Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Abstract

The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. Significance: Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials. See related commentary by Eggermont et al., p. 2677. This article is highlighted in the In This Issue feature, p. 2659

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

“…It will be very interesting to compare PFS and OS of both platforms according to both ranking systems at the time the ZERO program is going to publish long-term follow-up, too (currently only response data are available) (17). When comparing with classification systems used by adult oncology platforms like MASTER, which applies a similar molecular diagnostic platform as INFORM, one notices that most systems rely on clinical evidence (28). For example, the highest level used in MASTER (NCT/DKTK level m1A) is based on data from a prospective study or a meta-analysis in the same tumor type (29).…”

Transcriptomic profiling in canines and humans reveals cancer specific gene modules and biological mechanisms common to both species

“…The success of our models in classifying PULM, MEL, OSA, BLSA, TLSA, and BLSA, among 10-15 additional cancers considered, bodes well for these larger computation. See Li et al [68], Newton et al [72], and others [73,74] as examples of efforts similar in scope to those currently discussed.…”

Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype

“…Importantly, such PIK3CA mutant-independent and/or non-genetic mechanism of PI3K pathway activation will be captured by the transcriptional footprint-based PI3K signaling scores used in our study and will thus contribute to the values observed in non- PIK3CA mutant tumors. More generally, the diagnostic and therapeutic benefits of combined, comprehensive genomic and non-genomic analyses were recently demonstrated in patients with rare cancers [ 49 ], and are worth considering in the context of breast and other cancers where PI3K pathway alterations feature prominently [ 3 ].…”