Matthew Tontonoz

These days, anyone with an interest and about $100 can spit into a tube, mail it to a genetic testing company, and get back details on their DNA. This is known to some as recreational genomics. But the results of such tests can be anything but amusing when they include genes that influence cancer risk.

Two widely tested cancer-predisposition genes are BRCA1 and BRCA2. Certain inherited mutations in these genes are known to greatly increase the risk of developing several types of cancer, including 

 cancers. Genetic testing for BRCA mutations can identify people who may benefit from risk-reduction surgery, like a mastectomy; preventive medications; or targeted therapies.

But there is a huge catch: Commercial testing kits, like the one from 23andMe authorized by the US Food and Drug Administration, test for only the three most common BRCA mutations known to run in families of Ashkenazi Jewish ancestry. Someone could test negative for these specific mutations and still be at risk for cancer from other BRCA mutations that aren’t included in the test. This false sense of security might dissuade someone from finding out the full extent of their cancer risk. 

This is just one of the many reasons why doctors typically recommend that genetic testing be done under the guidance of a clinical genetics expert who can test for more than the most common BRCA mutations and help explain the results. Even then, questions remain about who should have testing.

Currently, doctors refer someone for genetic testing if they meet various clinical criteria, like having a family history of cancer or being diagnosed with certain cancers at a young age. But there is evidence that by limiting testing to just these individuals, some people with a BRCA mutation will be missed.

“We know from our data at Memorial Sloan Kettering that if you only test people with strong family histories, you miss half the cases,” says 

, Senior Vice President in the Office of the President and Medical Director of the Evelyn H. Lauder Breast Center at MSK.

Between those with a family history and the entire US population is a large unmapped territory. Just 0.3% of the population (one in 300 individuals) has a dangerous BRCA mutation. It’s not clear how to step up testing in a logical and efficient manner to capture those who are at risk.

But testing guidelines are indeed becoming more inclusive. In August, the US Preventive Services Task Force, an independent panel of health experts, issued updated BRCA testing recommendations. In addition to women with a known family history of breast or ovarian cancer, the updated recommendations include two additional groups: women who previously had breast or ovarian cancer and are now considered cancer free and women of an ancestry known to be at a higher risk, such as Ashkenazi Jewish women. One in 40 individuals of Ashkenazi Jewish ancestry (2.5%) have a harmful BRCA mutation. The updated recommendations were published August 20 in the 

Journal of the American Medical Association

, Chief of the Breast Medicine Service at MSK, and Susan Domcheck from the University of Pennsylvania, call the addition of women with prior breast and ovarian cancer “an important step forward” and applaud the decision to include ancestry as a reason for testing.

“Identification of individuals at risk of carrying a BRCA1/2 mutation can be lifesaving and should be a part of routine medical care,” they write.

Even as testing guidelines are becoming broader, there is evidence that people who are good candidates for testing are not currently availing themselves of it. For example, approximately 15% of women with epithelial ovarian cancer have a BRCA1/2 mutation. Given this high frequency, experts recommend testing for all people with ovarian cancer. But that doesn’t happen: Less than 30% of such women are actually tested. The numbers are even lower for underrepresented minorities and those from a low socioeconomic background.

On the flip side, Dr. Robson and his co-author caution that there are dangers to overtesting, especially when the tests in question are large multigene panels that can include up to 80 genes.

“While there may be value in expanding BRCA testing, particularly in the Ashkenazi Jewish population, this does not automatically mean that this expansion should be conducted using multigene panel tests,” they write. 

, Chief of the Clinical Genetics Service, are actively exploring the best and most strategically effective ways of testing. They are committed to making sure that the most beneficial testing is offered to the people who need it.

Information provided by MSK (“Information”) is not intended as a substitute for medical professional help or advice but is to be used only as an educational aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition. Use of the Information is further subject to 

Articles

Clinical genetics experts see value in testing more women for BRCA mutations.

Who Should Be Tested for a BRCA Mutation? The Science Is Evolving

Cells can die in several ways. One such method, discovered only within the past decade, is ferroptosis — literally, death by iron. This type of death requires iron and is linked to a cell’s use of oxygen for metabolism.

Ferroptosis is a main cause of ischemic heart disease, a condition caused by the death of cells in the heart muscle. But it likely serves other purposes too, like preventing cancer formation. Cells that might form tumors are instead killed by ferroptosis triggered by working tumor suppressor proteins.

Intriguingly, cancer cells that have spread, or metastasized, are more sensitive than normal cells to ferroptosis, a vulnerability that scientists seek to exploit.

“Ferroptosis is becoming a hot topic among pharmaceutical companies,” says 

, a cell biologist in the Sloan Kettering Institute whose lab is seeking to understand how ferroptosis works. “The idea is that if you can induce ferroptosis in a controlled manner, it might be a great way to treat cancer.”

, Dr. Jiang and colleagues, including two of his former postdoctoral fellows who are now professors in China, found that whether cells are vulnerable to ferroptosis or not depends on signals initiated by neighboring cells. When present, these signals guard against ferroptosis. 

The discovery sheds light on why metastatic cancer cells, which have lost these connections, are especially vulnerable to this type of cell death. It also suggests a new treatment strategy.

Neighboring cells relay signals by way of proteins called cadherins, which respond to physical contact. Dr. Jiang’s team discovered that these signals suppress the actions of a protein called YAP, which promotes ferroptosis. When cells lose contact with their neighbors, YAP is no longer suppressed and ferroptosis can be more easily triggered.

As cancer cells become more aggressive, they often undergo what is called an epithelial-mesenchymal transition (EMT). This means that they lose the adhesive properties typical of epithelial cells and become more mobile and invasive. The spread of cancer through metastasis is the main way that cancer kills.

But metastatic cells also lose the signals provided by cadherins when they are no longer stuck to their neighbors, which makes them vulnerable to ferroptosis.

The same properties that make certain cancers hard to treat may also promote their death by ferroptosis, scientists at the Sloan Kettering Institute have found.

Scientists See Potential in Cellular "Death by Iron" for Cancer Treatment

Scientists at Memorial Sloan Kettering are investigating ways to develop effective CAR T cell therapiesfor solid tumors. Results from a clinical trial in people with mesothelioma indicate that an experimental 

 is safe and may provide benefit to patients, especially in combination with other immunotherapies.

therapy has shown great promise for the treatment of certain blood cancers, like 

. By contrast, using this method to treat solid tumors has been more challenging.

On March 31, 2019, Memorial Sloan Kettering (MSK) researchers presented results from a 

. This hard-to-treat cancer usually affects the tissue surrounding the lungs, called the pleura.

, a physician-scientist at MSK who is leading the trial, the CAR therapy proved safe and showed signs of efficacy in a small number of patients. Adusumilli presented these results at the annual meeting of the American Association for Cancer Research, held this year in Atlanta. The study was featured in the meeting’s press program.

“Traditionally, these patients with advanced-stage solid tumors have had poor outcomes despite aggressive treatment,” Adusumilli said. “These results are encouraging for patients who have limited treatment options.”

This trial included 21 patients: 19 with pleural mesothelioma, one with metastatic lung cancer and one with metastatic breast cancer. They received CAR-T cells built to target a molecule called mesothelin found on the surface of the cancer cells. The CAR-T cells were infused directly into the space between the pleura.

A few weeks after the CAR-T infusion, 14 patients received another immunotherapy treatment called Keytruda (pembrolizumab). This drug, a type of checkpoint inhibitor, blocks a molecule on immune cells called PD-1 and boosts immune responses. Adusumilli and colleagues had 

 that this combination was effective in treating cancer in mice.

Two patients who received the PD-1-blocking drug had a complete response, as measured on PET scans, at 38 and 60 weeks after treatment. Five patients had a partial response and four had stable disease.

Patients tolerated the CAR-T treatment well. There were no CAR-T—related side effects. Severe cytokine release syndrome, which is characterized by dangerously high fevers and has complicated CAR therapy for other cancers, did not occur in any of the patients.

“The combination of CAR-T cell plus checkpoint blockade has been long awaited,” said 

, one of the pioneers of CAR-T therapy. “This is the first study to support its possible efficacy in solid tumors.” The study represents 10 years of effort at MSK to develop a CAR therapy for solid tumors, he adds.

. These prototype cells are built with an activity-boosting molecule called CD28 and target a molecule on B-cell leukemia and lymphoma called CD19. This cell-surface molecule is a good target for CARs because it is found on all B-cell cancers but not on other tissues that are critical for life.

Mesothelin is a potentially good target for CARs because it is present abundantly on solid tumor cancer cells but minimally on normal tissues. In addition to mesothelioma, mesothelin is found on pancreatic cancer, triple-negative breast cancer, lung cancer and others. Drs. Adusumilli and Sadelain designed the mesothelin-specific CARs used in this study. The CAR-T cells used in this study were engineered in MSK’s cell manufacturing facility, led by 

“We are encouraged by these results,” Dr. Adusumilli said. “We hope they spur interest in the potential of CAR-T cell therapy for solid tumors.”

This article was originally published by 

Results from a clinical trial in people with mesothelioma indicate that an experimental chimeric antigen receptor-T cell therapy is safe and may provide benefit to patients, especially in combination with other immunotherapies.

Matthew Tontonoz

Who Should Be Tested for a BRCA Mutation? The Science Is Evolving

Scientists See Potential in Cellular "Death by Iron" for Cancer Treatment

CAR Therapy for Solid Tumors Draws Attention at Annual Cancer Conference

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