Clinical Next-Generation Sequencing for Precision Oncology in Rare Cancers

Abstract

The European Society for Medical Oncology defines rare cancers as 5 or fewer cases per 100,000 persons per year. For many rare cancers, no standard of care exists, and treatment is often extrapolated. Identifying potentially targetable genomic alterations in rare tumors is a rational approach to improving treatment options. We sought to catalog these mutations in rare tumors and to assess their clinical utility.For this retrospective analysis, we selected rare tumor patients from a dataset of patients who underwent clinical tumor genomic profiling. Sarcomas were excluded. To index potentially actionable alterations, patients' reports were reviewed for mutations in cancer-associated genes and pathways. Respective clinical records were abstracted to appraise the benefit of using a targeted therapy approach. Actionable alterations were defined as targeted by a drug available on-label, off-label, or in clinical trials.The 95 patients analyzed had 40 different tumor subtypes, most common being adenoid cystic (13%), cholangiocarcinoma (7%), and metaplastic breast (6%). At least one genomic alteration was identified in 87 patients (92%). The most common identifiable mutations were in (23%), (10%), (9%), (8%), (7%), (7%), and (6%). Thirty-six patients (38%) with 21 different tumors had at least one potentially actionable alteration. Thirteen patients received targeted therapy. Of these, 4 had a partial response, 6 had stable disease, and 3 had progressive disease as the best response.The addition of genomic profiling to management of rare cancers adds a potential line of therapy for cancers that have little or no standard of care. In our analysis, tumors with a alteration responded well to inhibitors..

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

“…The presence of mutations in PIK3CA in nearly 50% of cases suggests that they are not only different to IC‐NST but may also represent a unique subgroup, as the PIK3CA mutation frequency in other BL/TN breast cancers is only ∼8% . Apart from PIK3CA , exome and targeted sequencing studies have revealed frequent mutations in TP53 (69%), PIK3R1 (11%), ARID1A (11%), FAT1 (11%), and PTEN (11%) , and possibly also NOTCH and MCL1 . Interestingly, a very high frequency (97.5%; 39/40) of A14V mutations in ribosomal protein L39 has also been reported in a CAST PCR study , which may have implications for the therapeutic application of nitric oxide synthase inhibitors.…”

Phosphatidylinositol 3‐kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities

“…Rare cancers for which, to our knowledge, comprehensive genomic profiles have not been previously published by The Cancer Genome Atlas (TCGA) (although some have been reported outside of TCGA), include adenoid cystic, anus, neuroendocrine, nonmelanoma skin, salivary gland, small intestine, thyroid, vaginal and vulvar, and unknown primaries (Fig. A‐I).…”

“…We also focused on reporting PI3K pathway alterations in rare tumor types, for which few or no studies are available . Overall, PIK3CA continues to be the most frequently altered gene, predominantly in squamous cell histologies, including anal (32%), vulvar (23%), and unknown primary (22%) sites.…”

How many samples are needed to infer truly clonal mutations from heterogenous tumours?

“…Targeting "driver mutations" in cancer is considered an important new approach to therapy that takes into consideration a varied mutational landscape present in tumours, even when arising in the same tissue [34][35][36]. The paradigm set by TKI therapy of CML and ALK inhibition in a small subset of patients with non-small cell lung cancer is quite compelling.…”