News | Radiation Therapy | March 08, 2016

Clinical Review Explores Role of Radiotherapy in BRCA Mutation Breast Cancer Treatment

Results could help radiation oncologists better target treatment

radiation therapy, BRCA mutation, breast cancer treatment, Red Journal study

March 8, 2016 — In light of conflicting and inconclusive clinical data on the benefit of radiation therapy (RT) in cancer patients with the BRCA1 and BRCA2 mutation, a clinical review examined the current status of data regarding BRCA1 and BRCA2 deficiency and radiation therapy sensitivity. The authors also reviewed a potential strategy to intensify the effects of RT by poly(ADP-ribose) polymerase inhibitors (PARPi), the pharmacologic drugs under investigation as monotherapy for the treatment of breast cancer in patients with BRCA1 and BRCA2 mutations. 

Authors Junran Zhang, M.D., Ph.D., and Charlene Kan, M.D., Ph.D., Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio, and University Hospitals Seidman Cancer Center, Cleveland, found mixed results from clinical and laboratory research into the sensitivity of cancer cells with the BRCA1 and BRCA2 mutation in their clinical review, “BCRA1 Mutation: A Predictive Marker for Radiation Therapy?”

The review was published in the International Journal of Radiation Oncology • Biology • Physics (Red Journal), the official scientific journal of the American Society for Radiation Oncology (ASTRO).

“Although there has been concern that treating patients with BRCA 1 and BRCA2 mutation with radiation could cause more toxicity and possibly increase the risk of secondary malignancies, retrospective clinical studies have not proven this,” Zhang said.

Available data provides no real evidence that a genetic alteration in BRCA1 and BRCA2 has a significant role in RT-induced toxicity and secondary cancer risk, Zhang and Kan said. However, an increase in the risk of contralateral breast cancers in BRCA mutation carriers is significant.

Zhang and Kan cited numerous studies on the topic, including a multinational study by Pierce et al (77), which compared women with BRCA1 or BRCA2 mutation treated with either breast-conserving therapy and RT or mastectomy alone. In that study, Pierce and colleagues found that the local recurrence rates were higher in those treated with both breast-conserving therapy and RT (30.2 percent) at 20 years than in those treated with mastectomy (5.5 percent) at 20 years (77). No difference was noted in overall survival or regional or systemic recurrence. The risk of contralateral breast cancer was high regardless of whether adjuvant RT was given, exceeding 40 percent, suggesting that low-dose scatter from RT does not seem to increase the risk of developing breast cancer.

Zhang and Kan explained that DNA repair, including the vital double-strand break repair, is key for normal and cancer cell survival. Double-strand breaks (DSBs) are the most cytotoxic forms of DNA damage, they said. DSBs can be caused by replication stress or a principle cytotoxic lesion from ionizing radiation (IR) and radiomimetric chemicals.

BRCA1 and BRCA2 are two of the most important proteins required for homologous recombination (HR)-mediated DSBs repair, they said. Hereditary breast and ovarian cancer (HBOC) syndrome, which is related to a high risk of developing breast cancer and ovarian cancer, is due to the mutation in the BRCA1 and BRCA2 proteins.

“BRCA1 mutations lead to the sensitivity to IR. We and others have reported that BRCA1 promotes HR and non-homologous end joining (NHEJ), which are two major pathways required for repair of DSBs induced by IR. However, which DSB repair pathways controlled by BRCA1 play a more important role in the regulation of the response to IR remains unknown,” Zhang said.

The concept that RT might be particularly effective in BRCA1-deficient tumors is still theoretical, she said.

“Some studies suggest these BRCA1 and BRCA2 cancers are more sensitive, which would indicate better outcomes when treated with radiation; however, others do not,” she said. “The most recent studies indicate that these women benefit from radiation to the same degree as those with sporadic breast cancers.”

Zhang and Kan also discussed the potential for PARP inhibition (PARPi) treatment, a hot topic in the field of DNA repair in recent years. BRCA1 cells are deficient in DSB repair, making them sensitive to DNA damaging agents. This discovery opened up the possibility of the BRCA1- and BRCA2-controlled pathways being used for more effective cancer treatment through PARP inhibition and other novel therapeutic approaches, Zhang and Kan wrote.

“As our understanding of the mechanisms and biochemical details of the role of BRCA1 in DNA damage response increases, the potential methods to target treatment for patients with BRCA1 deficiency will emerge and will have an enormous effect on future RT and chemotherapy protocols,” they said.

“Success requires the in-depth characterization of the pathways controlled by BRCA1. It will be of great interest to observe how PARPi and other novel therapeutic approaches based on the molecular pathways controlled by BRCA1 and BRCA2 affects the clinical outcomes of RT, in particular, in breast cancer treatment.”

Well-funded clinical trials are needed to determine if PARPi is feasible and safe, Zhang said. Further research may also identify combinations of chemotherapy with or without radiation that may be more effective in those with BRCA1 and BRCA2 mutations.

For more information:

Related Content

Videos | Radiation Therapy | February 20, 2019
ITN Associate Editor Jeff Zagoudis speaks with Vinai Gondi, M.D., director of research and CNS neuro-oncology at the
Joseph J. Cappello Named Executive Director of Are You Dense Nonprofits
News | Breast Density | February 20, 2019
The boards of Are You Dense Inc. and Are You Dense Advocacy Inc., founded by the late Nancy M. Cappello, Ph.D.,...
Study Unveils Blueprint for Treating Radiation-Resistant Brain Tumor

NIH-funded researchers showed how gliomas may be treated with radiation and drugs that block DNA repair. Image courtesy of Castro lab, Michigan Medicine, Ann Arbor


News | Radiation Therapy | February 19, 2019
February 19, 2019 — Researchers at the University of Michigan recently searched for new brain tumor treatments by exp
Congress Directs FDA to Establish Federal Breast Density Inform Standard
News | Breast Density | February 19, 2019 | Jeff Zagoudis, Associate Editor
As part of a federal spending bill passed late Friday, Congress directed the U.S. Food and Drug Administration (FDA) to...
Amazon Comprehend Medical Brings Medical Language Processing to Healthcare
News | Artificial Intelligence | February 15, 2019
Amazon recently announced Amazon Comprehend Medical, a new HIPAA-eligible machine learning service that allows...
Videos | Radiation Therapy | February 15, 2019
ITN Associate Editor Jeff Zagoudis speaks with Vinai Gondi, M.D., director of research and CNS neuro-oncology at the
New Targeted Therapy for Recurrent Brain Tumors Implanted for First Time
News | Radiation Therapy | February 15, 2019
University of Minnesota Health (M Health) is the first in the United States to begin offering GammaTile Therapy, a new...
Densitas Enters Partnership Agreement With TeleMammography Specialists
News | Breast Density | February 14, 2019
Breast imaging analytics company Densitas Inc. announced a new collaboration partnership with TeleMammography...
Hologic Launches Unifi Analytics Business Intelligence Tool
Technology | Analytics Software | February 12, 2019
Hologic Inc. announced the U.S. launch of Unifi Analytics, a business intelligence tool that allows healthcare...
Mount Sinai's Digital 3-D Mammography Van Rolls Into New York City
News | Mammography | February 11, 2019
Mount Sinai Hospital recently launched the Mount Sinai Mobile Mammography Program (MMP), bringing essential breast...