How genetic screening altered the course of treatment in an aggressive form of breast cancer
Recent trends indicate that early onset of breast cancer is becoming more prevalent, with about 5-10% being inherited. While treatment options have considerably increased over the past few years, it is becoming clear that they may not work for all types of breast cancers. Recently, genetic testing to identify gene mutations associated with breast cancer is gaining prominence, mainly because of its role in early identification of individuals at risk, and for choosing optimal therapeutic option and even predicting the prognosis. While genetic testing can play a lead role for individualization of treatment in patients already diagnosed with cancer, a surprisingly less-talked about, but important scenario is the addressal of anxiety and uncertainty in relatives of cancer patients who consider themselves at risk of developing the disease. Discussed here is a case where genetic testing not only proved to be an important tool to facilitate effective treatment, but also where the family was made aware of the potential cancer threats that may await them in the future.
Smita (name changed), a 55-year old female, was diagnosed with breast cancer (ER-ve/PR- ve/Her2+ve) that had metastasized to the lung, liver and the brain. The patient was put on Herceptin treatment, but the progression of the disease did not seem to abate. The patient had a family history of pancreatic and breast malignancy in first and second-degree relatives, respectively. Considering the progression of her cancer, and the strong familial history, she was advised by genetic counselors at HCG, Bengaluru, to consider undergoing genetic screening. She agreed to try this option and consequently underwent both somatic and germline analysis. The test results came back positive for PIK3CA and p53 mutations in addition to a pathogenic BRCA1 mutation. In the field of molecular oncology, it is well known that BRCA1 is a tumour suppressor protein that helps repair damaged DNA, while the PIK3 (phosphatidyl 3-kinases) are cellular enzymes that play an active role in cell-pathways that are involved in cell growth and survival. Mutations in genes that regulate these proteins have been shown to be strongly associated with many types of cancers, including that of the breast. In addition, clinical studies have shown that individuals with PIK3CA mutations are resistant to Herceptin, but may preferentially respond to mTor inhibitors such as Everolimus. This information obtained from genetic screening appeared to be strongly relevant to Smita’s condition.
Dr Mithua Ghosh, Director of Research and Development at HCG, explains that though such information is useful clinically, it is important to understand that most clinical trials that have reported these findings have been in non-Indian ethnic groups and regions, and hence there is no guarantee that such alternative treatment options would work for Indian woman. Despite such limitations in research findings, Dr Ghosh’s directive is to offer an alternative treatment plan. In Smita’s case, the mutations gave an indication as to why Herceptin was not effective for her. After discussions with the counselors and oncologists, Smita was taken off of Herceptin and instead started on Everolimus and is now under constant follow-up.
In the pre-genetic screening era, the ambit of clinical care would have ended at providing treatment to the patient. However, with the genetic screen results at hand, Smita’s children were also advised to undergo genetic screening for mutations in the BRCA gene. Out of her 3 children, one son and one daughter were found to be positive for pathogenic BRCA1 mutation. Since clinical studies have shown that genetic alterations in BRCA1 gene strongly increase the risk of breast, ovarian and prostate cancer, Smita’s family members were advised constant surveillance and routine screening for cancer as a preventive measure. Some at-risk women may also consider prophylactic mastectomy or prophylactic salpingo-oophorectomy. However, it is a known fact that genetic mutations only increase the probability of a potential later cancer event and most likely cannot be the sole causative factor.
According to Dr Ghosh, genetic screening is typically advised to patients with an early onset of disease, previous family history of cancer, recurrent cancers, and many other criteria as recommended by the National Comprehensive Cancer Network (NCCN) guidelines. Such patients undergo genetic counselling where the patient is interviewed in depth and all histories documented. For many, the cost of the genetic testing is unaffordable, and only about 50-60% patients agree to genetic screening, although this trend is on the rise as the benefits of genetic screening are becoming more prevalent. In addition to the index patient, family members are also counselled to undergo testing for positive mutations, with the aim of potentially catching the cancer progression early on and preventing any cancer associated mortality. Keeping abreast of the latest technology in genetic testing is important for the doctors, while patients must be sufficiently counselled as to its pros and cons.