We’ve made significant progress in the treatment of gastrointestinal malignancies over the last ten years. More than ever before, treatment is being tailored to molecular features of tumors within each individual patient that subdivide disease categories beyond just the cancer’s tissue or organ of origin. Known as “precision medicine,” these new treatment strategies represent progress toward the ultimate goal of individually customized therapy based on comprehensive molecular profiling of each individual tumor.
For example, we now understand that the EGFR antibodies cetuximab (Erbitux) and panitumumab (Vectibix) should only be used alone or in combination with chemotherapy in patients with colorectal cancers that do not harbor activating mutations in the RAS gene (approximately 50% of patients). RAS encodes a protein that functions in cancer cells by relaying growth and survival signals from EGFR on the cell surface to the nucleus. In patients without RAS mutations, targeting EGFR with one of the antibody drugs can disrupt this signaling cascade, leading to cancer cell death and tumor shrinkage in a subset of patients. However, specific mutations permanently activate the RAS protein (imagine a switch stuck in the on position) so that targeting EGFR no longer has any impact on the cancer cell. Treating those patients leads to side effects, costs money, and provides no benefit to anyone. So if you have advanced colon or rectal cancer, your doctor should be able to tell you if you have a RAS mutation or not.
Stomach and esophageal cancers also require molecular sub-classification in order to determine optimal therapy for advanced disease. We now understand that approximately 20% of patients with these diseases have increased copies of the HER2 gene[ii]. A member of the same family of genes as EGFR, HER2 is another example of a growth factor receptor that relays growth and survival signals from the cancer cell environment to the nucleus (which is where the cell’s DNA sits as well as the machinery for cell division). In cancers where there are extra copies of the HER2 protein on the cell surface, we know that targeting the protein with a therapeutic antibody known as trastuzumab (Herceptin) in combination with standard chemotherapy has the potential to enhance tumor shrinkage and prolong survival. But it only works when there are extra copies, and it’s something your doctor should be testing for routinely when you’re diagnosed with advanced stomach or esophageal cancer.
We have now entered the era of immunotherapy in cancer, which is very good news indeed. Unfortunately progress in gastrointestinal cancers has been slower than in some other tumor types, and much work still needs to be done to design strategies that will re-activate the immune system against these diseases. We already know that the PD1 inhibitor pembrolizumab (Keytruda) has remarkable activity in cancers that demonstrate a molecular feature known as deficient mismatch repair[iii]. This describes a very specific way in which normal cells acquire the mutations necessary to become cancer, and it has to do with the malfunction of “housekeeping” proteins that clean up mutations occurring with normal cell division. When the malfunction of one of these housekeeping proteins is encoded in the DNA we inherit from our parents, it results in a disorder called Lynch syndrome and leads to a markedly increased risk of colorectal cancer as well as other tumor types. But it can also occur spontaneously in approximately 20% of colorectal cancers, and when that happens we’re able to identify it through simple testing of surgical or biopsy specimens. This is a critical test for patients with advanced colorectal cancer because if it’s positive then PDL1 inhibitors like pembrolizumab are an outstanding treatment option with great potential for helping patients feel better and live longer. Interestingly, deficient mismatch repair is also found in subsets of other gastrointestinal cancers, including stomach and liver cancer, and PDL1 inhibitors have shown promise for these patients as well[iv].
These examples are only the beginning of precision medicine in gastrointestinal cancers. Panel based testing for hundreds of potentially relevant mutations is now commercially available, and in some cases rare mutations have been identified that suggest the use of targeted drugs that are either approved for other tumor types (referred to as off-label use) or that are being investigated in the context of clinical trials. It’s important to understand that these tests identify potential novel treatment strategies in only a small minority of patients to date, and that the technology is rapidly changing. Who pays is also a question that the cancer community is in the process of answering, as insurers are reluctant to pay for tests that have not yet been unequivocally demonstrated to prolong the lives of cancer patients. That said, these panel-based tests are only going to get better at identifying relevant mutations or other molecular features of tumors that hold the promise of more efficiently designed clinical trials and longer, happier lives for patients with gastrointestinal cancers.
Allegra et al. J Clin Oncol. 2016;34(2):179.
[ii] Bang et al. Lancet. 2010;376(9742):687.
[iii] Le et al. N Engl J Med. 2015;372(26):2509
[iv] Muro et al. J Clin Oncol 33, 2015 (suppl 3; abstr 3) and Melero et al. Abstract available online at http://www.esmo.org/content/download/88721/1622334/file/ESMO-2016-abstracts-excl-LBA-and-press-programme.pdf