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  Table of Contents  
Year : 2014  |  Volume : 51  |  Issue : 2  |  Page : 150-153

Ignore molecular oncology at your peril

1 Department of Education, BSES Municipal Hospital, Andheri, India
2 Department of Medical Oncology,Tata Memorial Hospital, Mumbai, India
3 Department of Medical Oncology,Fortis Hospital, Kolkata, West Bengal, India
4 Editor, Indian Journal of Medical and Pediatric Oncology, Meerut, Uttar Pradesh, India
5 Department of Medical Oncology,Basavatarakam Indo American Cancer Hospital, Hyderabad, India
6 Department of Molecular Genetics, Max Hospital, New Delhi, India
7 Department of Medical Oncology,Apollo Hospital, Chennai,Tamil Nadu, India

Date of Web Publication7-Aug-2014

Correspondence Address:
P M Parikh
Department of Education, BSES Municipal Hospital, Andheri
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.138258

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How to cite this article:
Parikh P M, Prabhash K, Bhattacharyya G S, Sirohi B, Rajappa S, Verma A, Raja T. Ignore molecular oncology at your peril. Indian J Cancer 2014;51:150-3

How to cite this URL:
Parikh P M, Prabhash K, Bhattacharyya G S, Sirohi B, Rajappa S, Verma A, Raja T. Ignore molecular oncology at your peril. Indian J Cancer [serial online] 2014 [cited 2021 May 16];51:150-3. Available from: https://www.indianjcancer.com/text.asp?2014/51/2/150/138258

We are living in exciting times in the management of cancer patients. Cancer survival rates in developing countries have doubled of the last several years. [1] In fact, more than half the patients with cancer now survive form >10 years. For breast cancer, for all stages, the 10 years survival is now 78%. [1] And for lung cancer, the % of patients that survived for 1 year represents the same number that now survives for 10 years. [1],[2] In fact, the survival for Stage IV nonsmall cell lung cancer (NSCLC) has increased by 3 times over two decades [3] Similar increase in 1, 5 and 10 years survival have also been seen in other cancers [Table 1]. [1] Decreases in deaths from lung, prostate, and colorectal cancer (CRC) accounted for nearly 80% of the decline in death rates among men, while decreases in breast and CRC made up 60% of the decrease among women. [1]
Table 1: Discrepancy in 1 year survival between developed and developing countries for common cancers

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Unfortunately, the outcomes for cancers in developing countries like India lag behind. It is often said that the 5 years survival here lower by as much as 33%. [2] And figures continue to lag behind. The changes in 1 year survival rates for developed and developing countries are compared in [Table 1]. [4] Even among the developed countries, there are differences. For instance, African-American men have 18% higher incidence rate and 36% higher cancer death rate compared to white men. [5]

The reason is simple. We are unable to or do not implement what knowledge is available globally. Most of us would like to pass the buck by saying that the infrastructure is inadequate, treatments are not available and/or patients present more advanced stage of the cancer. But are we really using what we have to the fullest? Do we keep up to date with and use the ever expanding knowledge to give the best treatment to our patients?

This issue of the Indian Journal of Cancer has two articles focusing on molecular characteristics of cancers. This is not a flash in the pan! In fact, the most dramatic increase in manuscripts being submitted to oncology journals belongs to the molecular and genetics category. And all of us agree that the most dramatic change in outcome of cancer patients has been with the availability of personalized medicine - with molecules that target cancer cells with specific genetic alterations (or their consequences). The story of imatinib is now so old that it is going off patent next year. [6] Hence, there is no need to remind anyone that it dramatically changed the 7 years survival in chronic phase chronic myeloid leukemia from <20% to 86%. [7] So also rituximab, transtuzumab and gefitinib have proven that targeted therapy is here to stay with significant improvements in outcome of non-Hodgkin's lymphoma, breast cancer and NSCLC respectively. [8]

The world's first biosimilar monoclonal antibody (rituximab - reditux), worlds first biosimilar transtuzumab (hertraz, canmab), generic imatinib and gefitinib are all available in India. [9],[10],[11] No doubt these relatively cheaper targeted therapy agents are still too expensive to cover all eligible patients - sometimes being used for <5% of those who deserve it. [12] The real question is whether we are optimizing the treatment of those who can avail these drugs. Are we providing personalized medicine with precision? Or are we using standard of care, management guidelines and Phase III clinical trials to "cheat" individual patients from precision medicine? Are we covering up our ignorance by casually dismissing probing questions? Is the lack of time from a busy practice preventing us from diligently updating our knowledge and keeping abreast with current literature? (Google search for molecular oncology results in 4,240,000 hits; PubMed provides 39,622 references; clinicaltrials.gov has 3533 clinical trials; NLM provides 479 books). What is needed is a deliberate and in-depth study of direct clinical application of cancer genomic information in the scientific literature to enable genome driven precision medicine. Implementation in daily practice requires three steps. State of the art molecular techniques (like next generation sequencing [NGS]) are used to characterize the genome of the tumor cells as well as the corresponding normal somatic cells from the patient. This information is then matched with potential targets and pharmacokinetics of cancer therapeutic molecules. Finally, the understanding is converted into the wisdom of precise decision making for individual patients.

It is common understanding that if breast cancer cells are human epidermal growth factor receptor (HER2) positive, the patient is to be offered transtuzumab as part of the treatment irrespective of the stage of the disease. Addition of trastuzumab to paclitaxel following AC chemotherapy associated with substantial improvement in overall survival (OS) (adjusted hazard ratio: 0.63; 95% confidence interval: 0.54-0.73; P < 0.0001). [13] The ASCO meeting of 2014 also demonstrated that addition of lapatinib to transtuzumab only increases toxicity without any survival advantage. [14] However, your patient deserves better! Evaluating circulating tumor cells (CTCs) has an important role. It has prognostic significance since a higher rates of death observed when baseline CTC count ≥5/7.5 ml (37%) versus <5 (27%). [15] It also has a predictive value since treatment with trastuzumab reduces the number of CTCs in peripheral blood - showing the need to re-evaluate CTCs during follow-up. The accompanying combination chemotherapy should also be selected appropriately. Keeping in mind the concern regarding cardiac toxicity, leukemia incidence and overall safety profile, the updated results from the BCIRG 006 trial show that trastuzumab-based regimen in the adjuvant setting should include taxotere, carboplatin, herceptin regardless of their topoisomerase II status - particularly for low-risk patients for whom the risk-to-benefit ratio is very important. Furthermore, crucial is the evaluation of epidermal growth factor receptor (EGFR) expression in breast cancer tumor cells! This is because EGFR heterodimerization with HER2. If EGFR expression assessed by tissue microarray is high (seen in about 16% of cases), breast cancer patients receiving concurrent adjuvant transtuzumab will have reduced benefit (P = 0.003). [16] Prognostic and predictive value of p53 mutation were also identified in a series of 178 tumors using polymerase chain reaction (PCR)-single-strand conformational polymorphism. Mutations within exon 4, but not in the DNA contact region, were associated with particularly poor prognosis. This is different from the single-base substitutions and transversion mutations in exon 6, exon 7, or the "hotspot" codons (175, 245, 248, 273) which had only a small reduction in patient survival compared with normal p53.

In India, use of gefitinib for lung cancer is well established, since 2003. Today at least 11 generic brands are available, making the drug affordable for most patients. While United States Food and Drug Administration withdrew its approval in the first line in 2005, its use in India expanded for patients with lung adenocarcinoma at all stages during their management. [17],[18] This was based on pharmacogenomic differences between Asian and Caucasian people. [19] So it is considered as standard of care to treat patients with adenocarcinoma of the lung having EGFR mutations with gefitinib in the first line setting. Most of us also know that EGFR testing by genetic mutation analysis is what is clinically relevant and evaluating expression by immunohistochemistry should no longer be relied upon. However, some of us accept the mutation test result without understanding the method and extent of analysis done. Some laboratories process the tumor sample only for exon 19 and 21 mutations. This would give an incomplete picture and by relying on such an incomplete result, might deny the patient optimal precision treatment. Whether the testing was by PCR or NGS is also important - since uncommon or hitherto unknown mutations in the EGFR gene also have treatment implications (we will explain the differences in a future manuscript). NGS also enables identification of other "drugable" genetic changes. Widely recognized is that a small number of patients will have very significant rearrangements affecting the anaplastic lymphoma kinase (ALK) gene (like EML4-ALK) and has the potential to benefit impressively from the mesenchymal-epithelial transition/ALK/reactive oxygen species inhibitor crizotinib). But how many of us pay attention to the RET gene and its inhibition. Not to be left behind, squamous cell and small-cell lung cancer patients also deserve specific genetic evaluation for changes like fibroblast growth factor receptor 1 amplifications and discoidin domain receptor 2 mutations. [20] Enrichment for genomic partitions neighboring conserved kinase motifs and massively parallel sequencing are already being used to identify breakpoints that cause kinase fusions. [21] For patients on therapy with tyrosine kinase inhibitor (TKI) early signs of response can be documented by using pharmacodynamic analyses (monitoring G1 arrest) of inhibition of glucose metabolism by fluorothymidine/flurorodeoxygluconse-positron emission tomography (PET) scans, a classic example of fusing two modern techniques. [22]

Coming back to the patient with EGFR mutation positive adenocarcinoma of the lung, not many oncologists explain to the patient that this decision is because gefitinib will lead to better response rate, progression free survival as well as quality-of-life. What if the patient opts for chemotherapy instead of TKIs? Having an EGFR mutation indicates that such patients respond better even to chemotherapy. However do we explain to them that their OS will be compromised unless they get treated with TKIs at some time during the course of their treatment (either as first or second line). [23] Only this insight explains why EGFR-mutant lung cancers have up to 80% likelihood of experiencing tumor regression and survival exceeding 2 years, whereas the OS remains <12 months for unselected patients with lung cancer treated with chemotherapy alone. And if a patient treated with platinum doublet chemotherapy now requires second line TKI, how do we precisely choose between gefitinib and erlotinib? Based on EGFR mutations rather than copy numbers, there is evidence that gefitinib outperforms erlotinib (64% vs. 42%). [24] What if the patient on a TKI develops progressive disease? If the patient had activating EGFR mutations, continuing EGFR TKI leads to longer survival (32 vs. 23 months). [25]

Colorectal cancer is another focus area for molecular genetics steering management in a precise manner. KRAS testing is well-recognized as essential for selecting the right targeted therapy strategy for such patients. However, all tests and all reports are not comparable. So is the variation in our understanding. It is no longer acceptable to look only at the mutation hotspot on exon 2 of KRAS - like G12, G13 and even Q61. Neither can such genetic alterations be predicted on PET computed tomography. [26]

In other words, RAS mutation is not a single all or none phenomenon in tumors, and multitude of possibilities in mutant alleles and gene copy number dictate the heterogeneity of patient outcomes. Understanding of the biological, biochemical, and prognostic significance of RAS pathway alterations in colorectal tumors will enable us to precisely decide treatment options.

For example, mutations in exon 4 (identified at amino acid residues K117 and A146 and associated with lower levels of GTP-bound RAS and mitogen-activated protein/extracellular signal-regulated kinase dependence and resistance) predict a more favorable response. [27] In fact, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) is currently available that identifies patients with better OS independent of tumor-node-metastasis staging (median survival of 80.4 months in the mutant group vs. 42.4 months in the wild type group), the prognostic significance verified from the Cancer Genome Atlas. [28] And currently available technology can also overcome the limitation of intratumor genetic heterogeneity by a simple PCR-based assay interrogating somatic variation in hypermutable polyguanine repeats can provide a rapid and reliable assessment of mitotic history and clonal architecture in human cancer. [29]

What about patients who cannot afford molecular testing? There is hope even for such cases. In some instances, light microscopic morphological characteristics can be a poor man's guide to molecular genetic alterations. Nuclear ellipticity (P = 0.02) and chromatin textural contrast (P = 0.02) predict KRAS mutations KRAS group, the later having a cut-off point of 798, with a sensitivity of 89.7%. On the other hand, tumor grade has no bearing on KRAS status. [30]

In summary, molecular genetic testing has become an integral part of precision oncology in today's day to day practice. Their role exists at all steps in the rational personalized decision making in oncology [Table 2]. Ignoring molecular oncology will be to the detriment of your patients' outcome and to the peril of your competence as well as your reputation.
Table 2: Application of molecular genetics in today's day to day oncology practice

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  References Top

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29.Naxerova K, Brachtel E, Salk JJ, Seese AM, Power K, Abbasi B, et al. Hypermutable DNA chronicles the evolution of human colon cancer. Proc Natl Acad Sci U S A 2014;111:E1889-98.  Back to cited text no. 29
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  [Table 1], [Table 2]


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