Basket Cases: Changing the Way Cancer Is Treated

When determining treatment plans, some doctors are turning to genetic mutations that caused the cancer instead of the cancer type. 
BARBARA SADICK
PUBLISHED: APRIL 15, 2016
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Cancer patients have traditionally been treated based on where their tumors originate — lung tumors with treatments for lung cancer, breast tumors with therapies developed specifically for breast cancer. But what if doctors started caring less about where a tumor first emerged and more about the genetic mutations that caused it to appear in the first place? That principle is at the essence of precision medicine, a science focused on understanding each particular tumor and the molecular messages it sends, and treating it accordingly.

Ultimately, this branch of investigation could mean that a breast and a prostate cancer are treated with the same medicine, or that two people with melanoma of the same stage and location are given entirely different therapies. It's something that's already happening more and more in the world of cancer treatment, and it's given rise to a host of clinical trials with a new type of design.

Known as "basket trials" or "umbrella trials," these studies enroll patients with a variety of cancer types, find the specific mutations or abnormalities that drive their tumors, and then match the patients with medications that target those glitches. It doesn't matter where a cancer first emerged; tumor genetics are what determine trial eligibility. In basket trials, patients are eligible if their tumor harbors a specific genetic mutation that is a target for the therapy in question. A basket trial could enroll patients with several different types of tumors (skin, lung or colon cancer), but all of the tumors would share the same genetic abnormality. Alternatively, an umbrella trial might enroll patients with the same underlying origin of cancer (such as breast or pancreatic), but allocate patients to treatment with one of several different targeted therapies.

An example of a large umbrella trial is ALCHEMIST, or the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial, a government-sponsored study that is enrolling patients with early-stage, nonsquamous non-small cell lung cancer (NSCLC) after surgery. The trial will screen patients for EGFR mutations and ALK rearrangements, and then place them in two separate trials based on those biomarkers, evaluating treatment with either EGFR-targetingTarceva (erlotinib) or ALK-targeting Xalkori (crizotinib) versus placebo. Other large trials, such as NCI-MATCH and TAPUR, are enrolling patients with numerous cancer types and looking for a variety of genetic abnormalities to treat with targeted drugs, and so combine both approaches.

Many clinical trials of cancer drugs include some degree of personalization these days, but basket and umbrella trials remain a minority among studies because the level of collaboration they involve can make them difficult to organize. The costs of biopsies and genomic sequencing are also challenges. Still, experts say, we can expect to see more and more of these trials emerging over time.

MEDICAL EVOLUTION

In February of 2001, The Human Genome Project announced that a sequencing of the human genome had been completed. That project identified the locations of, and provided information about, the structure and organization of specific genes. It was the breakthrough that ushered in a new era of oncology research that has allowed investigators to study the genetic makeup of cancer tumors and reclassify them according to their composition.

A decade-and-a-half later, in his January 2015 State of the Union address, President Barack Obama recognized the significance of this line of study, and its evolution into an actionable body of work, by announcing the launch of the Precision Medicine Initiative, calling for $215 million dollars in government spending for fiscal year 2016. Seventy million dollars of that initial allocation went to the National Cancer Institute (NCI) for research in targeted, precision oncology.

Indeed, within the last decade, a significant focus within cancer research has been the push to understand how tumor genetics drive different cancers, and how to develop more focused drugs to target these molecular abnormalities. "The last decade has seen the development of several targeted therapies that can be very effective for a subset of patients with certain types of cancers, including lung cancer or melanoma. The challenges now are to try and extend these developments to other patients and to develop strategies to treat resistant tumors," says Amanda Redig, a medical oncologist at Dana-Farber Cancer Institute.



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