Past Issues
Issue 09 | September 2017
Strand Gene Word
Retinoblastoma
In the News
India is staring at a breast cancer epidemic. But do we have the awareness and tools to prevent one?
NSGC Panelists Discuss Strategies to Convert Variants of Unknown Significance to Known Significance
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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. We present 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
Liquid Biopsy Guided Treatment of Breast Cancer: Decision Support for Targeted Therapies
Dr. Shefali Sabharanjak
Strand Life Sciences
Abstract
- Amelia, a breast cancer survivor (initial Dx in 2011) was diagnosed with recurrent invasive ductal carcinoma in 2015. The tumor was ER+ve, PR+ve and HER2-ve.
- Genetic Analysis of the tumor, post-recurrence, helped to identify 16 distinct mutations in 15 genes.
- Identification of mutations in the PIK3CA and CCND1 genes led to the inclusion of everolimus and palbociclib, respectively, into Amelia’s treatment regimen
- Response to therapy was excellent and was monitored using periodic PET-CT scans as well as liquid biopsies.
- Clonal evolution and potential recurrence of the disease was indicated by the persistent increase in BRAF mutation in ctDNA, although radiographic techniques indicated that the patient was free of disease.
- Liquid biopsy-enabled molecular analysis can add another dimension to cancer detection, providing conclusive decision support for choosing the most suitable targeted therapeutics.
Introduction
Liquid biopsy-enabled periodic assessments of cancer are navigational aids that oncologists can effectively use to monitor cancer therapy closely. In fact, liquid biopsy is the singular detection technique that can facilitate effective and highly personalized treatment of cancer. Taking the guesswork out of the equation, with every recurrence of cancer, can go a long way in improving a patient’s quality of life, while also enabling the choice of precise therapeutic drugs. Indications about the emergence of cancer are also provided by liquid biopsies.
A recently published case of an estrogen receptor positive (ER+ve) breast cancer is an excellent example of the benefits of using liquid biopsy in cancer treatment (1).
In India, Strand Life Sciences offers a 152-gene test plus highly sensitive liquid biopsy tests to monitor cancer, in a similar manner.
Patient Profile
A 38- year-old female patient, let’s call her Amelia, presented with recurrent breast cancer in the lymph nodes, in Aug 2015. The disease had been first diagnosed in 2011. Immunohistochemistry analyses indicated that the tumor was ER+, PR+ve and HER2-ve. Amelia’s tumor was classified as a T2N1aM0 invasive ductal carcinoma. Surgical excision of the tumor was performed with adjuvant chemotherapy delivered to the patient.
Amelia was treated with dose-dense doxorubicin and cyclophosphamide followed by paclitaxel, followed by radiotherapy to the right breast (May 2012).
Amelia also received tamoxifen and leuprolide therapy in the period between 2012 and 2015.
Tumor Recurrence and Genetic Analysis
Amelia’s breast cancer recurred in 2015, detected on a PET-CT scan in eight small lymph nodes in the left supraclavicular region and one lymph node in the right paratracheal area.
Genetic analysis of the tumor biopsy helped to identify mutations (substitutions and gene amplifications) in 15 genes (Table 1).
Table 1. Mutations identified from an ER+ve, PR+ve and HER2-ve breast cancer biopsy
Mutations in PIK3CA result in uncontrolled proliferation of cells. Blocking a downstream effector of PIK3CA, mTORC1 (mammalian target of rapamycin1) is an effective strategy to counter this proliferative effect. Amelia was therefore treated with everolimus (5 mg /day, Mon,Wed, Fri) along with letrozole (2.5 mg /day) and palbociclib (75 mg/ day, for days 1-21 of a 28-day cycle), in August 2015. Palbociclib is an inhibitor of signalling mediation by CyclinD1-CDK4/6 kinase. Amplification of the CCN1 gene, evident in the genetic analysis, supported the inclusion of palbociclib in the treatment regimen.
This therapy was administered for one year with follow-up PET-CT scans in January 2016 and April 2017. Proliferation of the cancer in subclavicular lymph nodes was not evident in both scans.
Liquid Biopsies to Keep Tabs on the Cancer
In addition to the PET-CT scans, the patient’s response to the therapy was monitored using liquid biopsies (January 2016 – April 2017) as shown in Table 2.
Table 2. Liquid Biopsy Enabled Monitoring of Tumor Progression (1)
A mutation in BRAF was detected in the liquid biopsies, possibly emergent as a response to the therapy, indicating ongoing evolution of the tumor. The increase in the proportion of this mutation in ctDNA indicates clonal evolution of the tumor. The clone that has a dysregulated MEK1/MEK2 pathway in which BRAF is an upstream regulator, can be treated with trametinib, in the next round of treatment. Significantly, the PET-CT scans have shown absence of disease, at this stage. In contrast, the liquid biopsy has provided very definite indications of clonal evolution and potential recurrence of the disease.
The cyclinD1- CDK4/6 pathway has the retinoblastoma protein encoded by the RB1 gene, as a downstream effector. A mutation in this gene was evident in the liquid biopsy performed in June 2016. Accordingly, Amelia was prescribed pazopanib, instead of palbociclib, to overcome the dysregulation created by the RB1 mutation. In response, the RB1 mutation was not detected in follow-up liquid biopsies.
The overall trajectory of Amelia’s cancer therapy is summarised in Figure 1.
Figure 1. Summary of Amelia’s cancer journey- Interventions enabled by liquid biopsies (1)
Summary
- Liquid biopsies can provide accurate molecular snapshots of cancer throughout a treatment regimen.
- Breast cancer treatment, in this case, evolved from chemo-radiotherapy to the use of targeted therapy drugs like palbociclib and pazopanib.
- Identification of emergent mutations, eg BRAF, via liquid biopsies, has provided decision support for the inclusion of trametinib in the subsequent round of therapy.
- Personalized delivery of cancer therapy can be brought about in a cost-effective manner, with a combination of genetic analyses of solid tumors and liquid biopsies.
References
- Xu B, Krie A, De P, Williams C, Elsey R, Klein J, et al. Utilizing Tumor and Plasma Liquid Biopsy in Treatment Decision Making for an Estrogen Receptor-Positive Advanced Breast Cancer Patient. Cureus [Internet]. 2017 Jun 29 [cited 2017 Sep 19];9(6):e1408. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28856074
I am Dimple Bawa – This is my story
Breast cancer is on the fast track to become the number one killer amongst Indian women. Prophylactic germline screening of women in their early twenties is one of the ways to spot, and stop, aggressive forms of breast cancer such as triple-negative (ER-ve, PR-ve, HER2-ve) breast cancer (TNBC). Ms. Dimple Bawa is one such patient who could have benefitted from early screening, especially since her mother was diagnosed with TNBC. The story of her fight with hereditary breast cancer is an extraordinary one.
Genetic Analysis Confirms Hereditary Retinoblastoma in a Young Patient
– Dr. Shefali Sabharanjak
Strand Life Sciences
Abstract
- Sujay Jaishanker*, a 2-year-old child, developed leukocoria, in the right eye, when he turned one.
- Genetic diagnosis was advised to the patients in addition to other investigations for suspected incidence of retinoblastoma.
- A pathogenic variant of RB1 was found in his genome
- Parents were advised to watch out for signs of retinoblastoma in the contralateral eye and also to monitor him for symptoms of other cancers.
- Germline analysis confirmed the diagnosis of retinoblastoma and also alerted Sujay’s parents to the possibility of passing on the variant to other progeny.
Introduction
Retinoblastoma is a frequently occurring cancer evident in very young kids, worldwide. In fact, it represents 3% of all the pediatric cancers, globally (1,2). Retinoblastoma is highly treatable if a confirmed diagnosis is obtained early enough. There exists a huge disparity between the outcomes of retinoblastoma in developed and developing countries. The success rate in treating retinoblastoma cases is 93% (5-year survival rate) in European countries and is as high as 96.5 % in the US. In contrast, the mean survival rate for retinoblastoma is 40-79% in the developing world (3). Confirmed diagnoses of retinoblastoma, aided by genetic analyses, can go a long way in increasing the survival rate of retinoblastoma patients.
Patient Profile
Sujay was an active, cheerful child born to Amrita* and Sukrut Jaishanker*, a young couple who ran a local chain of coaching classes in Chennai (names of individuals are fictional, in order to preserve patient privacy). They were naturally overjoyed and were following their child’s progress keenly. Photographing each stage of Sujay’s development had become their daily habit. As the kid turned one, Amrita noticed that some of Sujay’s photos showed a white spot on the right eye. For some time, she ignored it as an artifact of the camera settings but gradually, she started noticing that Sujay developed a preference for things on his left. The white spot in his pupil was becoming more and more prominent.
Her concern prompted her to take Sujay to a pediatrician. Suspecting a case of retinoblastoma, the pediatrician referred her to an ophthalmologist as well as to a well-known geneticist in Chennai. Sujay’s ophthalmologist diagnosed his condition as retinoblastoma and in concurrence with the geneticist, advised a genetic test to confirm the diagnosis.
Results of Genetic Testing
Sujay was advised the Strand Germline Cancer Test to establish the genetic basis of his retinoblastoma. This is a lab-developed test that looks for mutations in the RB1 gene, known to be involved in hereditary predisposition to retinoblastoma.
Key Interpretations
- Sujay’s retinoblastoma resulted from the likely pathogenic variant of the RB1 gene.
- He is heterozygous for this mutation indicating that he has one normal and one mutant copy of the RB1.
- His parents should be tested to ascertain, whether, the mutations is inherited or de novo in nature.
- Mutations in the RB1 are inherited in an autosomal dominant manner and hence one copy of the likely pathogenic variant is sufficient to result in the development of this cancer.
Summary
- Sujay, a 2-year-old-child, was diagnosed with retinoblastoma.
- Genetic testing was advised in order to confirm the diagnosis of retinoblastoma and arrive at a differential diagnosis of the vision problems, quickly.
- The Strand Germline Cancer Test helped to identify a ‘likely pathogenic’ variant of the RB1 gene in Sujay’s case.
- Diagnosis of retinoblastoma was confirmed with this genetic analysis.
- Sujay’s parents were advised to undergo mutation-specific testing in order to understand whether the mutation is inherited via either of the parents or de novo in nature.
- Mutation-specific testing would also allow them to understand their risks for having a second child bearing the same gene variant.
- Therapeutic options like enucleation, brachytherapy, external beam radiation, chemotherapy, photocoagulation, and cryotherapy were explained to Sujay’s parents.
- Early identification of the mutation status of RB1 is essential because a deficiency of this gene also increases a person’s risk for developing bladder cancer, lung cancer, melanoma, breast cancer and osteosarcoma (Genetics Home Reference). The chances of developing retinoblastoma in the contralateral eye are also high, owing to the presence of the inherited mutation.
- Sujay’s parents have now been alerted to the presence of the RB1 mutation and can adopt preventive health measures like regular medical examinations to look for signs of other cancers.
References
- Union for International Cancer Control. Retinoblastoma [Internet]. 2014 [cited 2017 Aug 30]. Available from: https://www.who.int/selection_medicines/committees/expert/20/applications/Retinoblastoma.pdf?ua=1
- Yun J, Li Y, Xu C-T, Pan B-R. Epidemiology and Rb1 gene of retinoblastoma. Int J Ophthalmol [Internet]. 2011 [cited 2017 Sep 1];4(1):103–9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22553621
- Naseripour M. “Retinoblastoma survival disparity”: The expanding horizon in developing countries. Saudi J Ophthalmol [Internet]. 2012 Apr [cited 2017 Sep 1];26(2):157–61. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1319453412000306
*Names changed to protect patient privacy