Translating advances in molecular oncology to the bedside
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Cancer can be a very personal and individualized disease, with predictable and unpredictable outcomes.
Precision medicine has been touted as the next gold standard in oncology, utilizing personalized medicine prescribed for targetable mutations in individual diseases.
However, the compilation of patient genomic data continues to hold value in our collective understanding of the complex genetics of cancer. As we learn more about the pathogenesis of cancer, our ability to tailor individual cancer therapy to target genetic lesions subsequently increases.
Recent advances in basic science, cloud computing and clinical care have led to changes in practice guidelines and stand to transform cancer care.
PCAWG Consortium
In a collection of papers published in February in Nature and other Nature journals, interpersonal communication and cooperation on a global scale yielded groundbreaking advances in our understanding of oncology.
In the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, more than 700 scientists scattered across four continents analyzed 2,778 cancer genomes from 2,658 patients — paired with matched normal samples — as well as 1,188 matched transcriptomes.
The international group detailed multiple findings, ranging from the summation of coding and noncoding somatic driver mutations, to the detection of structural variations in all 2,658 patient samples using whole-genome sequencing.
The authors developed ShatterSeek, a method to detect chromothripsis, which is the massive, near-random rearrangement of chromosomal regions after a genetic catastrophic event. The relationships of chromothripsis with aneuploidy and with copy number changes in both oncogenes and tumor-suppressor genes uncovered layers of complexity in the transformation from cell to cancer.
In another paper, the researchers interpreted the evolutionary history of cancer driver mutations in their data set by harnessing the power of numbers to time mutation clusters.
The authors also catalogued a comprehensive collection of mutational signatures in cancer associated with environmental exposures. Included in their collection of publications were analyses describing mitochondrial genomes, hypoxia-associated mutational processes and viral insertions into cancer genomes.
The massive scale of this effort required 16 working groups, innumerable processing hours, and cloud computing to bring this collaboration to fruition. The data from the PCAWG study are publicly available for download in VCF-format files and aligned BAM files to scientists and researchers for further analysis.
From this research, our understanding of cancer, its pathogenesis and targetable weaknesses can be distilled to further advance oncology therapy applied in the clinical setting.
Tumor-agnostic therapy
An example of how our improved understanding of cancer has been applied to the clinical setting can be seen with tumor-agnostic treatment, a concept that is relatively new and has developed alongside the field of molecular oncology.
Applying tumor-derived genomic information to alter clinical management of chemotherapy regimens was heralded in 2017, with the FDA approval of pembrolizumab (Keytruda, Merck) for adults and children with progressive tumors with DNA mismatch repair deficiency or microsatellite instability-high lesions.
The approved handful of tissue- or tumor-agnostic therapies also includes nivolumab (Opdivo, Bristol-Myers Squibb) for microsatellite instability-high and DNA mismatch repair-deficient tumors, and larotrectinib (Vitrakvi, Bayer) and entrectinib (Rozlytrek, Genentech) for NTRK gene fusions.
Pembrolizumab received an additional FDA approval in June for adults and children with tumor mutational burden-high (TMB-H; defined as tumor mutation 10 mut/Mb) solid tumors, presenting another application of tumor-agnostic therapy.
Data from the prospectively planned, retrospective analysis of the nonrandomized, multicenter KEYNOTE-158 trial supported this approval, demonstrating a 4% complete response rate and 25% partial response rate among the 15.9% of patients with TMB-H tumors. The ORR for these patients was 29% (95% CI, 21-39), with median follow-up of 11.1 months.
Median duration of response was not reached (range, 2.2+ to 28.8+ months), but 57% of patients showed durable responses for at least 12 months, and 50% of patients had durable responses for 24 months or longer.
Germline, somatic mutational testing in ovarian cancer
Molecular oncology findings also contribute to practice guideline changes, leading to overarching advancement in patient care.
An example is the release of a new recommendation from ASCO for epithelial ovarian cancer testing. Well-described in large-scale studies is the necessity for germline testing of BRCA1, BRCA2 and other ovarian cancer susceptibility gene mutations in newly diagnosed patients, as part of a cancer predisposition workup.
As shown in the 2018 SOLO1 trial, maintenance therapy with PARP inhibitors led to higher rates of PFS among women with somatic BRCA1- and BRCA2-mutated tumors. Based on these data, the ASCO guidelines recommend somatic tumor testing for pathogenic/likely pathogenic BRCA1 and BRCA2 mutations to be able to offer therapeutic options with FDA-approved medications, such as PARP inhibitors.
In addition, ASCO advises women with clear cell, endometrioid and mucinous ovarian cancer to undergo somatic tumor testing for DNA mismatch repair mutations, which can guide therapy using targeted immune checkpoint inhibition with FDA-approved drugs.
New frontiers
These topics highlight the exciting developments of molecular oncology as it bridges basic science and clinical care, leading to practice guideline changes.
The field continues to develop as our understanding of the complexities of cancer genomics grows. The scientific community stands on the cusp of new frontiers for cancer care, aided by our increasing knowledge of molecular oncology.
References:
ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Nature. 2020;doi:10.1038/s41586-020-1969-6.
Konstantinopoulos PA, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.02960.
Marabelle A, et al. Ann Oncol. 2019;doi:10.1093/annonc/mdz253.018.
Marabelle A, et al. J Clin Oncol. 2020;10.1200/JCO.19.02105.
Moore K, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1810858.
For more information:
Wen-I (Wendy) Chang, MD, is assistant professor at The Warren Alpert Medical School of Brown University and attending physician at Hasbro Children’s Hospital. She can be reached at 593 Eddy St., Providence, RI 02903; email: wen-i_chang@brown.edu.
To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com.
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