Tumor Board with suggestion of trametinib (MEK inhibitor for NF1 R440*) and nivolumab (anti–programmed death 1 inhibitor for PD-L1 positivity). Patient also gave informed consent for an open-label navigational I-PREDICT study (ClinicalTrials.gov identifier: NCT02534675). The patient was started on trametinib 1 mg by mouth daily and nivolumab 240 mg intravenous every 2 weeks. CT 2.5 months after therapy was initiated showed partial response (left to right, best response 53% reduction by RECIST 1.1). Along with the reduction of tumor, tumor markers also normalized (CA153 before the therapy: 68.5 U/mL, nadir: 25 U/mL [normal range: 0-25 U/mL], CA125 before the therapy: 80 U/mL, nadir: 12 U/mL [normal range: 0-34 U/mL]). The patient tolerated the therapy well without major drug-related adverse events (experienced grade 1 rash). Treatment is ongoing for 19 months at the time of last follow-up. CA, cancer antigen; CT, computed tomography; I-PREDCIT, Investigation of molecular Profile-Related Evidence Determining Individualized Cancer Therapy for patients with aggressive malignancies; PD-L1, programmed death-ligand 1.

FIG 2.

Survival outcomes by MS and compliance to MTB recommendations. (A) PFS by MS reflecting degree of matching (see Methods; n = 113 patients). The median PFS for the whole cohort was 5.1 months (95% CI, 3.8 to 6.4) and by MS category: 0%-39% 3.9 months (95% CI, 2.9 to 4.8) and 40%-100% 9.3 months (95% CI, 6.8 to 11.8). Higher MS was statistically significantly related to longer PFS (Wilcoxon P = .002). HR was calculated by Cox regression. (B) OS by MS reflecting degree of matching (see Methods; n = 113). The median OS for the whole cohort was 12.9 months (95% CI, 9.0 to 16.8) and by MS category: 0%-39% 11.9 months (95% CI, 9.7 to 14.1) and 40%-100% 18.8 months (95% CI, 14.8 to 22.8; Wilcoxon P = .08). (C) PFS according to the compliance to recommendation of MTB. Median PFS by compliance with MTB recommendation: all recommendations followed 9.0 months (95% CI, 7.7 to 10.3), part of recommendations followed 6.0 months (95% CI, 4.0 to 8.0), and physician's choice (did not follow any recommendations) 4.0 months (95% CI, 2.9 to 5.1; Wilcoxon P = .004). HR was calculated by Cox regression. (D) OS according to the compliance to recommendation of MTB. Median OS by compliance with MTB recommendation: all recommendations followed 17.1 months (95% CI, 10.1 to 24.1), part of recommendations followed 17.8 months (95% CI, 9.2 to 26.4), and physician's choice (did not follow any recommendations) 10.8 months (95% CI, 8.0 to 13.6; Wilcoxon P = .046). HR was calculated by Cox regression. HR, hazard ratio; MS, matching score; MTB, Molecular Tumor Board; OS, overall survival; PFS, progression-free survival.

FIG 3.

Response rates in patients whose therapy changed after Molecular Tumor Board stratified by MS reflecting degree of matching (see Methods; n = 111 patients [two patients were excluded from the analysis, given SD ongoing at < 6 months of follow-up]) Patients who had MSs ≥ 40% (n = 26) were more likely to have favorable clinical response than patients who had MSs < 40% (n = 85): ORR is defined as CR or PR (P = .001). Clinical benefit rate includes SD for ≥ 6 months, PR, and CR (P < .001). See also Table 3. Because of rounding, numbers do not add to 100% in cohort with MS < 40%. CR, complete response; MS, matching score; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Molecular Tumor Board–guided matched therapy correlated with improved breast and gynecologic cancer outcomes

FIG A1.

CONSORT diagram of patients with breast (n = 129) and GYN (n = 36) cancers presented at MTB. ^aTwo patients (1.2% of 165) were also part of the published IPREDICT study; the majority of patients were different because the IPREDICT study included a face-to-face MTB as well as an electronic MTB, although this study includes only patients presented in a face-to-face MTB. GYN, gynecologic; MTB, Molecular Tumor Board.