Precision Therapy and a New Kind of Disappointment

She had come to see me as a second opinion; diagnosed with uterine serous cancer, one of the more aggressive types of uterine cancers. At surgery they found that it had metastasized to her nodes—stage III disease. The surgery was successful though and she had been treated with adjuvant chemotherapy with the hope it was curative. Two years later, she developed abdominal pain. A work-up showed that her CA-125 was elevated, which prompted a scan, and a diagnosis of hepatic metastases. Her doctors recommended repeat treatment with chemotherapy—carboplatin and paclitaxel. “It didn’t work the first time, so I am not sure doing it all over again makes sense.”


She looked incredibly well otherwise—a woman with cancer who had often heard, “but you don’t look sick!” We talked about options and I explained why retreatment with carboplatin and paclitaxel indeed made sense—because it stood the best chance of shrinking the tumor, maybe even getting her to remission. But then, the truth—“However,” I said, “it won’t cure you. Hopefully, though, it will give you much more time.”

“Isn’t there anything else?”

I offered her genomic testing of her tumor, in hopes that we could identify a mutation that was amenable to a clinical trial or a targeted treatment. “I hope someday, all of my patients will benefit from it. For now, though, I think it might be useful to see if we can find a clinical trial that you could participate in, assuming you have a mutation identified.” After discussing it more, she excitedly signed consent—the hope for a “driver mutation” and one that could be inhibited was so promising. I must admit, seeing her enthusiasm made me excited as well.

Her test came back negative; no mutations were identified. I was so disappointed and worried about how she would take the news. Indeed, at her next visit, she seemed excited, until I told her we had not identified a tumor mutation. She cried then, as if sensing that better options, even a cure, were no longer possible. I continued, “You still have options, though—good ones. I think I would proceed with chemotherapy.” 

Oncology is truly at a crossroads. We are attempting to move away from a one-size-fits-all approach to cancer therapy and into smarter, more precise treatments. As an academic oncologist, I am excited about the prospects of curing more cancers, or short of that, turning these diseases into a more chronic illness—one that our patients can live through so they get to experience rich, engaged, and fulfilled lives. We are seeing such strides now: trastuzumab for HER2-positive breast cancer, vemurafenib for BRAF-mutation associated melanoma, and crizotinib for non-small cell lung cancer with an ALK mutation. With all of this progress, I half expected that we would identify subgroups among women with gynecologic cancers, and they too could be offered more precise treatments.

But that hasn’t happened—and for many who undergo genomic tumor testing, no mutations are identified. It’s an odd disappointment that I’ve experienced, learning that to date, there is nothing “abnormal” about something so abnormal as cancer. I wondered if my colleagues had experienced this disappointment as well and reached out to Lecia Sequist here at MGH, and Associate Editor at The Oncologist. Lecia’s specialty is in lung cancer, and she has been at the forefront of precision therapy for this disease. I assumed this was not a situation she faced, at least not as often as I. But I was wrong.

I also met my patient as a second opinion. She had presented with a persistent cough and had been shocked to learn that she had advanced lung cancer. Like most in the public, she didn’t think a never-smoker like herself could get lung cancer. She and her husband researched the diagnosis immediately online and discovered that many never-smokers with lung cancer will have a mutation of some sort in their cancer that can be treated more precisely with targeted therapy, often with better results than chemotherapy can provide.

They agreed to hold off on chemotherapy until the genetic testing could be completed and were immensely thankful when they were told by their doctor that indeed she had one of these “miracle” mutations in her cancer— an EGFR mutation. They read online about patients that had been on EGFR-directed drugs with cancer under control for 5 years—sometimes even 10. They went to lung cancer fundraising galas and met some of these patients, heard their stories of cherished vacations or grandchildren born, all the milestones that “weren’t supposed to happen” given the one-year death sentence of advanced lung cancer—all thanks to that little mutation and that magic pill. They were filled with hope.

When I met her, she had already been placed on the appropriate EGFR therapy that formed a match with the tumor mutation. Her cough and shortness of breath had rapidly improved and the first set of CT scans had shown a picture-perfect response. All was going the right way and she and her husband breathed a sigh of relief and began to plan for a trip to Europe next year, and perhaps a cruise the year after that…. But then the second set of CT scans, a mere 3 months from the start of the drug, showed growth in the cancer. Both they and their doctor hoped it was some sort of fluke—perhaps a viral infection. Unfortunately the next CT scan showed more of the same and at this point her cough had started to creep back in.

So here they were in my office a mere 5 months after the diagnosis, with the same menu of chemotherapy choices as most lung cancer patients have from day one, but feeling cut-off at the knees, betrayed by the therapy that was supposed to be their miracle. They described feeling robbed of their chance at having those months and those normal life moments others had described as being so exceptional just because of their improbability. In many ways, they may have been worse off emotionally than if the mutation had never been found. And the next 8 months before her eventual passing were hard. No trips to Europe, no making peace with the situation—just bitter anger, hurt, and resentment.

Despite our advances in the last decade, the sophisticated diagnostics, and more precision treatments only hypothetical just a few years ago, the promises and benefits are not universal. While some will benefit enormously, others will not be candidates or will have only a mediocre benefit, or will not derive a benefit at all due to cancer’s complex resistance mechanisms that thwart our drugs. 

After hearing from Lecia, I’ve realized that alongside the achievements in precision oncology, there are still a large proportion of patients who are not benefiting and will not benefit from them. Whether it be the lack of a target on our current genomic testing as in my patient, or the quick progression on targeted treatment despite an identified mutation as in Lecia’s patient, we are facing different disappointments—as providers and patients.

I guess it comes down to the fact that discovery is an ongoing process and for many, we have not yet discovered the keys that drive all cancers, the therapies to address those mutations, and the tools to predict which treatment will afford the best response and outcome—an outcome our patients (and we) hope will mean a lifetime of living, despite cancer. I look forward to a time when we can fulfill this goal—it will be a time that could not come soon enough. Part of this effort will be to understand why some treatments work remarkably well in some patients—so-called “exceptional responders,” a topic covered recently in The Oncologist. To this end, the NIH has a major initiative to identify molecular indicators of response and the mechanism of action. Learn more about it here: http://www.cancer.gov/news-events/press-releases/2014/exceptionalrespondersqanda.