Cancer Genome Sequencing Will Mean More Targeted Therapies
October 1, 2014
As the cost of DNA sequencing plummets, the possibility of testing all cancer patients’ tumor genomes is becoming a reality. For just $1000 or so, a doctor might submit most any malignant specimen for a complete genetic work-up. The sample might be a core needle biopsy taken from a breast, a blood sample from a person with leukemia, or a snippet of a sarcoma removed in an operating room. In principle, checking a tumor for genetic changes should be straightforward, do-able.
But most cancer patients undergo surgery and other treatment long before their doctors consider sending a biopsy for full molecular evaluation. A recent published survey among oncologists at two prestigious Boston teaching hospitals suggests that a significant proportion of specialists have a low level of confidence about their knowledge of cancer genomics. Aside from some kinds of lymphoma and leukemia, some lung cancers and a few other malignancies, examining cancer cells for genetic mutations is not routine in oncology practice.
“Genomic testing of cancer cells seems like it should be available to all patients,” said Lori Marx-Rubiner. At age 48, she’s carried a diagnosis of metastatic breast cancer for five years. She lives in Los Angeles with her husband and teenage son, and blogs about her condition at Regrounding. Recently she took the helm at Metavivor, a non-profit organization that promotes research in metastatic disease.
“Now I learn as much as possible about my condition and treatment options,” she said. Marx-Rubiner, who holds a master’s degree in social work, participates in scientific meetings and advocates for people affected by breast cancer. Most of her treatments so far have been selected to interfere with hormone signaling. That’s because her biopsy – evaluated with old pathology methods when she received her initial, stage 2 diagnosis back in 2002 – showed high levels of estrogen receptors in the tumor cells. Such an old approach didn’t seem adequate for managing her case.
In the spring of 2014, she requested that her tumor be checked for genetic mutations. “I wanted to see if I might be eligible for a CDK inhibitor or another targeted drug,” she said. “If I’m going to take a risk on a new drug, I want the best shot possible.”
But finding the specimen taken years ago – and getting her insurance to cover the cost of genomic analysis – proved challenging. After weeks of frustration and hassle, the biopsy sample was found and sequenced. The findings haven’t yet affected her therapy plan. She is soon meeting with a new oncologist.
Carolyn Hutter, an epidemiologist and co-leader of The Cancer Genome Atlas (TCGA), has been working on tumor genomics for some time. The TCGA project, a collaborative work by NIH’s Cancer and Human Genome Research Institutes, aims to characterize over 10,000 human tumors at the molecular level. Sequencing genes in tumor cells – and seeing how those differ from a person’s germline, or inherited DNA segments – helps us to better understand the biological causes of cancer, she said in a phone interview. “It’s also useful because it can point to new targeted therapies.”
One example of a tumor-specific mutation that can direct treatment is an ALK mutation in lung cancer. Using this kind of genetic information about an individual’s tumor is not futuristic, she considered. Rather, it’s happening today. “Doctors are using DNA sequencing results to make decisions about therapy, to select targeted drugs,” she said. Already the FDA has approved two drugs for patients who have lung cancer with ALK abnormalities in the tumor cells – Crizotinib (Xalkori, Pfizer) and Ceritinib (Zykadia, Novartis).
Within the next few years, people with cancer arising in other organs – such as the breast, colon or pancreas, for instance – might have their tumors checked for ALK and other mutations. Whether or not their malignancy is called “lung cancer” because the growth originated in the lung, they might choose a drug based on having an ALK or other genetic variant for which a targeted medicine is available.
“We’re coming up with new definitions of cancer subtypes based on molecular findings,” Hutter said. Genetic profiling has wide potential, in terms of planning patients’ treatment and understanding prognosis in many cancer types. “But I don’t think we’ll completely abandon tissue of origin as a way of categorizing tumors,” she added.
image: NIH, The Cancer Genome Atlas Project (illustration for stomach cancer mutations)
image credit: Dr. Allison Kudla, Institute for Systems Biology, illustration of stomach cancer mutations featured on U.S. NIH website for The Cancer Genome Atlas Project
The flip side is that in some very advanced cases, when doctors can’t tell where a tumor originated, molecular profiling may provide a clue about where the malignancy is coming from, which could inform therapy. And if cancer-specific mutations are found in a malignant specimen, those might guide treatment with a targeted drug.
“It’s a complex system,” Hutter cautioned. A tumor may be remarkably sensitive to a drug initially, and then six months later develop resistance. “Cancer is heterogeneous. It’s always evolving,” she said. “So if you perform tumor genome sequencing at one time, or check for mutations once, that provides only a snapshot of the tumor’s molecular profile.” The malignancy can change over time, and may vary within a single patient, she emphasized. This means that doctors may need to monitor changes in tumor DNA over time, to watch for resistance to a drug, or new mutations that may develop during the course of treatment.
Although most doctors consider metastatic breast cancer incurable, Marx-Rubiner is cautiously optimistic about the future. She’s looking forward to a trip to Italy. “When I get back, I may change treatment,” she considered.
“I ask different kinds of questions now, and I expect different kinds of answers from my doctors.” The genetic information may be crucial, she said. “It may lead us to a trial drug that works, even one that’s not usually given for breast cancer.” She may need a repeat biopsy and tumor sequencing, Marx-Rubiner acknowledged. “But if they find a mutation and there’s a drug that works against it, that would be worth it.”
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