CC 2015: Study Finds Significant Genetic Differences Between Breast Cancers That Relapse and Those That Do Not

CC 2015: Study Finds Significant Genetic Differences Between Breast Cancers That Relapse and Those That Do Not

THIS IS AN A HA MOMENT – GENES DRIVE THE MACHINE AND THIS IS A TOUR DE FORCE DRIVE OF EXCELLENT RESEARCH.

IMAGINE FINDING AND THEN BOCKING THAT 1 IN 5 OR WHATEVER IT TURNS TO BE GENE TO SOW OR EVEN PREVENT A RECURRENCE iT WILL PROBABLY INVOLVE MULTIPLE FACTORS BUT WHAT A START!

By The ASCO Post
key Points:

  • Genetic differences were found between primary and recurring tumors, with some differences being acquired during the later phases when the cancers recurred and started to spread.
  • Among these later-stage mutations, the researchers found “compelling evidence” for the tumor suppression activity of two related genes called JAK2 and STAT3 that operate within the same signaling pathway.
  • These findings have led to the development of clinical trials for breast cancer using JAK inhibitors in the hope they will slow cancer progression.

Although most patients with breast cancer are cured after treatment, in about one in five patients, the cancer will recur, returning either to the same place as the original tumor or metastasizing to other parts of the body. Now, researchers have taken an important step toward understanding why some primary breast cancers return and others do not. They have found that the genetic factors driving the cancers that recur are different from those found in the cancers that do not. This discovery could enable doctors to identify patients at high risk of their cancer returning and to target the genes responsible for recurrence when the cancer is first diagnosed to prevent its return. Lucy Yates, MD, a clinical research oncologist from the Wellcome Trust Sanger Institute, Cambridge, United Kingdom, presented the results (Abstract 1804) to the 2015 European Cancer Congress in Vienna, Austria.

Study Background

Dr. Yates and her team analyzed data from the genetic sequencing of 1,000 breast cancer patients’ tumors. In 161 cases, this included samples taken from recurring tumors or metastases. They compared the cancer genes found in cancers sampled at first diagnosis with those found in relapsed cancers. They found that there were genetic differences between primary and recurring tumors, with some differences being acquired during the later phases when the cancers recurred and started to spread.

The researchers said these findings have important implications for personalized medicine. If individual cancers can change genetically over time, this means that treatments that target a particular genetic mutation, either in the clinic or in trials, may have to change as the disease progresses, guided by taking regular samples of cancer tissue rather than basing the treatment only on samples taken when the cancer is first diagnosed.

The study is the largest and most comprehensive performed to date, reported the researchers, in terms of the number of samples from relapsed breast cancers and the 365 genes involved in cancer-related pathways that have been investigated simultaneously.

“We have found that some of the genetic mutations that drive breast cancers that relapse are relatively uncommon amongst cancers that do not relapse at the point of primary diagnosis. We believe that the differences we have seen reflect genetic differences that can predispose a cancer to return, combined with mutations acquired throughout the period from first diagnosis to the subsequent relapse. Some of these genetic alterations are potentially targetable with drugs,” Dr. Yates said.

Within an individual cancer, a wide range of genetic or epigenetic alterations accumulate and may constrain later events, which can promote the survival of the cancer through relapse. Alternatively, specific environmental factors, such as the response of the immune system, different treatments, or the environment of the metastasis itself, may have an influence on the occurrence of rare cancer genes.

Findings

Among these later-stage mutations, the researchers found “compelling evidence” for the tumor suppression activity of two related genes called JAK2 and STAT3 that operate within the same signaling pathway. “Within some breast cancers, a disruption in this signaling pathway seems to be advantageous for survival of the cancer,” Dr. Yates explained. “Interestingly, this is in contrast to the role of JAK2 in some other cancers, where overactivity of the gene drives malignancy rather than suppresses it.”

Enhanced JAK-STAT signallng is known to play an important role in breast cancer stem cell development and cancerous cell line survival, and preclinical evidence seems to suggest that inhibiting the gene would be therapeutically advantageous. These findings have led to the development of clinical trials for breast cancer using JAK inhibitors in the hope that they will slow cancer progression.

“However, our findings suggest that, in a subset of cancers, inhibiting this pathway may have the opposite effect, and this requires further investigation. In general, the observation highlights the importance of understanding the diverse nature of breast cancers in the era of precision medicine,” Dr. Yates concluded.

 

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