Breast Cancer

  • Genetic tests now accurately predict which breast cancer cases are most likely to benefit from oestrogen-lowering drugs and which don’t
  • This means many women can get breast-conserving surgery rather than full mastectomy, depending on their genetic markers
  • Indian genetic markers have shown that 30 per cent of breast or ovarian cancer cases are hereditary. That’s thrice the prevalence in the West.
  • In Indians, most breast cancers are caused by faults in BRCA1 gene, while in the West, it is equally caused by markers both in BRCA1 and BRCA2 (These genes are present in every body)
  • This has resulted in more targeted treatment
  • Early results have also shown that certain ethnicities, rather than inheritance alone, like that of Konkani, Gujarati and Maharashtrian women, are more prone
  • It’s now possible to tell which women need not undergo radiotherapy after mastectomy

Myeloid Leukaemia: The Gleevec Example

  • In 2001, the discovery of imatinib mesylate (Gleevec) was a breakthrough for myeloid leukaemia
  • It silences a protein called BCR-ABL that causes this type of leukaemia
  • BCR-ABL results from an abnormal gene due to merger of chromosomes 9 and 22
  • Before this drug was discovered, only one in three patients survived beyond five years post diagnosis. Gleevec improved survival rates to 90 per cent.
  • Genetic tests to locate BCR-ABL can be done in India now

Lung Cancer

  • Crizotinib (Pfizer discovery, sold as Xalkori) effectively tames lung cancer caused by a rogue copy of ALK gene
  • Tests in India can now identify ALK

Melanoma

  • Roche’s vemurafenib (sold as Zelboraf) pinpointedly attacks a rogue protein released by a mutated form of BRAF gene, which instructs skin cells to replicate endlessly
  • BRAF test is available in India

Liquid Biopsy

  • Since the sample is blood, it’s called liquid biopsy.
  • Helps targeted therapy in breast, colorectal and bladder cancer

Why Hereditary Testing

  • Current generalised screening approaches may not completely capture the risk for hereditary cancers

Is it all in our genes?

Almost all cancers (expect a few) are driven or caused genetically. Cancers are either somatic or inherited. Somatic cancer occurs due to genetic changes in our body arising from external factors such as diet, environment, smoking, exposure to radiation etc. In a few cases, people are born with a gene mutation that they inheri­ted. This damaged gene increases the risk of cancer. This is referred to as hereditary cancer.

How do rogue genes work?

“When people inherit an abnormality, the genes don’t function normally and the risk of cancer increases…. Genetic testing helps in ­understanding the risk.”

Inherited cases of breast cancer are linked to two abnormal genes: BRCA1 and BRCA2. Everyone has BRCA1 and BRCA2 genes. They help repair cell damage, and keep breast, ovarian and other cells growing normally. When abnormalities (or mutations) in these are inherited, the genes don’t function normally, and the risk for breast, ovarian and other cancer risk increases. Having the gene doesn’t mean they have cancer. It just means the risk is higher.

Should one take a gene test?

Genetic counselling and ­testing are extremely helpful in ­understanding the risks one might face. Genetic tests are prescribed by doctors today. How­ever, with awareness, more patients are proactively seeking these tests since they are also related to early screening and prevention.

What does a test do?

It will essentially tell them if they have a defective gene, which may not necessarily cause cancer but does increase their risk compared to others. Someone who has a strong family history of cancer, or one who is generally anxious about the risk of developing cancer, can talk to a genetic counsellor.

How does one prepare for a test?

Genetic tests are fairly simple to do. All you need is a blood or ­saliva sample. There are easy collection methods. It is important to go through genetic counselling to avoid panic and addressing fears. Based on the sessions, individuals are categorised according to risk: high, moderate or low-risk. This allows them to make an informed choice while opting for the tests.

Cancer Can Be Prevented’

Most of the times, diseases are a result of interaction between the environment and our genes, says bio-scientist Dr Dwaipayan Bharadwaj.
Dr Dwaipayan Bharadwaj
‘Cancer Can Be Prevented’

JNU, and fellow of the National Academy of Sciences, was once a senior principal scientist working at a public-funded genomic project. He is pushing the frontiers of genetic understanding of many diseases. Excerpts from an interview with Zia Haq:

How has newer understanding of our genes helped make fighting diseases, such as cancer, easier?

“There are some ­simple things one can do to ­prevent a lot of ­genetic aberrations, such as getting ­married at the right time.”

As a scientist, I can say what my understanding is. First of all, there is a misconception regarding genes. People don’t understand it well. If I take a sample from your hair follicle or blood or any other part, I will find the same DNA everywhere. Now these genes can modify. A gene can be methylated, for instance (put simply, methylation is one of several mechanisms through which expression of a gene is switched on or off). That kind of modification happens. But you cannot modify gene sequencing. That is constant. That’s the basic science. Now, mutation is when there is change in the gene structure. Sometimes, a portion can get deleted or a whole portion gets added wron­gly, so that instead of making a specific protein that is needed, it is making a protein that is not needed. Those are mutations. This is DNA sequence.

Genetic tests are said to be pushing the frontiers of many diseases?

People are marketing a lot of tests these days. So, now from a patient’s point of view, if there is a problem with this DNA sequence I just mentioned, it is detected very easily, early in childhood in many cases. If an entire chromosome is missing or attached, it gives rise to well-known syndromes. Cancer is just one thing. Say, for example, Down Syndrome or Turner Syndrome, which is easily treatable if detected early. Paediatricians are aware of these diseases. Take haemophilia. We know very well that if there is a mutation in the factor 8 gene, you get haemophilia. You don’t need a gene test for that. There are many things we can do to prevent some genetic diseases.

Could you explain that?

A lot of new understanding and gen­etic advancements have undoubte­dly taken place. But let me tell you an interesting thing. Forget high-tech tests, there are some simple things that one can do to prevent a lot of genetic aberrations. For example, getting married at the right time. Now, late marriage means late fertilisation of an egg from an ovum that is there for 13-14 years. It’s a like a rubber band losing its elasticity. The more the age of the mother, the more the chances of genetic faults. So, marriage at an appropriate age is a good thing. Chances of chromosomal misses or new chromosomes getting added wrongly are high with late mothers. This is ‘embryonic lethal’, meaning not good for the developing baby.

Are genes always and the only culprit?

Cancer is many things, but it is also a lifestyle disease. Obesity and ­diabetes are also lifestyle diseases. Most of the times, it is a result of interaction between the environment and our genes. Suppose I have a lung cancer gene. So, I have a gene expression that makes me vulnerable to lung cancer. Now, to precipitate the cancer, I need smoking. Suppose I don’t smoke. Even though I have the gene, I am not going to get cancer because I am not giving the faulty gene the right environment to express by indulging in smoking. The same goes for obesity. I may have the obesity gene, but if I exercise every day and take a balanced diet, I don’t allow the gene to express.

A lot of genetic tests are available these days. Are they worth it?

Genetic testing will not help in all ­cases. For example, tests to detect dia­betes are a myth. Genetic faults are only 7.5 per cent responsible. What accounts for the rest? But fortunately, in diseases like cancer, it’s different. For example, a very common genomics-oriented diagnostic in the commercial market is herceptin for breast cancer. You see, one type of breast cancer is treatable. Herceptin is used to detect the Her 2 gene, which cau­ses that cancer. It’s a genetic marker. But it’s very expensive. Now that’s not the case with diabetes.

So cancer ultimately is a disease of the genes?

Yes, but genes plus environment. I did one study with the Minnesota Mayo Clinic. I took samples from migrant Indians there, from 30 local Indians here and they sent samples of 30 white Americans, who are mostly of Viking ethnicity because the Minnesota area mostly has people of Scandinavian origin. We then checked their genetic profile. Migrant Indians and local Indians should genetically be the same. But we found that the gene profile of ­migrant Indians and Americans were the same. That’s due to the external environment.

Has modern genomics thrown enough light on many complex diseases?

You also have to understand the limitations…that modern genomics is not right now ready, except in certain cases, for diagnostics. But yes, research is giving us new understanding of the biology of diseases. For instance, coronary artery disease and obesity. In these diseases, other than say cancers like breast cancer, none of them is even 50 per cent accurate. Remember in cancer, again, there are many types…we are saying pancreatic breast, cervical cancers etc. In certain areas where we are a little sure of the origin, we have better diagnostics. Like cervical cancer. It is caused by the papilloma virus. Now we even have a vaccine to prevent it. That’s why whenever we can know the biology better and the origin better, we have a better handle. But if I talk about gastrointestinal cancers and head cancers, we don’t have much yet.

A lot of people would want to know this. Can cancer be prevented?

Let me give you one story and you’ll understand. One small study recen­tly came from a Danish group. They took 30 people of the same age group. They took samples from their leg skeletal muscles before the test. They gave them an exercise regimen for one leg for three months and then tested the leg muscles again, looking for genetic changes. In three months, they found that the exercising leg was superior in all respects, genetically speaking. So, yes, things like balanced diet and exercise can help.

You have been working on genes and lifestyle diseases. Tell us some of the outcomes.

So our group has already published a lot on things such as whether there are genetic variations within the Ind­ian population and what those are, especially in the north Indian population. We have mainly four major types of population: Indo-­European, Dravidian, Tibeto-Burman and Australoasiatic. We had collected samples from the All India Institute of Medical Sciences. Our population group for the study was mainly Hindi-speaking north Indians or Indo-Europeans. Our sample size was 14,000. We discovered a gene called TMEM163 as being associated with type II diabetes. This was previously not known. We published it in 2014.  The next step is to say that it is a ‘causal for diabetes’, meaning we have to experiment and show its role in diabetes biology and to prove it as the causative gene. That work is on. Then we can call it a diabetes gene.

Medical reality has moved on to a host of new possibilities today that give us cause for optimism in the face of what, for long, was sure, painful death. Beckoning on the frontier are not just qualitatively new treatment options for the killer disease, but early detection of vulnerability itself.

At the heart of these advancements is a better understanding of cancers at the molecular level. Doctors now look at cancer as a disease of the genes, not of the affected organs. Our genes need to be decoded daily for us to function. Sometimes, there is a ‘misfeeding’ and a wrong code gets generated, causing cells to divide uncontrollably. That’s what we call cancer.

“Cancer mortality figures indicate low rates of ­early-stage detection and poor treatment ­outcomes in India.”
M.K. Mallath, Professor, Tata Medical Centre, Calcutta

Now, the good news. Cutting-edge recent advancements, such as immuno-oncology and the discovery of at least 50 new drugs, have now enabled what doctors call ‘targeted the­rapies’. Enthusiasts say it’s the closest thing to a cure. Some targeted therapies are, in fact, sharp-focused enough to att­ack only cancer cells, sparing the body of dangerous side-effects—as was entailed in the most bankable option till now: chemotherapy. Indian doctors aren’t shying away from trying out the new means, though few patients can afford the costs at this point in time. Yet, one thing is clear: the fight against cancer is getting smarter than we think.

A targeted therapy isn’t concerned with where the tumour is located, but what kind of a mutation of genes or markers has caused it. A  gene­tic marker is a gene within a chromosome whose location has been identified. This isn’t just a shift to a higher degree of micro-level sub­tlety, and hence to a more fine-grained picture, but also to a view along a different paradigm in understanding the causative linkages of a disease that’s still essentially a mystery.

The invention of Gleevac in 2001 was a milestone. Acting directly on the errant protein, it raised the survival rates of people beyond five years of being diagnosed with a specific form of leukemia up to 90 per cent from a third. And now, gene-targeting drugs are slowly taking over the fight. This June, results from studies on the first 50 patients receiving a drug called larotrectinib were announced at the annual meeting of the American Society of Clinical Oncology (ASCO), a mega event. After 12 months since they got started on the therapy, 60 per cent, or 30 of these 50 patients, had no signs of their cancer coming back. They are, of course, still being watched. The drug acts on a particular mutation in a gene called the tropomyosin receptor kinase gene.

For Indian oncologists, the mainstay of cancer treatment has for long been an indiscriminate regimen of chemotherapy (cell-destroying drugs) and radiation—they were akin to resorting to a scorched-earth policy on the whole body, for want of more fine-tuned means. But even after the technology became available, set diagnosis preferences were such that it was rare for a doctor to order a genetic test, for instance, to precisely locate a protein that had been wrongly programmed by a rogue copy of a gene to instruct cells to multiply uncontrollably. The focus was not on what was going on at a molecular level—in other words, its cause.

In fact, doctors always knew cancer was the result of mutations of specific genes. Yet, the orthodox approach was to inflict good amounts of drugs and radiation in the hope that these would work. Partly because genetics itself was poorly understood—as a frontier science, it still is, to a large extent—and also because there weren’t too many applications available that would provide required results. So, the fight was like a blindfol­ded soldier firing randomly, when what was needed was a sharp, sniper shot.

Meena Nandal, Schoolteacher And Radio Singer

Nandal survived advanced ovarian cancer, which had developed resistance to chemotherapy. After a genetic test revealed a mutation in the BRCA2 gene, she was given a PARP inhibitor drug. She is responding well and says a “positive mind” also helped her carry through.

The results could be disastrous because the treatment wasn’t—in most cases—even meant to work on the offending gene. In a scenario where there could be hundreds of unique faults, each with its own weakness—which, once identified, could be directly targeted—a broad-sweep fusillade will by definition have a much lower level of success. And this isn’t just a theoretical point: targeted therapies are indeed demonstrably improving survival, causing cancer to go into remission for longer periods.

Take Delhi schoolteacher and AIR singer Meena Nandal. She thought her “slight” pain was the result of some “stomach problem”, probably stress from being proactive with kids at school. Until she was told, in December 2011, that she had stage three ovarian cancer. The world seemed to stop for her. Initia­lly, the chemotherapy and radiation seemed to work. “I was free of cancer for about 18 months until it came back.” The treatment was restarted, but this time, it wasn’t working.

That’s when her doctor at Delhi’s B.L. Kapoor Memorial, Amit Aggarwal, decided to order a genetic test to try and see why the cancer cells were able to dodge his treatment. A sample was taken by the Bangalore-­based Strand Life Sciences Ltd, one of the many new entities with the required technical capability. The results were illuminating. Her cancer was traced to a mutation in the BRCA2 gene—the same gene that causes breast cancer. However, the mutation was provisionally categorised as a “variant of unknown significance” or VUS. That’s code for a mutation that has not been investigated yet. So, scientists at Strand Life Sciences decided to test her extended family.

A series of investigations and computer modelling showed there was no reason besides this VUS that could have caused her condition. Worse, it ran in her family. Her younger sister, a breast cancer survivor, carried the same BRCA2 gene mutation. So was her brother. In such cases, the patient tends to be resistant to chemotherapy, and current guidelines recommend a drug called PARP inhibitor. Thanks to the gene test, Nandal began responding to the targeted therapy and is currently in remission.

According to a recent epidemiology paper in The Lancet, nearly 1 million new cases of cancer are being diagnosed in India every year. This is still low compared to cancer rates in the West—adjusted for age, for instance, India’s combined male and female incidence is about a quarter of that of Europe. Yet, the mortality burden is similar to that of high-income countries. Between 6-7 lakh people died of cancer in India in 2012, according to the study. “Such figures are partly indicative of low rates of early-stage detection and poor treatment outcomes,” says Prof Mohandas K. Mallath of the Tata Medical Centre, Calcutta, who led the study.

As cancer becomes surprisingly common, Indians are scra­mbling to cope with and prepare for it. Last summer, Nirmal Kaur sat waiting outside her doctor’s office for what seemed like a verdict on her life. Having seen her mother and aunt struggle to beat breast cancer the past two years, she finally decided to find out if she carried the cancer-causing gene herself. Kaur’s test showed she had a 65 per cent chance of contracting breast cancer. “I am better prepared and my doctors have put me on a bi-annual screening regimen,” she says.

The advance is along two flanks. First, as genetic mapping techniques become more easily available in the country, it’s becoming easier to predict the vulnerability quotient of individuals to incurable diseases, such as cancer and Alzheimer’s, as in Kaur’s case. The idea here is to catch such diseases early so that they can be treated. At the same time, deeper and richer data on Indian genes has itself thrown up new understanding unique to the country. For instance, 30 per cent of Indian breast or ovarian cancers have been found to be hereditary. “That’s three times more than the incidence in the West,” says Dr Vijay Chandru, chairman of Strand Life Sciences.

“Just because you have a family history of the disease doesn’t mean you have it. Genetic mapping helps figure out if you are susceptible.”
S. Brahmachari, Former director, CSIR and founder, IGIB

Beyond general truths, studies of Ind­ian mutation patterns are also helping create institutio­nal knowledge specific to Indian ethnicities and demography, which enable further customisation of treatment. In Indians, for instance, most breast cancers are caused by a preponderance of faults in the BRCA1 gene, while in the West, it is equally caused by both BRCA1 and 2, says Dr Chandru.

But inheritance too is more than a randomly occurring thing: certain ethnicities have a higher susceptibility. It now seems Konkani, Gujarati and Maharashtrian women are more prone, so it’s possible for doctors to decide which women need not undergo radiotherapy. “The BRCA gene happened to be the hotspot test earlier too. But it was too expensive to look at the whole gene, so you would only look for specific markers tested in western women. People assumed the same would be true for Indian women, so they were probably missing a whole lot of cases,” adds Dr Chandru.

The other big advancement is in immunotherapy. In a sense, it’s a way of tricking our immune system, which normally fights infections, to also fight cancer. Our T-cells—which are like soldiers patrolling the frontline—successfully defend us from daily infections because they can recognise intruders like viruses and other pathogens. But cancer cells produce a protein which prevents T-cells from recognising them as enemies. Immunotherapy drugs make T-cells turn on cancer cells too and, in some cases, they have wiped cancers out.

Prevention is Better Than Cancer, Angelina Jolie, Actress

In 2013, Angelina Jolie underwent a preventive double mastectomy—removal of both breasts—after a genetic test showed she carried a faulty BRCA1 gene. Jolie also had her ovaries and fallopian tubes removed. She had an 87 per cent risk of breast cancer and a 50 per cent risk of ovarian cancer. “Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action,” Jolie later wrote in The New York Times.

Yet, experienced oncologists have a word of caution. Many promising discoveries have only led to replapses, sometimes after years. “I have used immunotherapy on three patients and it has worked very well in two,” says Dr Harit Chaturvedi, chairman, cancer care, Max Hospitals. He warns against getting carried away and thinking of these as magic bullets. “I personally feel we should be open to these advancements, but 95 per cent of cancers are still treated the traditional way in India,” he says. Why? For one, genetic tests may at this stage add value to only 2-3 per cent of the cases, he says. Immunotherapy, for instance, has no role yet in head and neck cancer. Costs are also a prohibitive factor, though with some heartening variations. When it comes to new therapies, few people can afford many of these. “If immunotherapy works, a patient will need it all his life. The costs work out to at least Rs 1-1.5 lakh a month,” Dr Chaturvedi says.

At the preventive level, technological advancements mean genetic tests are getting cost-effective and you could get a basic profile done for Rs 25,000. Firms such as Dhitionomics Technologies, Map My Genes and BabyShield offer off-the-shelf products. The first step, though, is seeing a genetic counsellor.

In totality, India is pushing the scienti­fic frontiers. Indian scientists took the first steps in understanding genetics in 1997, under the International Human Genome Project. Dr Samir Brahmach­ari, former director of the Council of Sci­entific and Industrial Research and founder of the Institute of Genomic and Integrative Biology (IGIB), hea­ded the project.  He says the aim was to “accumulate and use information from genetic mapping of people in the country for diagnosis, prevention and therapy of genetic disorders in India”. In 2008, the Indian Genome Variation Consortium helped scientists study how genetic variations occur based on geography and demography. “The idea was to have baseline data that all genetic scientists could refer to,” Dr Brahmachari tells Outlook. “Genetic diseases are seen as mutations in your genome structure. But just one simple mutation doesn’t make the disease; it’s a combination of mutations. These combinations are what we were trying to record.” The project also included mapping 100 people who lived up to 97 years of age and are healthy.

Establishing the probability of getting diseases could have significant impacts on survival chances, says Dr Ramananda Srikantiah Nadig, head of the clinical advisory board at Healthi. “Just because you have a family history of the disease doesn’t mean you have it. Genetic mapping helps figure out if you might be susceptible and help take the necessary precautions you need to fight the disease as early as possible.”

But the biggest benefit is still for those already battling cancer, who can now know if a certain drug will be helpful. Institutional efforts are now geared towards having a common platform into which all knowledge unique to Indian patients are fed. For instance, the IGIB and the All India Institute of Medical Sciences run the Go Med project, where doctors, in order to treat patients better, can forward a patient’s general and genetic history. “We have a web interface where doctors can add, get feedback on and consult patient history,” says Dr Muhammad Faruq, the scientist heading the project. It has a dual purpose: building a database and integrating genetics into regular treatment. The Go Med project has been working on numerous diseases, including cancer, to find new hotspot regions in the genetic architecture of people.

The big question: why isn’t there a cure for cancer yet? The answer is not straightforward, but offers a new layer of optimism. “Even if we can make cancer somewhat like what AIDS is today, it will be a milestone. In other words, make cancer manageable and survivable, until it’s made curable. Nobody dies of AIDS anymore,” Dr Chandru says.