Indian scientists have identified mutations in three genes and other aberrant genetic mechanisms that raise the risk of disease recurrence in women who have successfully completed treatment for breast cancer.
The findings could lead to genetic tests that predict the likelihood of disease recurrence in breast cancer patients and guide alternative treatment options, the researchers at the National Institute of Biomedical Genomics (NIBMG), Kalyani, and the Tata Memorial Centre (TMC), Mumbai, have said.
They have found that women with this three-gene mutation signature face a 2.4-fold higher risk of recurrence within five years of treatment for hormone-receptor-positive breast cancers which account for 50 to 60 per cent of such tumours worldwide, including in India.
Most patients with hormone-receptor breast cancers respond to so-called
endocrine therapy with anti-estrogen molecules and other anti-cancer drugs but 20 to 40 per cent of all women with breast cancer eventually develop recurrent disease.
A significant proportion of breast cancer patients with hormone-receptor-positive breast cancer develop resistance to endocrine therapy. Medical reviews of breast cancer treatment outcomes have found that such resistance accounts for 10 per cent of recurrence and up to 30 per cent of metastasis, a condition marked by the spread of breast cancer tumours to other organs such as the bones, liver, or lungs.
“The genetic mechanisms underlying this resistance are not fully known,” said Nidhan Biswas, an associate professor and a cancer genomics specialist at the NIBMG who led the study. “Our study was designed to probe the genetic factors that contribute to this resistance.”
Biswas, collaborating with Sudeep Gupta, a professor of medical oncology at the TMC, and others analysed whole genomes from tumour tissue samples from 20 women with endocrine treatment-responsive tumours and 20 women with endocrine treatment-resistant tumours.
They found mutations in three specific genes, called PIK3CA, ESR1 and TP53, in 40 per cent of the treatment-resistant tumours but only in 5 per cent of the treatment-responsive tumours, indicating that the mutations increased the risk of recurrence.
The NIBMG-TMC study was published in the journal Communications Biology on Monday.
Among the 20 treatment-resistant women, a follow-up analysis on a subset of nine women found that seven had relapsed within an average of one year after their therapy. The most frequent organs where metastasis occurred in treatment-resistant women were bones and the liver.
The researchers have confirmed their finding through a larger dataset from 84 women with the three-gene mutation signature and 145 women without these mutations, drawn from The Cancer Genome Atlas, an initiative by the US National Cancer Institute.
The genome analysis of treatment-resistant tumour tissues also revealed defects in DNA repair mechanisms that contribute to genomic instability and telomere shortening — the loss of protective DNA sequences at the ends of chromosomes that increase risks of genetic instability and disease.
“These findings may open up the pathway for new treatment options to target the genome instability mechanisms,” Biswas said. Drugs called PARP inhibitors, for instance, that target DNA repair defects have been under consideration as options in breast, ovarian and prostate cancer.
“Our findings add fresh evidence for the evaluation of PARP inhibitors in treatment-resistant breast tumours,” said Arnab Ghosh, the study’s first author at NIBMG. The other co-authors are Partha Mazumder at the Indian Statistical Institute, Calcutta, Rohan Chaubal and Pallavi Parab at the TMC, and Chitraparita Das, Subrata Das, Arindam Maitra at the NIBMG.
