By Robert Levy
The soundtrack of cancer research is filled with countless "a-ha" moments of discovery, and with the echoes of those moments — instances when scientific breakthroughs result in new and better treatments. Lately, those echoes have been multiplying.
For years, scientists have been probing the genetic vocabulary of tumors — the mistakes, encoded in DNA, that cause normal cells to mutate and become cancerous. At first, these findings were informative but not actionable — critical for understanding what drives cancer but not yet translated into effective therapies. More recently, the balance has shifted, with the arrival of a new generation of targeted drugs, many approved as standard therapies and many more undergoing clinical trials.
The availability of targeted therapies means that for many cancers, physicians can offer patients more personalized care. Treatment is increasingly geared to the genetic signature of each patient's tumor, the set of mutations and other abnormalities spurring its growth. In women's cancers in particular, doctors estimate that genetic information now guides the treatment of about 10-20% of patients with metastatic disease, a percentage expected to rise in the next few years as new targeted therapies become available.
"We're applying what has been learned in laboratory science to create new treatment options for patients," says Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber. "Many of these options are available today, as standard therapies, and others are producing very promising results in clinical trials."
Inherited vs. Acquired Mutations
Genetic information about patients and their cancer is obtained by two types of tests. Germline testing, done by a simple blood test or saliva sample, reveals a person's genetic inheritance, the genetic variations she was born with that may affect her risk for certain types of cancer. Somatic testing, usually performed on a sample of tumor tissue, indicates the genetic abnormalities that the tumor has acquired. These alterations may influence how the tumor behaves, whether it's likely to spread, and, critically, which targeted drugs it may be susceptible to. Many patients with advanced or metastatic cancer require both germline and somatic testing.
People who learn they have a genetic predisposition to cancer may opt to be monitored frequently for the disease, take steps to lower their risk, and inform their siblings and children of the test results so they can be tested as well. Patients whose tumors are found to harbor "druggable" mutations may be eligible for treatments that target those mutations.
In Gynecologic Oncology, "Our goal is that every patient undergo germline testing as well as somatic testing of their tumor," Dr. Matulonis remarks. The value of somatic testing is particularly evident in the case of ovarian cancer, where patients whose tumors are found to contain mutations in the genes BRCA1 or BRCA2 may be treated with drugs known as PARP inhibitors. BRCA mutations interfere with cancer cells' ability to repair DNA damage — a weakness that PARP inhibitors exploit by blocking other, standby DNA-repair pathways.
Another mutated gene ripe for targeting in gynecologic cancers is KRAS. As part of a trial available at Dana-Farber and led by Ryan Corcoran, MD, PhD, of Massachusetts General Hospital, investigators are studying a combination of the drugs trametinib and navitoclax in patients with ovarian, cervical, or endometrial cancer. Because KRAS is notoriously difficult to disable with targeted drugs, the drug duo muzzles one of the genes KRAS acts on, impeding the flow of cell-growth signals. The combination was shown to be safe in a phase I trial and is now being tested in patients with a range of cancers, including 25 with gynecologic malignancies, says Jennifer Veneris, MD, PhD, who, with Geoff Shapiro, MD, PhD, is involved in Dana-Farber's participation in the trial.
Jennifer Veneris, MD, PhD
Occasionally, somatic testing will turn up an exotic gene variation in a tumor — a mutation rarely found in that type of tumor but for which a targeted therapy is available.
One such case involved a patient from the Midwest diagnosed with metastatic endometrial cancer in 2015. After years of surgery, chemotherapy, and relapse, she came to Dana-Farber/Brigham and Women's Cancer Center, where her tumor tissue was analyzed by Profile, a program that scans for nearly 500 genomic alterations linked to cancer. The test showed the cancer to be "hypermutated," beset by an unusually large number of genetic irregularities, including one in a gene called POLE. Knowing that hypermutated tumors with POLE mutations are often vulnerable to drugs known as immune checkpoint inhibitors, her physicians treated her with one such agent.
In a short time, CT scans showed a sharp diminution in metastases throughout her body, and she continued to improve over time, says Dr. Veneris, a member of her care team and lead author of a published report on the case. While cases like these are rare, they point to the power and promise of somatic testing.
Targeting Breast Cancer
Genetic-guided treatment has gained a place in breast cancer care as well. As with gynecologic malignancies, patients with breast cancer who carry germline BRCA mutations may be eligible for treatment with PARP inhibitors. (BRCA mutations discovered on germline testing tend to be more significant — more likely to cause breast cancer and affect its behavior — than somatic BRCA mutations, which usually are minor typos in the genetic code that play no role in cancer.) And patients whose breast tumors carry a specific mutation in the PI3 kinase gene may be treated with the targeted drug alpelisib.
Approved drugs like PARP inhibitors and alpelisib lead a much longer list of targeted agents currently in clinical trials for breast cancer. "Tumor genetic testing is important for all patients with metastatic breast cancer, which can be performed on tumor tissue or on a liquid biopsy, which looks for tumor DNA in a blood sample," says Brittany Bychkovsky, MD, MSc, of the Division of Breast Oncology. "Increasingly, mutations detected by these methods can be targeted with standard therapies or agents in clinical trials."
Brittany Bychkovsky, MD, MSc
One such clinical trial, led by Ian Krop, MD, PhD, associate chief of Breast Oncology, is testing the targeted agent TAS-120 in patients with metastatic breast cancer carrying an FGFR amplification — redundant copies of the EGFR gene. Another trial, co-sponsored by Dana-Farber and led by Nadine Tung, MD, of Beth Israel Deaconess Medical Center, and Judy Garber, MD, MPH, chief of Cancer Genetics and Prevention at Dana-Farber, is examining the safety and effectiveness of the PARP inhibitor olaparib in patients with metastatic breast cancer who don't have a germline BRCA mutation but do have somatic mutations in BRCA1, BRCA2, or nearly 20 other genes involved in DNA repair.
A Center for BRCA
Dana-Farber's new Center for BRCA and Related Genes is a prime example of the place genetic testing has attained in cancer treatment. Established in August 2020, it unites specialists from multiple disease centers to provide the latest treatments to patients with cancers with BRCA or related mutations, regardless of the type of cancer they have.
"Dana-Farber has a rich tradition of discovery in the field of BRCA genes, both in basic research and in leading clinical trials of therapies targeting these genes" says Panos Konstantinopoulos, MD, PhD, director of translational research, Gynecologic Oncology, and co-leader of the center with Dr. Garber and Dipanjan Chowdhury, PhD. "The new center will focus on clinical treatment trials of new agents, trials of risk-reducing strategies, and studies of novel early detection markers, in addition to expert care of patients and testing of their family members."