By sequencing the whole exome of 44 early-stage gallbladder cancer samples taken from patients, researchers at Tata Memorial Centre, Mumbai, have been able to identify the mutations that cause the cancer. More importantly, based on the genomic analysis, the team has made it possible for clinicians to know in advance which gallbladder cancer patients are likely to benefit from a particular therapy that is currently being used for treating colorectal cancer.
Though rare globally, there is high incidence of gallbladder cancer in India and China. In India, the cancer is particularly seen in people living along the Gangetic plains. Women in Delhi alone have a high incidence of 21.5 per 100,000, which is the highest in the world. Yet, there are almost no treatment options available. This is now set to change.
A team led by Dr. Amit Dutt from the Integrated Cancer Genomics Laboratory at ACTREC, TMC found that in about 40% of samples sequenced, a particular signalling pathway (ErbB/HER) was significantly altered either by mutation or by having multiple gene copies. Changes in the gene copy number in the ErbB family of receptor pathway are responsible for causing colorectal cancer too.
The ERbB pathway belongs to the EGFR family. And in the case of gallbladder cancer, the ErbB2 binds to EGFR to activate the pathway. So the anti-EGFR therapy currently being used for treating colorectal cancer can potentially be used in gallbladder patients to stop the growth of cancer. Based on studies carried out in the laboratory, it is likely that the drug will inhibit the spread of gallbladder cancer. This becomes particularly important as gallbladder cancer is an aggressive disease — it spreads (metastasis) rapidly and the five-year survival rate is only about 20%.
“Based on genomic analysis we found that not all patients with ErbB2 mutation will benefit from the anti-EGFR therapy. That is because patients having a specific mutation in the KRAS gene (another member of the ErbB/HER pathway) that co-occurs with the ErbB2 mutation will not respond to the drug,” says Dr. Dutt. The results of the study were published in the International Journal of Cancer.
KRAS mutations
The KRAS mutations are of two types — G13D and G12V. “The G12V mutation is the strongest activating mutation. So patients who have this [G12V] mutation will not respond to the anti-EGFR therapy, while those who have the G13D mutation will partially respond to treatment,” he says. And patients with G13D mutation are sixfold more likely to respond to treatment compared with G12V mutation. Patients who do not have any of the two KRAS mutations will 100% respond to the therapy.
The researchers validated the ability of the drug to treat gallbladder cancer using a mouse model. Tumours were induced in mice by transplanting human gallbladder cancer cells. Three sets of cancer cells were transplanted. In one, cancer cells with only the ErbB2 mutation were transplanted. The second set of mice received cancer cells with ErbB2 mutation and G13D mutation. The third set of mice received cancer cells with ErbB2 mutation and G12V mutation. The drug was administered orally.
All the mice with only the ErbB2 mutation were successfully treated, while a few with ErbB2 mutations and G13D were treated. However, mice with ErbB2 and G12V mutations did not respond to treatment.
“For every gallbladder cancer patient, molecular profiling (which was not done till now) can be done to know whether the patient has KRAS mutation and if so whether it is the one that partially responds to treatment [G13D] or the one which does not [G12V],” Dr. Dutt says.
This approach will help clinicians take an informed decision to specifically identify patients who are more likely to benefit from the anti-EGFR therapy.
“So we can potentially save patients with G12V KRAS mutation from the toxic effect of chemotherapy drug,” Dr. Dutt says.
“The study gives a potential new target in precision medicine. It’s a step forward for treating early-stage gallbladder cancer and has clear practical application. It forms a basis to evaluate the drug in patients through clinical trials. And if the trial is successful then we can make it a standard of care,” says Dr. Shailesh V. Shrikhande from the Department of Gastrointestinal and Hepato-Pancreato-Biliary Surgical Oncology, TMC and one of the two first authors of the paper.
“In a cancer that is aggressive and where only 20% survive for five years, we got an impetus to work on this discovery and conduct clinical trials,” Dr. Shrikhande adds.
