Studies Find Cancer Comes in More Shades Than Pink

Bloomberg View , October 29, 2012

Once again, we have suffered through a full month of pink, pink and more pink, all in the name of “breast cancer awareness.” What once was a health-related cause has become the feel-virtuous-and-buy-stuff season wedged between back-to-school and holiday gift giving.

Products from Pilot pens to KitchenAid mixers to “Totally Pink Mad Libs” come in breast-cancer-awareness versions. National Football League players hit the field wearing uniforms with clashing pink trim. During the second presidential debate, the candidates’ wives both wore shocking-pink dresses, and, for the third, President Barack Obama sported a pink breast-cancer wristband. Nobody wants to seem less than enthusiastic about fighting breast cancer, so pink has replaced autumnal orange as the color of the season.

But all this pink reinforces a common fallacy -- one that used to drive me crazy after I was given a diagnosis of breast cancer in 2007. Back then, people inevitably offered their sympathy by telling me how their mothers or sisters or aunts or wives or best friends or colleagues or neighbors had had breast cancer. Everyone assumed what the pink ribbons teach us: that breast cancer is a single disease. Appreciating the good wishes, I stifled the urge to respond, “Probably not the kind I have.”

Five years ago, oncologists had already long understood breast cancer as several different diseases that, based on their underlying molecular behavior, react differently to different treatments. (My own cancer was HER2-positive, an aggressive form found in about a quarter of breast-cancer patients and responsive to Genentech Inc.’s (ROG) biologic Herceptin.)

Now we have even more reason to understand breast cancer as multiple diseases.

An enormous study published last month in the journal Nature analyzed samples from 825 breast-cancer tumors, using five different tests to find mutations in different aspects of their genetics. Researchers crunched the resulting data to classify the cancers into four general types: Luminal A, Luminal B, HER2-enriched, and basal-like. (They also identified a fifth type, dubbed normal-like, but didn’t have enough samples to adequately study it.) Given its underlying genetics, each type might be susceptible to a specific treatment approach.

The study refines the way oncologists understand the different versions of the disease. The biggest news was that the basal-like cancers had more in common with the most common ovarian cancer, called serous, than with other types of breast cancer.

Breast cancer isn’t just more than one disease, it turns out. Some “breast cancer” doesn’t seem unique to breasts.

The study is the latest to emerge from the Cancer Genome Atlas project, or TCGA, a seven-year effort funded by the National Institutes of Health that is cataloging genetic abnormalities in at least 20 different cancer types. The atlas had already included analyses of serous ovarian cancer; glioblastoma, the most common form of brain cancer; colorectal cancer; and lung squamous-cell carcinoma, the second-most-common form of lung cancer.

This research is accelerating a change in how oncologists define and treat cancers: not just by their site in the body but by their underlying molecular commonalities.

“If a certain subset of ovarian cancer appears to have the molecular commonalities of one type of lung cancer, a specific type of endometrial cancers and another subtype of breast cancer, then it may not matter where they came from when it comes to the practical question of how to treat them,” says Christopher Benz, a practicing oncologist at the University of California-San Francisco’s Carol Franc Buck Breast Care Center who worked on the study. “We should probably be treating them very similarly because the pathways that drive them are very similar,” says Benz, who worked on the breast-cancer study.

For patients with hard-to-treat cancers, the new understanding suggests new types of regimens. Perhaps, for instance, drugs used to treat ovarian cancer could fight basal- like breast cancers.

But defining cancers by genetic characteristics also upends all the institutional structures of cancer treatment, from the way clinics are organized and charities are defined to how drugs are developed and tested -- and the size of the markets they can eventually reach.

“I don’t know of any patient who goes to an EGFR clinic,” says George W. Sledge Jr., a professor at the Indiana University School of Medicine and the former president of the American Society of Clinical Oncology. He is referring to epidermal growth factor receptor, a molecule associated with several cancers. Instead, patients go to clinics that specialize in colorectal, lung or head-and-neck cancers.

That is because drugs aren’t the only treatments involved. Surgeons and radiation oncologists develop special expertise in particular parts of the body, as do radiologists and pathologists.

Some molecular receptors also behave differently in different organs, so a treatment that works in one part of the body may not work in another.

Defining cancers by molecular characteristics thus means introducing a sort of matrix management into diagnosis and treatment -- adding another dimension to the existing categories, rather than replacing them.

That could prove to be as simple as a chart or computer program that lets oncologists easily match the genetic profile of each patient’s cancer to the right treatment. Or, if determining treatments turned out to require complex judgments, it could lead oncologists to specialize by molecule, or group of molecules, as well as by organ. In that case, the tensions for which matrix management is famous in business would find new medical incarnations.

As for charities, right now they are eager for cures and happy to see anything that might speed up treatments. “I think they’ll be willing to adopt newer approaches,” Benz says.

But new disease definitions do threaten the brand identities of the cancer-fighting groups that define their causes by body part. They may find it hard to maintain patient solidarity as diagnoses and treatments fragment -- especially if people with different versions of, say, breast cancer have very different experiences and prognoses. If breast cancer is really a bunch of different diseases, some of which have more in common with other cancers than with each other, maybe they don’t all belong under the same pink umbrella.

It isn’t hard to envision the competition for resources getting nasty. If one type is common but already has some reasonably effective treatments, while another is rare and intractable, where should scarce dollars go: toward improving existing treatments for the many or finding hope for the few?

To make matters even more complicated, the more closely researchers look at the molecular biology, the more fragmented the cancers become. “As we subdivide these cancers by their molecular abnormalities,” says Benz, “we end up with a large number of what we call orphan diseases, because there aren’t just two or three or even four breast cancers. There are four basic types but many subtypes within those primary types.”

Identifying subtypes offers a chance to design increasingly effective treatments. But, as we will explore in my next column, these new definitions of cancer types may demand new approaches to drug development.