With cancer, it’s not necessarily where it starts but how it starts


Ever since 1761, when the Italian physician Giovanni Battista Morgagni published his detailed findings from 700 autopsies, cancers have been inextricably linked with the organs they inhabit.

Over the next 250 years, physicians would learn that even after a tumor had been fully excised from one organ, some remnant of the malignancy could spread to other organs through fluids like blood and lymph. With the advent of microscopes in the late 19th century, they would begin to appreciate tumors’ commonalities and differences in cellular detail. And with the decoding of the human genome, they would begin to discern the roles that DNA mutations play in helping cancers begin, grow and spread.

Through it all, doctors have organized their notions of cancer according to that fundamental principle of real estate: location, location, location.


FULL COVERAGE: If you think you know cancer, it’s time to think again »Oncologists often specialize in treating cancer in one organ, to the exclusion of all others. Treatment regimens for one type of cancer (thyroid, say) seldom resemble those of another (such as bone).

But that centuries-old view of cancer is changing.

As scientists and physicians better understand the genetic factors that initiate, drive and sustain cancer’s growth, they’ve noticed striking commonalities in cancers that once looked very different from one another.

The cells of certain lung cancers, for instance, have the same mistakes in their DNA-repair machinery as cells from melanomas, urothelial carcinomas and cancers of the head and neck. And the versions of the BRCA1 and BRCA2 genes that cause breast cancer to run in certain families also make ovarian and possibly prostate cancers more likely.

Organizing cancers by their location “has made sense for generations, but the results of molecular analysis are now calling this view into question,” David Haussler, Joshua M. Stuart and their fellow cancer researchers wrote in October 2013 in Nature. “Cancers of disparate organs have many shared features, whereas, conversely, cancers from the same organ are often quite distinct.”

Haussler and Stuart, both computer scientists at UC Santa Cruz, are co-directors of the Pan-Cancer Project — a spinoff of the National Institutes of Health’s Cancer Genome Atlas. The project enables researchers to analyze the genetic profiles of thousands of samples of more than 20 types of tumors.

This type of work made it possible to see that mutations of the KRAS gene, which regulates cell division, may be at the heart of as many as 1 in 4 lung cancers. And they may jump-start virtually all pancreatic cancers and close to half of colorectal cancers.

Likewise, the cancer-driving mutation known as Human Epidermal Growth Factor Receptor 2, or HER2, is seen in 15% to 30% of breast cancers and 10% to 30% of gastric and gastro-esophageal cancers. It’s also a factor in some cancers of the ovary, endometrium, bladder, lung, colon, and head and neck.

The discovery of links like these is leading to changes in cancer treatment. For example, some patients with pancreatic cancer are being put on the same medicine, and in the same oncology suites, as patients with certain types of lung cancer or Hodgkin lymphoma.

Ultimately, the discovery could lead to a rewrite of the taxonomy of cancers.

In May, the U.S. Food & Drug Administration took a major step toward breaking down those walls. It approved the immunotherapeutic drug Keytruda (also known as pembrolizumab) to treat metastatic solid tumors in any organ, so long as the malignant cells bear one of two distinctive abnormalities in their DNA-repair machinery.

Dr. Richard Pazdur, who directs the FDA’s Oncology Center of Excellence, called the agency’s decision “an important first for the cancer community.”

“Until now, the FDA has approved cancer treatments based on where in the body the cancer started,” Pazdur said at the time of the announcement. “We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

In May, the Food & Drug Administration approved the use of a cancer drug based on a tumor's genetic profile, not the organ where it is found. Dr. Richard Pazdur, director of the FDA’s Oncology Center of Excellence, called it "an important first."
(Andrew Harnik / AP )

A clutch of so-called “precision” cancer therapies began this process. The first of those — a drug called Gleevec (imatinib mesylate) — transformed the treatment of a rare blood cancer, chronic myelogenous leukemia. In research that spanned decades, scientists discovered a curious fusion of two genes in the cancers of CML patients and realized that this resulted in an abnormal protein that prompts cells to divide uncontrollably.

Gleevec boosted CML patients’ five-year survival from 30% to 89%. Now it’s also used to treat gastrointestinal tumors in which the same aberrant proteins are at work.

Scientists suspect the same family of proteins may have a role in a range of cancers, including melanoma and tumors of the breast, colon, lung and kidney. They’re exploring whether Gleevec or drugs like it might help treat patients with these cancers as well.

From there, it was off to the races. Erbitux (cetuximab) first gained FDA approval for use on head and neck and colorectal cancers with mutations in the KRAS gene. It is currently being evaluated as a treatment for some patients with non-small cell lung cancers that express KRAS and other cancer-driving mutations.

Herceptin (trastuzumab) was designed to treat a particularly aggressive form of hormone-sensitive breast cancer that’s driven by a mutation in the HER2 gene. Herceptin later won FDA approval as a treatment for gastric cancers with the same mutation. Another HER2-targeting breast cancer drug, Gilotrif (afatinib), was approved by the FDA last year to treat metastatic lung cancers that bear the HER2 signature.

Now, drugs known as PARP inhibitors, which target a faulty enzyme in DNA’s repair kit, are getting a close look from oncologists across cancer specialties.

This class of drugs first showed promise in the treatment of breast cancers linked to mutations in the BRCA1 and BRCA2 genes, and it quickly proved helpful in treating advanced ovarian cancers associated with those same mutations. Scientists now believe that close to one-quarter of advanced prostate cancers are also tied to the same gene variants, and clinical trials are underway to gauge whether the PARP inhibitor Lynparza (olaparib) could improve survival in men with those cancers.

Many other cancer therapies are likely to follow this path.

The search for ties that bind seemingly diverse cancers has already begun to change the way research is conducted. In 2015, the National Cancer Institute launched the $40-million Molecular Analysis for Therapy Choice trial, in which some 3,000 adults with advanced solid tumors and lymphomas will get drugs that specifically target the mutations in their cancers. They’ll be treated and tracked not on the basis of where their cancers originated but what their genetic tests reveal about the genes that allow those cancers to progress.

That, in turn, will further drive changes in treatment.



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