"I was just diagnosed with BRAF-mutated colon cancer." I've never heard anyone say that, but there's no reason I should not. Our knowledge of cancer genomics is increasingly enabling physicians to target therapies at the aberrant biochemistry that underlies individual tumors. This is truly taking personalized medicine 1 step further -- not only is therapy tailored to patients, it is also tailored to the unique deficits and/or vulnerabilities of each patient's tumor.
My thoughts along these lines were jump-started by a recent research study published in The New England Journal of Medicine. The report focused on mutations in ARID1A, a gene that is often mutated in ovarian clear-cell carcinomas and in endometrioid carcinomas. Among 119 cases of clear-cell carcinoma, 46% demonstrated ARID1A mutations; 10 of 33 cases of endometrioid carcinoma (30%) also showed ARID1A mutations. By contrast, no ARID1A mutations were found in the 76 high-grade serous ovarian carcinomas examined.
Both clear-cell and endometrioid ovarian carcinomas are relatively insensitive to platinum/taxane chemotherapy, which is the treatment of choice for high-grade serous carcinomas. Could this be related to the ARID1A mutations? If yes, would ARID1A mutations found in other tumor types also be resistant to platinum/taxane chemotherapy?
Cracking the Code to "Beat" CancerA study published in The New England Journal of Medicine in August described the effectiveness of PLX4032 in shrinking the tumors of 81% of metastatic melanoma patients with the BRAFV600E mutation. Of 32 patients studied, 2 had no sign of disease at the end of the trial and 24 had tumor shrinkage of 30% or more. Only 2 patients' tumors showed no regression at all.
When BRAF is mutated, the normal function of the B-raf protein is altered in ways that can lead to birth defects early in life or to cancer in adults. PLX4032 inhibits the mutated B-raf protein regardless of the cell type in which it resides, but only in tissues with the BRAF mutation.
Considering the striking impact of PLX4032 on malignant melanomas, and its focused action against the aberrant B-raf protein, would PLX4032 also be active against other tumors with this same BRAF mutation?
According to the database of the Cancer Genome Project of the Wellcome Trust Sanger Institute, BRAF is mutated in 45% of thyroid cancers. Not surprisingly then, a paper presented at the 2009 Annual Meeting of the American Society of Clinical Oncology showed that PLX4032 is active in thyroid cancers as well: tumor regression rates were 9%-16% in thyroid cancer patients with BRAFV600E mutations, and patients showed no tumor progression for 4-7 months.
A 2008 study reported that inhibition of BRAF caused apoptosis in melanoma cells, but only arrested growth in thyroid carcinoma cells, with little or no cell death -- which might explain why although PLX4032 is clearly active in thyroid cancer, it has such different effects in melanoma than it does in thyroid cancer.
A Rose By Any Other Name...So how might our understanding of tumor classification change as genomic medicine moves into the clinic? In tissues such as thyroid, which is unique in its affinity for iodine, or in breast cancers requiring estrogen to thrive, these characteristics should obviously be exploited in ways that achieve apoptosis or growth inhibition. But it might be equally important to exploit the ways in which other tumors -- which might be dissimilar at first glance -- are actually similar on a genetic level. Just as PLX4032 seems to be active in a variety of BRAF-mutated tumors, other chemotherapeutic agents can be designed to target tumors with common genetic variants. Or, conversely, just as clear-cell ovarian cancers with ARID1A mutations are unresponsive to platinum/taxane chemotherapy, we might be able to avoid the use of these chemotherapies in other tumor types with the same mutation.
The more we learn about cancer genomes, the more we're beginning to understand that "BRAF-mutant colon cancer" should be treated differently from BRAF-normal colon cancer. Whether we'll ultimately be able to unravel every genetic mutation in every tumor type remains to be seen. But, in the meantime, investigations into treatments tailored toward a range of tumor types with ARID1A and BRAFV600E mutations clearly provide a window into the future of clinical oncology.