NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU

Abstract

Purpose Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported. Methods All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations. Results 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4 months. Conclusion In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials. Trial registration number 284-10 (03.05.2018).

Next-Generation Sequencing-Directed Therapy in Patients with Metastatic Breast Cancer in Routine Clinical Practice

“…In total, 17 were off-label treatment and 10 (58.8%) of these induced a PFS ratio > 1.3; 15 agents were on-label treatment and 5 of these (33.3%) induced a PFS ratio > 1.3, demonstrating a clinical benefit of on-label and off-label therapy determined by NGS. Out of 30 patients, 13 (43.3%) demonstrated a PFS ratio > 1.3; other investigations with a similar intention showed comparable results (44% [ 28 ] and 44.4% [ 11 ]) or a lower proportion (30%, [ 29 ]) of mBC patients with improved PFS under matched therapy. In the 15 cases who started therapy with the mTOR inhibitor everolimus, mostly in combination with exemestan, the best response was SD in 3 patients.…”

“…It has been previously pointed out that only in a subgroup of advanced cancer patients who initially had been assigned to molecular profiling, sequencing-directed therapy was pursued [ 11 , 31 ]. In our analysis, 31.6% of the total cohort and 36.1% of those with actionable alterations were started on matched therapy.…”

“…However, off-label therapy with olaparib in a patient with a BRCA1/2 wild-type status but a germline PALB2 mutation, as identified by next-generation sequencing (NGS), resulted in a remarkable response [ 9 ]. Even beyond the scope of case reports, the use of companion diagnostics covering a large set of cancer-related genes, followed by on-label or off-label genotype-matched treatment, has prolonged PFS in about 40% of patients with refractory disease [ 10 , 11 ], or increased the objective tumor response rate [ 12 ] in patients with a variety of advanced solid tumors. Some alterations detected by molecular profiling, e.g., deletion of PIK3CA exons 7, 9, and 20 with a therapeutic recommendation for alpelisib in patients with mBC, are listed in clinical guidelines [ 13 ].…”

The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers

“…It has provided a platform for comprehensive molecular analysis of gynecologic malignancies and has revealed a wide spectrum of mutations and molecular differences, which can be exploited in different arenas, such as understanding of pathogenesis, accurate diagnosis and also targeted therapy [ 4 , 5 , 6 , 7 ]. Currently, NGS testing is largely performed on patients who fail to respond to traditional regimens or disease progression [ 8 , 9 ]. While this technology has been widely implemented, there are no standard recommendations from scientific bodies about its utilization in daily clinical practice.…”

“…Though the utility of NGS testing is gaining popularity in oncology clinical practice, there have been few studies evaluating its impact on treatment response or patient survival. In the literature, the benefits in gynecologic cancer treatment have been viewed as debatable [ 8 , 19 , 20 , 21 ]. This could be due to various reasons, including: (a) differences in the rate of utilization of the NGS test depending on whether the test is performed in-house or is outsourced; (b) low frequency of actionable mutations in gynecologic tumors; (c) optimal timing, whether the tumor is newly diagnosed, recurrent or metastatic as patterns of genomic alterations may differ; (d) patient clinical status or how well the patient can tolerate targeted therapy and whether they had been previously heavily treated; (e) broader or narrower sequencing approaches; (f) diversity of tumor types; (g) accessibility of the targetable drugs (often off-label drugs), and (h) intra- and inter-patient heterogeneity, among others.…”