Cancer thrives by mutating. But sometimes, a mutation leaves it vulnerable
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Cancer treatment is like an arms race. After a tumor evolves resistance to one drug, doctors switch to another therapeutic weapon — and on and on, until the tumor is vanquished or the drug cupboard is bare.

But a case study published Wednesday in the New England Journal of Medicine suggests this steady battle march can sometimes swing around on itself.

That’s what happened to a 52-year-old woman with advanced lung cancer. Her tumor cells mutated in such a way that they once again became vulnerable to the medication she’d taken early in her fight, even though her cancer had previously evolved resistance to that drug.

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The new findings suggest that doctors might do well to take repeated biopsies to check how a patient’s tumor cells are evolving and to consider revisiting the drugs they used at the start of the battle — because those drugs can sometimes have a second life.

“It’s really amazing,” said Dr. Gregory Riely, a lung cancer specialist at the Memorial Sloan Kettering Cancer Center who was not involved in the woman’s treatment.

“This is the first time clinically that we’ve seen a cancer mutate in such a way that it again becomes sensitive to a targeted therapy,” Riely said. “The typical resistance pattern is a straight line … with mutations developing along the way. These data suggest that we may be able to turn that around and make it a circle.”

Dr. Alice Shaw, an oncologist at Massachusetts General Hospital, diagnosed the patient in 2011 with an advanced form of lung cancer fueled by a cancer-causing enzyme called ALK. The woman, who never smoked, started taking the Pfizer drug Xalkori, which specifically targets ALK. At first, it seemed to work.

But after 18 months of treatment, scans revealed that her cancer was growing again. It had spread to lymph nodes in her abdomen. And a biopsy revealed a mutation that rendered her cancer immune to the drug.

The woman tried another ALK-inhibitor (a Novartis drug called Zykadia) plus a less targeted experimental agent, but neither therapy worked. After lesions cropped up in her liver, it became clear that the patient needed to try something else. Last year, she enrolled in a Phase 1 trial of a new ALK-blocker from Pfizer called lorlatinib.

The drug worked — at least at first. Initial scans showed a 41 percent reduction in tumor size, and the woman did well for about nine months. But as often happens, the cancer mutated again. This latest drug became useless, as well.

Then came the twist: Genetic testing revealed that the very same mutation that conferred resistance to lorlatinib actually made the tumor vulnerable again to the first anticancer drug the woman had taken. The patient went back on Xalkori, and for the next six months her tumors shrank and her liver function improved.

She eventually succumbed to the disease, but she defied expectations. Most patients with advanced lung cancer die within a year. This woman survived for four.

In cancer treatment today, biopsies are often taken only once, to establish a diagnosis and determine an initial course of therapy.

Shaw said her patient’s case highlights the need to biopsy repeatedly during treatment and tailor drug regimens accordingly. This is becoming increasing necessary, she said, as cancer therapies become more precise, targeted, and personalized.

“These biopsies are really critical in revealing mechanisms of resistance,” Shaw said, “and they can sometimes reveal some surprising mechanisms that may actually make you rethink the use of drugs that you wouldn’t have thought of before.”

Shaw published the case report along with her colleagues at Mass. General and scientists at Pfizer.

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