image: Microscope in MSK Research Lab
Credit: Memorial Sloan Kettering Cancer Center
A new tactic for overcoming breast cancer drug resistance
The most common type of breast cancer, estrogen receptor positive, has been effectively treated with hormone therapy combined with drugs that block cell division called CDK4/6 inhibitors. However, it has been impossible to predict how long people will respond to this drug combination. In some patients, the disease is controlled for years, but in others, the cancer starts progressing again after just a few months. This presents a dilemma for doctors trying to decide whether to scale up or down this treatment regimen.
To understand why resistance emerges, a research team led by physician-scientist Sarat Chandarlapaty, MD, PhD, analyzed samples from thousands of breast cancer patients receiving the combined therapy. They found that tumors with a short-lived response to treatment had a mutation in the p53 gene. The researchers discovered that an enzyme called CDK2 plays a key role in allowing the p53-mutated tumors to begin growing again. Further, working with breast cancer models in the lab, they found that blocking CDK2 and CDK4/6 together could put these p53-mutated tumors into a deep, arrested state.
Researchers are now beginning to test CDK2 inhibitors in combination with CDK4/6 inhibitors in clinical trials at MSK. “This could provide a major advance for the large group of people whose breast cancers have mutations in p53 or related genes,” Dr. Chandarlapaty says.
Read more in Cancer Cell.
Prostate cancer radiotherapy proves effective earlier in treatment course
Patients with metastatic castration-resistant prostate cancer saw improved disease control and superior quality of life using a therapy called 177Lu-PSMA-617 (Pluvicto®) compared with second-line hormonal approaches, a phase 3 clinical trial led by MSK medical oncologist Michael Morris, MD, found.
In 2022, the U.S. Food and Drug Administration approved 177Lu-PSMA-617 for patients with metastatic castration-resistant prostate cancer that had spread despite treatment with an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy. 177Lu-PSMA-617 selectively seeks out a specific protein on the cancer cell surface called PSMA, delivering radiation that destroys the cancer cell. The FDA approval was based on a clinical trial co-led by Dr. Morris.
Results from the new, phase 3 trial potentially expand the use of 177Lu-PSMA-617 to patients who have not yet received taxane therapy. The randomized trial in 468 patients showed that 177Lu-PSMA-617 prolonged progression-free survival (the period when the disease did not progress) in people who received it compared with those given a second ARPI.
“A standard approach for patients with metastatic prostate cancer has been to give an ARPI, and then if that fails, to give a taxane,” Dr. Morris explains. “But some doctors and patients have been delaying taxane therapy due to side effects, and instead switch to a different hormonal therapy. This trial suggests patients will be happier, with fewer side effects and a better quality of life if we proceed straight to 177Lu-PSMA-617.”
Read more in The Lancet.
MSK Presentations at ASTRO Annual Meeting
MSK researchers presented radiation treatment advances at the American Society for Radiation Oncology (ASTRO) Annual Meeting, which took place September 29–October 2, 2024. Among the highlights:
MSK-led study provides new guidelines to prevent a rare complication from targeted radiation therapy
Stereotactic body radiation therapy (SBRT) is a type of targeted radiation used to treat cancers that have spread (or metastasized) to the lung, liver, and spine, among other places, while minimizing damage to healthy tissue. A rare complication from spine SBRT known as radiation myelitis can cause swelling in the spine, leading to tingling or numbness in the limbs, difficulty maintaining balance, or paralysis. These symptoms can resolve after treatment but sometimes persist. Minimizing the risk of this complication requires new research to create updated dosing guidelines.
A new study led by radiation oncology resident Christopher Jackson, MD, MS, and radiation oncologist and early drug development specialist Daniel Higginson, MD, has provided insights into the optimal SBRT dose for those with spinal metastasis. Their team reviewed the medical records of over 1,400 patients who received SBRT for spinal metastasis, including the radiation dose each patient received, the side effects, and the outcome of treatment. The goal was to find the dosing sweet spot, where patients responded well to treatment without experiencing radiation myelitis.
Based on the data they collected, the study’s authors identified new radiation dose guidelines to minimize the risk of radiation myelitis. These new guidelines will help inform the optimal SBRT delivery for patients with spinal metastasis worldwide.
Read more in the International Journal of Radiation Oncology, Biology, Physics.
Proton therapy effective against previously treated head and neck cancers
A phase 2 clinical trial led by radiation oncologist Nancy Lee, MD, shows that proton therapy can stop the progression of recurrent head and neck cancers that have received previous radiation therapy.
Even after effective treatment, head and neck cancers can return in the same area. If these cancers received radiation the first time, it can be especially challenging to treat them with another round. The cancer becomes resistant, and the surrounding healthy tissue can’t tolerate the additional doses without toxic side effects.
Proton therapy, an advanced, very precise form of radiation using charged particles, can reduce the dose to normal tissues. The phase 2 trial showed that proton therapy can stop these recurrent cancers from growing and extend survival. Among 88 patients, after five years, the cancer had been controlled in 38% of patients, and 32% had survived.
“These are remarkable results for patients who had received multiple lines of other therapy and were quite sick with their disease — and yet we were still able to provide a long-term survival benefit,” Dr. Lee says. “These results suggest proton therapy is an effective, less toxic alternative to standard radiation therapy.”
Read more in the International Journal of Radiation Oncology, Biology, Physics.