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Genetic mutations could help guide treatments for appendix cancer
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Researchers at UC San Diego Health have identified distinct genetic mutations in appendix cancer that could lead to new targeted treatment approaches, according to study findings published in JCO Precision Oncology.
Appendix cancer — which accounts for less than 1% of gastrointestinal tumors — often is treated with chemotherapy based on treatment guidelines for colon cancer.
However, researchers found genetic mutations in appendix cancer that differ from those in colon cancer, and mutations in two genes — TP53 and GNAS — appeared to be good predictors of survival.
“For rare tumors like appendix cancer, obtaining molecular profiles will help identify potential treatment options [because] we do not have the clinical trial data to help guide treatments as we do in common tumors,” John Paul Shen, MD, assistant professor in the department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, said in a press release. “Equally important, the mutation profile can be used as a biomarker to separate high-risk patients who need intensive treatment from low-risk patients who may not need such an intensive treatment.”
HemOnc Today spoke with Shen and Olivier Harismendy, PhD, assistant professor of medicine in the division of biomedical informatics at UC San Diego Health, about the rarity of appendix cancer, the rationale for this study, what researchers found, and the next steps for research.
Question: How rare is appendix cancer?
Shen: Appendix cancer is 100-fold less prevalent than colon cancer. However, it is not so rare that we never see it in our clinics, which is why we need new systemic therapies for these patients.
Q: Why are most treatment strategies for appendix cancer derived from those used to treat colon cancer, and how great is the need for more effective treatments?
Shen: A single institution will not be powered enough to run a prospective clinical trial for appendix cancer. We had 80 patients with metastatic disease within a 10-year timespan at UC San Diego. Clinicians have been treating these patients with chemotherapy that has been tested in colon cancer, because that is the next closest organ. However, in this study, we show that appendix cancer is quite different from colon cancer, and we need to find out what exactly that difference is.
Q: Can you explain the rationale of your study?
Shen: We wanted to better understand the molecular underpinnings of appendix cancer. There had been a lot of smaller observations looking at the different genes in appendix cancer, but there was not a study of this size that could definitively look at the big picture.
Harismendy: Appendix cancer is a heterogeneous disease, and we thought it to be important to expand upon prior smaller studies with a much larger cohort of patients to confirm some of our earlier observations. We wanted to determine why some patients with appendix cancer respond to standard treatment while others do not.
Q: How did you conduct the study?
Shen: There were 700 patients sequenced on the Foundation Medicine platform, which covers the sequence of about 350 genes, the most common genes mutated in cancer. A subset of these were patients from UC San Diego, where we received institutional review board approval for a retrospective study so that we could look at clinical outcomes.
Harismendy: Foundation Medicine supplied the breadth of the cohort, however, they did not have the depth of information. We aimed to add depth to this patient population by identifying treatment, outcomes and more precise pathological description of disease.
Q: What did you find?
Shen: The No. 1 conclusion was that appendix cancer is quite distinct from colon cancer. We also found that there are important distinctions within appendix cancer. In low-grade tumors, we saw frequent GNAS gene mutations, whereas in high-grade tumors, we saw much more frequent TP53 mutations. We also saw mutual exclusivity between those two. Also, about 4% to 5% of tumors had microsatellite instability. This is something to note because these patients may benefit from immune checkpoint therapy, which is already FDA-approved and available in the clinic right now.
Harismendy: Very few clinicians or pathologists in the community will have seen a case of appendix cancer and may not be confident in characterizing the lesion. This study showed the mutational profile can serve as a proxy for grade.
Q: What are the implications of the findings?
Shen: We do not want to overstate our findings and suggest we change practice. However, I think that there are several important questions that come out of this. One question is: If a low-grade tumor in its early stage was resected with negative margins, is there a benefit for adjuvant chemotherapy? This needs to be addressed in a future clinical trial. Additionally, we need to look at TP53-mutant appendix cancer as different from low-grade appendix cancer. Although this study did not answer what the best treatment is for these high-grade mutant cancers, it will help us figure this out in the future. We are not studying a homogenous disease and there are different molecular subtypes with intrinsic differences in expected survival.
Q: What will next research steps be?
Shen: UC San Diego has a research group that has several ongoing projects, one of which is looking at which patients benefit the most from surgery plus heated intraperitoneal chemotherapy. Another study is looking at the benefit of adjuvant therapy and whether it is absolutely necessary in certain select patients.
Harismendy: Appendix cancer remains a very difficult disease to study. This collaborative work with Foundation Medicine was instrumental in better understanding this disease. Whatever the next study is, it will require continued collaboration and data sharing among institutions to better understand this very rare disease. – by Jennifer Southall
Reference:
Ang CSP, et al. JCO Precis Oncol. 2018;doi:10.1200/PO.17.00302.
For more information:
Olivier Harismendy, PhD, can be reached at UC San Diego Moores Cancer Center, 3855 Health Science Drive, La Jolla, CA 92093; email: oharismendy@ucsd.edu.
John Paul Shen, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0426, Houston TX 77030; email: jshen8@mdanderson.org.
Disclosures: Shen reports research support from IDEAYA Biosciences. Harismendy reports no relevant financial disclosures.