Does Molecular Heterogeneity Explain a “Mixed Response”

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Does Molecular Heterogeneity Explain a “Mixed Response” on Follow-Up Scans? Insights from EGFR Mutation Testing

August 3rd, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/08/03/do ... n-testing/

An important question about cancer imaging that we hear a lot is about a so-called “mixed response” to systemic therapy, in which a scan shows some areas of the cancer shrinking as others grow, or new lesions appear. Why does this happen, and what should we do when we see a mixed response?

A publication from China assessed heterogeneity of EGFR mutations in 180 patients who had paired tissue sampling from different locations of their cancer offers some insight here, at least with regard to EGFR mutations and EGFR tyrosine kinase inhibitors (TKIs), a relatively simpler version of cancer treatment and response than we see in a broader lung cancer population. Patients discussed in this paper fell into one of four groups: two primary tumors detected at different times (called metachronous lesions), a primary cancer and lymph node, a primary cancer and distant metastasis, or paired samples from multiple lung nodules. EGFR mutations were detected in 119 primary tumors (50.6%), 15 (30.6%) lymph node metastases, 16 (45.7%) distant metastases, and 19 (46.3%) pulmonary nodules (these are high numbers, befitting an Asian population more than a North American or European one). Evaluating at the matched samples from the same patient, the investigators saw that 25 of the 180 pairs (13.9%) were discordant. Looking at the different groups, the discordance rate was 9-14% in all of the pairing combinations except for the situation of multiple lung nodules, where the biopsies were discordant in one in four cases (10 of 41, 24.4%). The patients who had a discordant pattern of EGFR mutations were the ones most likely to show a mixed response to EGFR TKI therapy.

Among patients who had molecular testing done from samples done at different times, the rate of discordance was lower in people who had received no systemic therapy (4 of 43, 9.3%) or chemotherapy only (8 of 59, 13.6%) than in people who had been treated with an EGFR TKI (10 of 38, 26.3%). In fact, this is exactly what we would predict, since we can imagine that the “selective pressure” of being on an EGFR TKI will lead to growth of cancer cells without EGFR mutation (or that have an EGFR resistance mutation), but otherwise, that shouldn’t happen except randomly (and therefore very infrequently, and slowly). In fact, the report describes several cases of a mixed response in which the primary tumor with an EGFR mutation was responding as a new lesion appeared and was found to not have an EGFR mutation.

What are the implications of these findings? First, it appears that in a significant minority of cases, we can see discrepant results depending on whether one area of a cancer is biopsied or another — and this work suggests that those with multiple pulmonary nodules are even more likely to have molecular heterogeneity between different nodules. We now also have a potential explanation of how treatment can be associated with mixed responses that we see clinically. For that matter, why is the response rate to EGFR TKIs in patients with an EGFR mutation (only) 60 or 70%, vs. the 100% that we would expect from the science? Presumably, it’s because many of the 30-40% who don’t respond have growing lesions taht don’t have an EGFR mutation, or the sample that showed a mutation was a minority of the overall cancer that doesn’t truly represent most of the cancer’s biology.

While this principle is illustrated relatively clearly in patients with EGFR mutations, we can also extrapolate these findings to those obtained with standard chemo. Chemotherapy has its own molecular correlates — we know that some people respond well, and others respond poorly — though we don’t understand them nearly as well as the relationship between EGFR mutations and EGFR TKIs. Still, we can envision that when we see some cancer lesions shrinking better than others after a couple of cycles of chemo, it’s likely because the molecular features of the responding areas make them more susceptible to the effects of the chemotherapy than the resistant areas.

What does this imply about how to manage these situations. Similar to what I’d described in some recent discussions of “acquired resistance” to EGFR TKIs or ALK inhibitor therapy, mixed responses likely represent a molecularly heterogeneous state. In general, we view mixed responses as an individualized situation in which we weigh the degree of response vs. progression in our recommendation to switch treatment or continue on; essentially, we can use the results described above to support the idea that if most of the cancer is still responsive to targeted therapy, it makes sense to continue the EGFR TKI or ALK inhibitor (or chemo) as we weigh the need to add local therapy or chemotherapy to address the growing portion: you’re essentially treating the sensitive part with ongoing therapy, and the resistant portion of the cancer with another treatment strategy.

Overall, this work provides more evidence that molecular testing provides valuable insight, though at a cost of forcing us to redefine our over-simplified models.

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NikoleV