Unique Questions Associated With the Increasing Prominence of Precision/Genomic Medicine in Routine Cancer Care

The speed of our knowledge expansion regarding the molecular basis of cancer— which has transformed essentially all aspects of malignant disease management, from risk assessment and prevention to the role of tumor-agnostic antineoplastic drug delivery—has been nothing short of breathtaking.

It is sometimes difficult to remember that it was not that long ago when the only tool available to assign a potentially meaningful genetic risk of cancer was a detailed family history, assuming this information was available. Further, there were quite limited implications that such an assessment might favorably affect individual patient clinical outcomes, and there was even less utility for cancer prevention efforts for possibly affected relatives. Fortunately, this state of affairs has rather dramatically changed with the widespread availability of detailed germline and somatic tumor testing, which have become standard of care in multiple settings.

Not surprisingly, along with these scientific and clinical developments come additional questions unique to this specific arena, some very practical and others quite conceptual in nature but still requiring at least an attempt to provide rational responses.

For example, in the first category, the practical, one might directly ask, “How quickly is it necessary to obtain the results of genetic tests for an individual patient with cancer?” In the second category, the conceptual, it is reasonable to inquire why BRCA mutations, recognized for their deleterious influence on the lifetime risks for the development of breast and ovary cancers, have from an evolutionary perspective persisted within the general population.

What follows is an attempt by this commentator to provide brief responses to these provocative questions.

Regarding the issue of testing timing, it is essential to divide the issue into several clinical scenarios based on the desired use of the molecular data.

1. If the data inform immediate therapeutic choices (eg, the presence or absence of an EGFR mutation or ALK rearrangement within a metastatic non– small cell lung cancer), data realistically need to be available quickly and certainly within days following receipt of the specimen by a testing laboratory. Rapid reporting is essential to avoid delaying treatment or causing the treating oncologist to initiate inappropriate cytotoxic chemotherapy, which may compromise survival when a molecularly targeted therapeutic is indicated.1
2. If the testing is being employed to examine for the presence of a possible future option (eg, next-generation sequencing for less common cancer-specific molecular abnormalities or uncommon tumor-agnostic drug indications), the timeline for obtaining the test results might realistically be extended in most circumstances to a number of weeks or even longer. Further, if the oncologist is considering testing for the selection of a maintenance targeted therapy (eg, a PARP inhibitor in BRCA-mutant or homologous recombination–deficient ovarian cancer), it would not be unreasonable to wait to test until a meaningful response to the primary cytotoxic chemotherapy program has been observed and it is clear the patient will be a potential candidate for this approach.
3. Finally, if the testing is being undertaken to assess for the presence of a germline abnormality, with implications for both patients and their families, it would not be inappropriate to delay testing until necessary discussions have been held and questions addressed to ensure the implications of the possible findings have been considered for both patient and the family. Although one individual may be ready to have germline testing performed shortly after diagnosis, it may be most appropriate for a variety of personal reasons to delay that discussion with other patients.

In summary, there is not a single correct answer to the issue of optimal timing of molecular/germline testing. The determination is both situational and personal, and thorough discussions regarding the tests to be undertaken and the implications of the findings are essential.

In response to the second question, that of why BRCA mutations have persisted within the gene pool and particularly within specific groups (eg, individuals of Ashkenazi Jewish background), all that is possible to provide is a rational hypothesis, ideally with supporting data from the recognized short available human evolutionary record.

In all-too-briefly highlighting here the relationship between cancer and evolution, it is relevant to note the long-recognized relevance of this fundamental process to biology, in general,2 and the nature of cancer and its progression, in particular.3,4 There is evidence that malignant clones increasingly populate normal organs with aging, which supports the fact that cancer is principally (although certainly not exclusively) a disease of older individuals.5,6 Importantly, it is essential to appreciate there is no meaningful evolutionary disadvantage associated with this biological process because it is recognized that “natural selection works effectively only up to and during reproductively active life.”3

So is there a rational hypothesis for why BRCA mutations might have an evolutionary advantage, recognizing there is likely no disadvantage associated with the development of cancer after “reproductively active life”?

Researchers examining the extensive, well-annotated Utah Population Database linked this information with records regarding BRCA mutations and observed that the group of women with such a mutation had a greater number of children compared with women with wild-type BRCA.7 The investigators also found the anticipated higher mortality in the post-reproductive period, but the finding of heightened fertility provides a provocative hypothesis for a possible evolutionary advantage associated with this germline molecular abnormality. A final fascinating point to be highlighted is the observation that with the widespread availability of contraception, the differences in fertility persisted but were reduced in magnitude.

Again, what has been reported is a hypothesis, and realistically nothing more, but one supported by potentially meaningful objective data. It is reasonable to anticipate that future studies of complex evolutionary processes may answer other perplexing questions in modern medicine, both conceptual and of actual clinical relevance.8

References

1. Scott JA, Lennerz J, Johnson ML, et al. Compromised outcomes in stage IV non-small-cell lung cancer with actionable mutations initially treated without tyrosine kinase inhibitors: a retrospective analysis of real-world data. JCO Oncol Pract. 2024;20(1):145-153. doi:10.1200/ OP.22.00611
2. Dobzhansky T. Nothing in biology makes sense except in the light of evolution. Am Biol Teacher. 1973;35(3):125-129. doi:10.2307/4444260
3. Greaves M. Evolutionary determinants of cancer. Cancer Discov. 2015;5(8):806-820. doi:10.1158/2159-8290.CD-15-0439
4. Merlo LMF, Pepper JW, Reid BJ, Maley CC. Cancer as an evolutionary and ecological process. Nat Rev Cancer. 2006;6(12):924-935. doi:10.1038/nrc2013
5. Martincorena I, Fowler JC, Wabik A, et al. Somatic mutant clones colonize the human esophagus with age. Science. 2018;362(6417):911-917. doi:10.1126/science.aau3879
6. Risques RA, Kennedy SR. Aging and the rise of somatic cancer-associated mutations in normal tissues. PLoS Genet. 2018;14(1):e1007108. doi:10.1371/journal.pgen/1007108
7. Smith KR, Hanson HA, Mineau GP, Buys SS. Effects of BRCA1 and BRCA2 mutations on female fertility. Proc Biol Sci. 2012; 279(1732):1389-1395. doi:10.1098/rspb.2011.1697
8. Landim-Vieira M, Pinto JR. Can evolution-based studies inform modern medicine? Science. 2024;385(6716):1420-1421. doi:10.1126/science.ads2585