Study finds relationship between PTEN loss, potential for immune response in BRCA 1/2-deficient ovarian cancer

April 16, 2018, Perelman School of Medicine at the University of Pennsylvania

The protein known as phosphatase and tensin homolog (PTEN) is frequently mutated or affected by cancer as tumors develop. Now a new study from the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania shows PTEN may serve as a marker for whether a patient with BRCA 1-2 deficient ovarian cancer is likely to respond to checkpoint inhibitor therapy. Researchers found the tumors that had PTEN loss were less likely to generate an immune response than tumors that maintain PTEN levels. They will present their findings at the American Association for Cancer Research Annual Meeting in Chicago on Wednesday (Presentation #5729).

BRCA1/2-deficient ovarian cancer is a specific subset of ovarian cancer. Genes known as BRCA1 and BRCA2 are involved in cell growth and the repair of damage to DNA. Mutations or deficiencies in these genes can cause DNA to go unrepaired, which increases the chance of developing cancer. These cancers are often initially susceptible to treatments that damage the 's DNA, such as platinum chemotherapy, but most develop resistance and require other treatment strategies. One strategy is the use of anti-PD1/PDL1 immunotherapies. Although clinical trials have collectively shown a disease control rate of approximately 45 percent using this approach in ovarian cancer, they have yet to establish selective benefit in BRCA1/2-deficient cancers, which should generate stronger anti-tumor immune responses given their higher mutation rate.

Researchers in the Basser Center for BRCA analyzed data on 86 ovarian tumors, from the Cancer Genome Atlas (TCGA—68) as well as from Penn (18), to evaluate potential immunosuppressive mechanisms in BRCA1/2 deficient tumors and to identify factors that may determine response to PD1/PDL1 inhibitors.

"PTEN is a genomic marker we already routinely measure, and based on published data we wanted to know if we could use it to predict which BRCA1/2 mutated tumors are likely to respond to checkpoint inhibitors and which are not," said the study's senior author Katherine L. Nathanson, MD, deputy director of the Abramson Cancer Center and director of Genetics at the Basser Center for BRCA. Adam Kraya, Ph.D., a post-doctoral fellow at Penn, was the study's lead author and will present the findings at AACR.

The TCGA analysis showed tumors with PTEN loss in the background of BRCA1/2 deficiency had lower levels of cytolytic immune molecules and immune-activating pathways that would normally drive immune responses against tumors. In Penn ovarian tumors, the levels of immune molecules like CD3, CD8, FoxP3, and PRF1 were found at significantly lower levels with PTEN loss. These data suggest that immune cells were not able to infiltrate tumors as effectively nor mount anti-tumor responses when PTEN is lost. In other words, PTEN loss correlates with loss of molecules that can generate an immune response.

"This is an effect we've seen in other disease types like melanoma and leiomyosarcoma, but this is the first study to identify the effect in BRCA-deficient ," Nathanson said.

Nathanson and her team are also investigating a similar question in breast .

Explore further: Retaining one normal BRCA gene in breast, ovarian cancers influences patient survival

Related Stories

Retaining one normal BRCA gene in breast, ovarian cancers influences patient survival

August 22, 2017
Determining which cancer patients are likely to be resistant to initial treatment is a major research effort of oncologists and laboratory scientists. Now, ascertaining who might fall into that category may become a little ...

BRCA1 mutations in breast and ovarian cancer can predict treatment resistance

July 25, 2016
Mutations in the BRCA1 gene are one of the most common risk factors for breast and ovarian cancers. Although tumors that harbor BRCA1 mutations initially respond well to cancer treatments, many tumors eventually become less ...

FDA approves first drug for tumors tied to breast cancer genes

January 12, 2018
(HealthDay)—The U.S. Food and Drug Administration on Friday approved the first drug aimed at treating metastatic breast cancers linked to the BRCA gene mutation.

Risk of breast and ovarian cancer may differ by type of BRCA1, BRCA2 mutation

April 7, 2015
In a study involving more than 31,000 women with cancer-causing mutations in the BRCA1 or BRCA2 genes, researchers at The Basser Center for BRCA, the Abramson Cancer Center, and the Perelman School of Medicine at the University ...

Deficiencies in repair of DNA identified in many types of solid tumors

May 17, 2017
A new investigation of more than 48,000 stored tumor samples finds evidence of a key deficiency in a repair mechanism designed to keep DNA from being mutated and causing cancer.

Novel combination therapy shown to be effective in ovarian cancer

December 19, 2017
Researchers at The Wistar Institute have found that combining PARP inhibitors, recently approved for the treatment of BRCA-mutant ovarian cancer, with another small molecule inhibitor was effective to treat ovarian cancers ...

Recommended for you

'Druggable' cancer target found in pathway regulating organ size

November 20, 2018
It's known that cancer involves unchecked cell growth and that a biological pathway that regulates organ size, known at the Hippo pathway, is also involved in cancer. It's further known that a major player in this pathway, ...

A study suggests that epigenetic treatments could trigger the development of aggressive tumours

November 20, 2018
A study headed by the Institute for Research in Biomedicine (IRB Barcelona) and published in the journal Nature Cell Biology examined whether the opening of chromatin (a complex formed by DNA bound to proteins) is the factor ...

Redefining colorectal cancer subtypes

November 20, 2018
There is a long-standing belief that colorectal cancer (CRC), which causes some 50,000 deaths in the United States each year, can be categorized into distinct molecular subtypes. In a paper published recently in the journal Genome ...

Proposed cancer treatment may boost lung cancer stem cells, study warns

November 20, 2018
Epigenetic therapies—targeting enzymes that alter what genes are turned on or off in a cell—are of growing interest in the cancer field as a way of making a cancer less aggressive or less malignant. Researchers at Boston ...

New drug discovery could halt spread of brain cancer

November 19, 2018
The tissues in our bodies largely are made of fluid. It moves around cells and is essential to normal body function.

A molecule for fighting muscular paralysis

November 19, 2018
Myotubular myopathy is a severe genetic disease that leads to muscle paralysis from birth and results in death before two years of age. Although no treatment currently exists, researchers from the University of Geneva (UNIGE), ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.