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‘Our focus is on identifying other genes that contribute to hereditary cancers’

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Dr T Rajkumar, Director and Scientific Director, Cancer Institute (WIA), Adyar elaborates about the ongoing research work at the institute as well as his perspective on what should be the priorities and economics of onco drug therapy, in an interaction with Usha Sharma

The Cancer Institute (WIA), Adyar, Chennai was first mooted in 1954 by Dr Muthulakshmi Reddy, India’s first woman medical graduate and set up a year later under the auspices of Women’s India Association (WIA). This year, the institute completes its 60 years of service. What unique research projects have been taken up by the institute towards cancer diagnosis, care and prevention?

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Dr T Rajkumar

The institute has four components: The hospital section which provides state-of-the-art cancer care to all patients irrespective of their socio-economic status; the research section which includes the Department of Molecular Oncology, which works on cervical, breast, gastric, ovarian, bone and hereditary cancers; the college which offers DM, MCh, MD courses in medical oncology, surgical oncology and radiation oncology, respectively; PhD programmes in oncology, diploma courses for technicians, etc. and fourthly the preventive oncology and epidemiology section which carries out field studies and trials, runs the Madras Metropolitan Tumour Registry and the Dindigul District Tumour registry, maintains the hospital tumour registry etc. The institute was a pioneer in the multi-modal form of treatment way back in early 1960. This multi-modal approach uses initial radiation or chemo-radiotherapy to shrink locally advanced head, neck and breast cancers and then operate on them. This has contributed significantly to improve cure rates. The institute was also a pioneer in early detection by population-based screening in the 1960s and followed it up in the 80s by training the Tamil Nadu Government’s health workers in visual inspection after application of acetic acid and trained technologists for reading PAP smear.

You received the Kobayashi Foundation Award for Cancer Research in recognition of your work which provides a new level of understanding on drug resistance in aggressive bone cancer among children and adolescents (osteosarcomas). What is the progress of your research in this front?

We have been trying to identify novel molecules which help overcome drug resistance in osteosarcomas. Lichen-based extracts are being evaluated not only for anti-cancer activity but also for overcoming drug resistance.

As the Professor and Head, Dept. of Molecular Oncology, Cancer Institute (WIA), you have established a population-based Hereditary Cancer Registry covering Madras Metropolitan Area, which was funded by WHO between January 2002 to December 2003,thereafter by Cancer Institute (WIA). Much of your research work involves looking for links between genes and incidences of cancer. What are the outcomes of these studies and what does this mean both for clinical oncologists like yourself as well as patients?

About five to 10 per cent of the common cancers such as breast cancer can be hereditary. Our hereditary cancer programme consists of the hereditary cancer clinic, laboratory for mutation detection and a population-based hereditary cancer registry. Mutation analysis was done free of cost for all eligible patients and the genes tested included BRCA1 and BRCA2 [for hereditary breast and ovarian cancers], MSH2 and MLH1 [for hereditary non-polyposis colo-rectal cancers]. Our analysis had revealed novel deleterious mutations in our patients, which contributes to around 25 per cent of all deleterious mutations. The most common deleterious mutation seen in our clinic is a deleterious mutation prevalent in Ashkenazi Jewish population. However, our patients are non-Jewish and in 30 per cent of the patients, there was no family history of any other member being affected with breast and or ovarian cancers. The affected patients are from different parts of South India and from different castes and religious backgrounds. Given the tendency for marriages within the caste, there is a possibility of this mutation being prevalent in these castes and this needs to be confirmed.

The hereditary cancer programme benefits the person already affected by cancer, since there are therapeutic decisions which could be influenced by the mutation. As an example, breast conservation surgery in a lady carrying a deleterious mutation in BRCA1 or BRCA2, is fraught with an increased risk for local recurrence, increased risk of developing opposite side breast cancer and offers the potential to use newer drugs such as PARP inhibitors. More importantly, it also helps other unaffected family members of the same family, if they are found to carry the same deleterious mutation. In these members, early detection, prophylactic surgeries, chemoprevention and life style modifications will help reduce the risk of developing cancer. Long-term follow-up of these carriers (of deleterious mutations) is needed.

What percentage of the Indian population faces hereditary cancer problems? Tell us about the key areas which have the potentials for hereditary cancer and what kind of research work are you conducting?

Our research is now focusing on identifying other genes which can contribute to the hereditary cancers. We are now using a panel of 56 genes in our next generation sequencing platform to address this. Additionally, up to a third of the mutations seen are classified as ‘mutations of unknown significance.’ We are trying to identify at least in some of these mutations if functional studies could be done to address the issue. The newly donated Ion Torrent PGM unit with a rapid turn-around time will help patients in having mutation detection done within a week to 10 days, so that decision of the best management options can be taken. This will benefit patients suffering from breast, ovarian, lung, and colon cancer. As ever, the institute will support the poorer patients.

You are involved in the evaluation of the Dendritic vaccine for the treatment of cervical cancer. What is the progress?

We were the first in the country to develop Dendritic cell vaccine for the treatment of cervical cancer. Dendritic cell vaccine is a form of immunotherapy and has shown promise in several cancers. Our phase I study, funded by DBT, showed that this form of treatment is well tolerated. One of the patient who received Dendritic cells primed with her own tumour lysate proteins and subsequently had cisplatin chemo for a very large lung metastasis is free of disease for more than seven years. Based on our results, we have submitted the phase II trial in stage IIIB cervical cancer to DCG (I) and are awaiting for the clearance.

How many biomarkers have you developed and which cancers are these linked to? You are involved in / leading gene expression studies in cervical, breast and gastric cancers. How far are we from having prognostic markers for these cancers?

The Department of Molecular Oncology has been funded by DST, Government of India to help develop potential diagnostic biomarkers for cervical, gastric and breast cancers. In cervical cancer, PAP smear plays an important role in screening women for early detection in the pre-cancerous stage itself. While in the Western countries, this has been the main stay, in India it does not seem to be a feasible method due to the fact that it needs a qualified and trained pathologist/cyto-pathologist for interpreting the smear. We simply do not have the number of pathologists for a population-based study. Additionally, the interpretation can be subjective particularly in the borderline smears. To this end, we have developed a novel double antibody sandwich ELISA to detect p16, a protein which is expressed after the human papilloma virus infection becomes potentially deleterious [patent Application number 475/CHE/2014, filed on 03-02-2014]. Testing for HPV infection has its limitation since 95 per cent of women infected with HPV will clear the infection and hence will need re-testing after a year. Over expression of p16 in contrast occurs only when the HPV infection affects the cell deleteriously. Hence, p16 protein over expression is a down-stream event and once detected will need to be acted upon. p16 over expression is seen in the pre-cancerous stages of the cervical cancer itself and hence can be used for population based screening. The other major advantage of this ELISA-based test is that it can be at the point of care such as primary health centres and does not require highly qualified staff. A technician familiar with the use of the ELISA plate reader should be able to provide the results from the smear lysates and in an objective manner.

What has been your strategy for diagnosing early stage gastric cancer?

Gastric cancer is a lethal disease in our country, especially in South India, since more than 90 per cent of cases are detected at an advanced stage. Population-based screening using endoscopy or barium meal will not be feasible in our country due to the sheer number of individuals required to be screened. A better alternative is to identify potential plasma- based biomarkers for early detection of gastric cancer. We have used micro array studies to identify differentially expressed genes in gastric cancer compared to normal stomach. We then validated this using quantitative RT-PCR and the validated genes were then shortlisted based on whether they were secreted or potentially secreted. 15 proteins were then further validated in gastric tissues, cancers, paired normal and apparently normal gastric tissues. Once we validated the differential protein expression, we then looked for the levels of the protein in the plasma of healthy normal individuals whose OGDscopy (oesophago-gastro deuodenoscopy) was normal; in individuals with benign gastric conditions such as gastritis, ulcer etc. and in patients with gastric cancer. We found that 10 out of the 15 protein bio-markers could be used to differentiate plasma from cancer patients and plasma from healthy individuals or from patients with benign gastric pathologies. A large scale validation is under-way using 400 cancer patient samples and 800 control samples.

A similar strategy was used in breast cancer to identify differentially expressed genes. We are now trying to validate the protein levels in tissues from breast cancer patients and tissues from patients with benign pathologies.

These studies are being funded by the Indian government through DBT & DST but you have also worked on WHO projects. What has been your experience as far as ease of administration of funds, etc. is concerned.

We have received most of our funding from DST and DBT. Our experience with these agencies has been good, although last year due to budgetary cuts, some of the projects had their funds released late.

You had published a paper in The Indian Journal of Cancer Chemotherapy, (10: 73-82, 1988) titled ‘Drug therapy in oncology – its priority and economics’. What are your views on Mumbai’s Tata Memorial Hospital recommendation that prices of certain cancer drugs should be brought under price control? Your perspective on what should be the priorities and economics of drug therapy.

The essence of the article referred to still stands good. Use of combined modality treatment in most cancers will achieve a better result. Hence, in the management of most cancers all the three primary therapeutic modalities should be employed. The pricing on anticancer drugs as well as on adjuvant drugs used during chemotherapy [anti-emetics, G-CSF, etc.] needs to be realistic in our environment. Most of the patients seen in our country are from the lower socio-economic strata and do not have insurance and hence are dependent on state-run institutions and not for profit institutions. Some of the targeted therapies, such as Herceptin used for HER2 positive breast cancer are very expensive, so much so that hardly one to five per cent of the patients in premium institutions such as Cancer Institute [WIA], Adyar or Tata Memorial Hospital can afford it. The arrival of bio-similars is eagerly awaited, which can help bring down the cost. The top priority for any not-for-profit institution is to optimise its resource utilisation to allow more patients to be cured. When there are patients competing for the beds, prudence dictates that the bed be offered to one who has the potential to be cured. Every institution has its bed strength limited to a certain level wherein they can provide quality care to all it admits for treatment with an intent to cure. Over burdening of such institutions will be counter-productive, as the quality of care will come down. The answer to this is to have more centres which are either supported by the government or by not-for-profit institutions, to take care of the patients from the lower socio-economic strata. In this regard, the Tamil Nadu Government’s Chief Minister’s Comprehensive Health Insurance Scheme helps the government hospitals and the not-for-profit institutions in becoming self-sufficient

Is there a way for the government’s pricing authority, the NPPA, to balance profits permitted to drug manufacturers with access to oncology therapy?

The Indian patent regime permits local manufacture of generic drugs for critical illnesses if the international pharma majors pricing is unrealistic for our country. However, there has been a negative trend with some of the newer targeted therapies. Some of these drugs cost a fortune and the increase in survival rate is from few days to few weeks. The oncologists also need to be careful when prescribing such expensive drugs which virtually can break a household’s resource but provide virtually nothing to the family.

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