Issue 03 | March 2017

Welcome to Strand Genomics-A Monthly E-zine from Strand Life Sciences

Strand Life Sciences welcomes you to Strand Genomics, our monthly E-zine that includes articles of interest to physicians. This e-zine brings the latest news in the world of genetic diagnostics, to your doorstep. The E-zine features carefully crafted articles as well as curated news in the field of cancer therapy and genetic analyses to support the implementation of personalized medical care. We invite you to peruse as well as share these articles. Please also feel free to write back to us with comments and questions at strandlive@strandls.com

Genetic Counselling for Patients Diagnosed with Breast Cancer: An Unmet Need

Dr. Rashmi Upadhyay and Dr. Shefali Sabharanjak
Strand Life Sciences

Abstract

  • Access to genetic counselling is an underserved need in India.
  • Breast cancer patients surveyed in a recent study (Kurian et al., 2017) reported a significant gap between the need for genetic counselling and access to such options.
  • Increased access to services such as genetic counselling and genetic testing is recommended for women who are at a higher risk of developing breast cancer. The three most common groups are:
    • History of  cancer in the family
    • Onset of cancer at less than 50 years of age
    • A diagnosis of Triple Negative Breast Cancer (TNBC)

Introduction

Genetic counselling is an interactive process with a trained genetic counsellor to evaluate an individual’s risk of developing a certain medical condition e.g. a higher chance of developing breast cancer. Genetic counsellors work at the interface of the doctor and the patient, allowing additional time and detailed analysis to allow the patient to understand her/his medical condition better as well as the results of testing on her/his family members.

Since dealing with cancer care is overwhelming for both, the affected person as well as the family members, a genetic counsellor can help patients make informed decisions about genetic testing.

At Strand Life Sciences, all our genetic counsellors have received rigorous training to evaluate and handle different cancer care scenarios- hereditary as well as sporadic cancers.

Genetic Testing and Counselling Among Patients With Newly Diagnosed Breast Cancer (Kurian et al., 2017)

Even though BRCA1 and BRCA2 gene tests were made available some twenty years ago, we still do not have enough data on the patients’ experience with genetic testing and counselling. Recently, a paper appeared in the February issue of JAMA on the importance of genetic counselling of patients who were newly diagnosed with breast cancer (Kurian et al., 2017). In this study which was conducted by the University of Michigan, women aged 20 through 79 years diagnosed with stages 0 to II breast cancer between July 2013 and September 2014 were surveyed 2 months prior to surgical intervention. The survey focused on how many patients chose to undergo genetic testing and whether patients expressed their need for genetic testing to their physicians. Access to a genetic counsellor was also assessed via this survey.

2529 women (71%) responded to the survey. 56.8 % Caucasian women, 17.8% were of African-American lineage, 17.5% women were Hispanic and 8.8% women were of Asian origin.

Table 1. Categorizarion of survey respondents (Kurian et al., 2017)

Categorizarion of survey respondents
In the high-risk category, 80.9% individuals wanted to undergo genetic testing and 70.9% of these people discussed this option with their physician. Yet, the number of people who had access to genetic counsellors was significantly low at 39.6% and ultimately the number of people who actually underwent genetic testing stood at 52.9% (Table 1). A similar trend is seen in the average-risk group wherein 59.3% people wished to avail of genetic testing, 35.9 % people discussed the option with their physician, 14.4% people had access to a genetic counsellor and only 17.8% people underwent genetic testing. The most frequently cited reasons for this deficit in medical care were:

  1. My doctor didn’t recommend it (56.1 %)
  2. Too expensive (13.7%)
  3. I did not want it (10.7%)
  4. My family did not want me to get it (0.2%)

The data indicates a significant gap in the delivery of genetic counselling services to breast cancer patients. Another interesting finding of the study was the fact that Asian women in the high-risk category (bearing deleterious mutations that cause breast and ovarian cancer) were underserved with respect to genetic counselling and testing. If genetic counselling is an unmet need in developed nations in the USA (although assessed from a self-reported survey of patients from two locations), the situation cannot be better in countries like India.

Prevalence of Breast and Ovarian Cancer in India

In India 145,000 new breast and ovarian cancer cases are recorded every year, which is about 62.2 % of the new cases reported in the US (http://globocan.iarc.fr/old/FactSheets/cancers/breast-new.asp, Accessed on 22/03/2017).

However, the mortality rate in India is 50% unlike in the US, where it is 18% (http://globocan.iarc.fr/old/FactSheets/cancers/breast-new.asp, Accessed on 22/03/2017). The median age of BOC patients in India is lower than that of their counterparts from the US (Table 2).

Table 2: Incidence of Breast cancer cases in India and USA

Incidence of Breast cancer cases in India and USA
The high mortality of breast and ovarian cancer patients in India is at least partially attributable to the lack of awareness about this inherited cancer and lack of preventive genetic screening (Gupta, Shridhar, & Dhillon, 2015).The Indian Council for Medical Research (ICMR) provides clear guidelines for genetic testing of women who are at high risk of developing breast cancer owing to hereditary factors. One of the reasons for the high mortality that is cited is the lack of awareness and socioeconomic factors that prevent access to awareness as well as genetic testing (Agarwal, Pradeep, Aggarwal, Yip, & Cheung, 2007; Agarwal & Ramakant, 2008; Leong et al., 2010). The high prevalence of pathogenic mutations in BRCA1 and BRCA2 as well as in other genes associated with hereditary breast and ovarian cancer, in India, has been highlighted in a recent study published by Mannan et. al (Mannan et al., 2016). In fact, a high prevalence of inherited BRCA1 and BRCA2 mutations has been demonstrated in population groups where the age of diagnosis is less than 40 years, as well as in women with high incidence of cancer amongst first degree relatives, in the same study.

Access to adequate genetic counselling and genetic testing can possibly help to reduce this mortality rate in breast cancer patients in India. Prof. Mary-Claire King, the scientist who established the causative role of the BRCA1 gene in inherited breast cancer, has recently stated that in her opinion “All women above 30 should undergo genetic testing and understand their personal BRCA1 and BRCA2 status.” (http://www.thehindu.com/news/cities/bangalore/Breast-cancer-is-a-cancer-of-prosperity-Mary-Claire-King/article17348900.ece, February 23, 2017).

Summary

  • Awareness and access to genetic counselling and testing for cancer is an underserved need amongst women.
  • Breast cancer patients surveyed in a recent study (Kurian et al., 2017) reported a significant gap between the need for genetic counselling and access to it.
  • Lack of awareness and low access to healthcare services such as genetic counselling and genetic testing are some of the factors that contribute to the high mortality rate of breast cancer patients in India.
  • Increased access to services like genetic counselling and testing is recommended for all women of reproductive age, where there is a family history of cancer and especially when there is an early onset (< 50 years) of cancer.

References

Agarwal, G., Pradeep, P. V., Aggarwal, V., Yip, C.-H., & Cheung, P. S. Y. (2007). Spectrum of Breast Cancer in Asian Women. World Journal of Surgery, 31(5), 1031–1040. https://doi.org/10.1007/s00268-005-0585-9

Agarwal, G., & Ramakant, P. (2008). Breast Cancer Care in India: The Current Scenario and the Challenges for the Future. Breast Care (Basel, Switzerland), 3(1), 21–27. https://doi.org/10.1159/000115288

Gupta, A., Shridhar, K., & Dhillon, P. K. (2015). A review of breast cancer awareness among women in India: Cancer literate or awareness deficit? European Journal of Cancer, 51(14). https://doi.org/10.1016/j.ejca.2015.07.008

Kurian, A. W., Griffith, K. A., Hamilton, A. S., Ward, K. C., Morrow, M., Katz, S. J., & Jagsi, R. (2017). Genetic Testing and Counseling Among Patients With Newly Diagnosed Breast Cancer. JAMA, 317(5), 531. https://doi.org/10.1001/jama.2016.16918

Leong, S. P. L., Shen, Z.-Z., Liu, T.-J., Agarwal, G., Tajima, T., Paik, N.-S., … Foulkes, W. D. (2010). Is breast cancer the same disease in Asian and Western countries? World Journal of Surgery, 34(10), 2308–24. https://doi.org/10.1007/s00268-010-0683-1

Mannan, A. U., Singh, J., Lakshmikeshava, R., Thota, N., Singh, S., Sowmya, T. S., … Subramanian, K. (2016). Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India. Journal of Human Genetics, 61(6), 515–22. https://doi.org/10.1038/jhg.2016.4

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A Patient Story

Story of Meena Nandal an advanced ovarian cancer patient

Ms. Meena Nandal is an advanced ovarian cancer patient who had developed resistance to chemotherapy. While looking for other treatment options, Ms. Nandal got a genetic test done. Fortunately, genetic testing revealed a mutation in the BRCA2 gene, which qualified her to receive a PARP inhibitor, to which she is responding extremely well. It’s been about nine months since Ms. Nandal has been on the new treatment regimen. Since then, she has been free of cancer and is enjoying an enhanced quality of life, without any of the usual side effects associated with cancer treatment.

Watch now.

Hereditary Breast and Ovarian Cancer – Identification of a VUS Mutation with Potential Pathogenicity

Dr. Shefali Sabharanjak
Strand Life Sciences

Abstract

  • A 55-year old ovarian cancer patient underwent genetic testing.
    The patient was found to be heterozygous for a Variant of Unknown Significance (VUS) mutation that altered a conserved residue in the BRCT domain of the BRCA1 protein.
  • Comparative analyses with a known pathogenic variant [(c.5123C > A, p.Ala1708Glu)(Vaclová et al. 2016)] that resulted in a similar substitution, allowed for the classification of the VUS as a ‘VUSD- Variant of Unknown Significance with a probably damaging effect‘.
  • The identification as well as reclassification of the patient’s BRCA1 mutation established her eligibility to receive PARP inhibitor therapy (Mirza et al. 2016; Oza et al. 2015; Swisher et al. 2017; Crafton et al. 2016; Jenner et al. 2016).
  • Mutation-specific testing was advised to her children, a son aged 31 years and a daughter aged 21 years.

Introduction

Humaira (name changed to protect patient privacy) was diagnosed with ovarian cancer at the age of 55 years and referred to Strand 2 years later. After diagnosis, she was prescribed chemotherapy as well as was advised to undergo genetic counselling to understand whether her cancer was inherited or sporadic.

Patient Pedigree

Humaira’s mother had been diagnosed with ovarian cancer and died at 78 years. Additionally, two of her mother’s sister (second-degree relatives of Humaira) had also been diagnosed with breast cancer, both of them at the age of 35 years. One aunt had succumbed to the disease whereas the other one was a cancer survivor. Humaira’s paternal uncle was also diagnosed with cancer (the family was unable to provide more information about the type of cancer, in this case).

Based on the family pedigree, the Strand Germline Cancer Test was advised to Humaira to understand the genetic causes of the hereditary breast and ovarian cancer prevalent in the family.
genetic causes of hereditary breast ovarian cancer

Figure 1. Family Tree of Proband (indicated by the red arrow).

Results of the Genetic Test

Humaira was found to be heterozygous for a variant of the BRCA1 gene. The mutation, in exon 17, was identified as a ‘variant of unknown significance’, or a ‘VUS’ mutation.

Gene Variation Zygosity Clinical Significance
BRCA1 chr17:41215920G>C c.5123C>G p.Ala1708Gly Heterozygous Variant of Unknown Significance

Interpretation

A diagnosis of a VUS mutation is always problematic from a clinical viewpoint since there is inadequate literature support for using the identified gene variant as a rationale for additional therapy.

At Strand Life Sciences, we use an extensive array of in silico analytical tools to determine the pathogenicity of the identified gene variants. In this case, the protein substitution p.Ala1708Gly was found to be similar to another codon alteration (c.5123C > A, p.Ala1708Glu), that results in a similar substitution- p.Ala1708Glu. The latter substitution variant has been known to be pathogenic (Vaclová et al. 2016).

Additionally, the identified VUS alters a conserved residue in the BRCT domain of the BRCA1 protein. This domain (residues 1650-1863) is involved in the interactions between BRCA1 and other phosphoproteins. Based on the similarity between the identified VUS and the previously known mutation, the VUS was classified as ‘VUSD- Variant of Unknown Significance with a probable damaging effect’.

Conclusions

Genetic as well as in silico analyses indicated that Humaira was heterozygous for a BRCA1  VUS which is likely to be pathogenic.

The re-classification of this variant, as a potentially damaging gene mutation, established her eligibility to receive PARP inhibitor therapy (Mirza et al. 2016; Oza et al. 2015; Swisher et al. 2017; Crafton et al. 2016; Jenner et al. 2016)).

Mutation-specific testing was advised to her children, a son aged 31 years and a daughter aged 21 years, in order to ascertain their chances of developing breast as well as ovarian cancer. Ad hoc knowledge of their genetic status as carriers of this pathogenic VUS will allow them to take advantage of surveillance strategies.

References

Crafton, S.M., Bixel, K. & Hays, J.L., 2016. PARP inhibition and gynecologic malignancies: A review of current literature and ongoing trials. Gynecologic Oncology, 142(3), pp.588–596. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27168003 [Accessed January 21, 2017].

Jenner, Z.B., Sood, A.K. & Coleman, R.L., 2016. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncology, 12(12), pp.1439–1456. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27087632 [Accessed January 20, 2017].

Mirza, M.R. et al., 2016. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. New England Journal of Medicine, 375(22), pp.2154–2164. Available at: http://www.nejm.org/doi/10.1056/NEJMoa1611310 [Accessed January 16, 2017].

Oza, A.M. et al., 2015. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. The Lancet Oncology, 16(1), pp.87–97. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25481791 [Accessed January 16, 2017].

Swisher, E.M. et al., 2017. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. The Lancet Oncology, 18(1), pp.75–87. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27908594 [Accessed January 21, 2017].

Vaclová, T. et al., 2016. Germline missense pathogenic variants in the BRCA1 BRCT domain, p.Gly1706Glu and p.Ala1708Glu, increase cellular sensitivity to PARP inhibitor olaparib by a dominant negative effect. Human molecular genetics, p.ddw343. Available at: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddw343 [Accessed March 22, 2017].

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