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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 302-306

Rare mutations in breast cancer and implications in the clinic: Oscillation between sharp horns of dilemmas!

Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission07-Apr-2020
Date of Decision21-Apr-2020
Date of Acceptance28-Apr-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Jyoti Bajpai
Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_136_20

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How to cite this article:
Singh GK, Bajpai J, Chougule A, Chandrani P. Rare mutations in breast cancer and implications in the clinic: Oscillation between sharp horns of dilemmas!. Cancer Res Stat Treat 2020;3:302-6

How to cite this URL:
Singh GK, Bajpai J, Chougule A, Chandrani P. Rare mutations in breast cancer and implications in the clinic: Oscillation between sharp horns of dilemmas!. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Sep 17];3:302-6. Available from: https://www.crstonline.com/text.asp?2020/3/2/302/287206

  History Top

A 44-year-old, premenopausal woman without a family history of breast cancer in a first-degree relative asked for an opinion in March 2020. She had a history of a benign lesion in her right breast 22 years back, which was kept under observation.

  Diagnosis Top

She underwent regular screening with mammography (MMG) and ultrasonography (USG), as per the prevalent local practice. In January 2020, her screening and diagnostic MMG showed microcalcification in the deep left breast, while the USG revealed multiple bilateral nodules in the breasts. Subsequent magnetic resonance imaging of the breasts after 1 month showed bilateral mass lesions in the lower outer quadrant of the right breast (1.9 cm) and the central quadrant of the left breast (1.2 cm). Biopsy from the right breast mass was suggestive of nodular sclerosing adenosis, whereas the left breast showed a Grade II ductal carcinoma in situ (DCIS), with necrosis and multifocal lymphovascular invasion. The tumor was estrogen receptor (ER)-positive and progesterone receptor (PR)- and HER2/neu-negative.

  Molecular Testing and Treatment Top

Genetic analysis of the lesion with a 56-gene panel revealed a rare heterozygous mutation in the SMARCA4 gene (c.727G>A [p. Gly243Ser]). The patient was extremely concerned about this rare mutation and wished to explore all the possible therapeutic and preventive options. The molecular tumor board's decision was to proceed with the standard surgical treatment of the DCIS, followed by hormone therapy with tamoxifen. Close obervation was advised for the benign lesion in the other breast.

  Excerpts from the Discussion in the Moecular Tumor Board Top

Hereditary breast cancers comprise 5%–10% of all breast tumors. Next-generation or massively parallel sequencing methods are screening aids for the diagnosis of heterogeneous hereditary cancer syndromes. Commonly implicated genes, such as the high-risk BRCA1 and BRCA2, lead to an 85% lifetime risk of developing breast cancer.[1] However, inherited mutations in other genes are also implicated in its causation. These genes are classified as high-risk (TP53, STK11, CDH1, PTEN, PALB2, and NF1), moderate-risk (2–4 times increased risk) (ATM, CHEK2, and NBN; for Lynch syndrome, MUTYH, BRIP1, RAD51C, RAD51D, BARD1, FANCA, FANCC, FANCM, BLM, and WRN genes) and low-risk genes [Table 1].[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11]
Table 1: Hereditary genes - risk and associated malignancies

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There is a growing interest in exploring the heterozygotes for other recessive syndromes involved in breast cancer predisposition. As a result of the paucity of data in the Indian context, it is difficult to comment on the prevalence of BRCA1/2 genes. About 6%–10% of the patients with breast carcinomas have a mutation in the BRCA gene, irrespective of their family history.[12] The low-risk genes have a low clinical significance; however, they can lead to anxiety in patients and their families and are encountered frequently in daily clinical practice. The cumulative risk of breast cancer and its subsequent management strategy varies widely among different mutation carriers. These mutations are also associated with various clinical syndromes [Table 2].[13],[14],[15],[16],[17],[18],[19]
Table 2: Common genes in hereditary breast cancer, associated syndromes and management strategies

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The SMARCA4 gene has not yet been characterized for any predisposing role in breast cancer. The evidence suggests that SMARCA4, along with other SWI/SNF complex genes, is significantly mutated in several cancers.[20] On the other hand, the observed mutation (G243S) in the 243rd codon of SMARCA4 is a missense mutation changing glycine to serine in the protein. The glycine residue at this site is conserved, and a mutation at this site could potentially affect the protein function. Computational algorithms for the prediction of the effect of a mutation on protein structure and function (SIFT, PolyPhen-2, etc.) suggest that the mutation (G243S) is likely to be disruptive. However, the prediction has not been confirmed by systematic functional studies. The mutation is also reported in ClinVar (Variation ID: 408659), but its clinical significance is uncertain. A single case report of a SMARCA4 germline mutation in a patient with ovarian cancer is the only available literature suggesting any possible role of this gene in predisposition to cancer.[21] In summary, the SMARCA4 (G243S) variant has a high impact on SMARCA4 function based on computational prediction. However, the available biological and clinical evidence is currently insufficient to determine its role in disease. More investigation for the possible role of SMARCA4 in germline predisposition is suggested to help in the better diagnosis and treatment of future cases.

  SMARCA4 in Breast Cancer Top

The SMARCA4 gene encodes a protein that regulates transcription via its helicase and ATPase activities. This gene is often somatically mutated or silenced in 4.01% of all cancers such as lung, colon, bladder, breast, endometrium, liver, and kidney cancers, alluding to its tumor suppressive nature.[22] SMARCA4 is somatically mutated in 2.09% of the patients with breast carcinoma, and it promotes it by reprogramming lipid synthesis.[22],[23] SMARCA4 loss due to mutation causes profound downregulation of cyclin D1, which limits the CDK4/6 kinase activity.[24] Reduced cyclin D1 in SMARCA4-deficient small cell carcinoma of the ovary of hypercalcemic type (SCCHT) and non-small-cell lung cancer (NSCLC) leads to enhanced sensitivity to CDK4/6 inhibitors.[24] This enhanced sensitivity to CDK4/6 inhibitors was appreciated in both SCCHT and NSCLC despite the different organs of origin and mutational profiles.[24] Although the use of these inhibitors has been approved in hormone-receptor-positive breast cancer, their use in SMARCA4-mutated breast cancer could be an interesting area of research in the future.

Contrasting to the BRCA1/2 mutations, wherein the epithelial ovarian cancer is a frequent conjoiner, SMARCA4 mutation is often coupled with the rare type of SCCHT.[25] Furthermore, it is associated with poor prognosis in breast cancer.[26] Interestingly, in our patient, the sequence change at codon 243 replaced glycine with serine in the SMARCA4 protein (p. Gly243Ser). This particular variant has been reported in the literature in other malignancies with unknown significance, but not in breast carcinoma.[27]

  Management of Hereditary Breast Cancers Top

Management of hereditary breast cancers can be divided into two parts– preventive care and curative measures [Figure 1]. Recommendations for preventive care are based on the assumed cumulative breast cancer risk, wherein a risk of ≥20% is considered high, for example in case of BRCA1/2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, and NF1 mutations; whereas 10%–20% is considered moderate, as seen in BRIP1, RAD51C, RAD51B, BARD1, FANCA, FANCC, FANCM, NBN, BLM, and WRN mutations.[1] Radical measures such as prophylactic mastectomy and risk-reducing bilateral salpingo-oophorectomy (RRBSO) are considered in high-risk gene carriers and usually not in those with moderate-risk; however, these measures may be considered if other high-risk factors like strong family history, etc., are present.[1],[28] Chemoprevention with tamoxifen and raloxifene, as well as exemestane and anastrozole, has been shown to reduce the breast cancer incidence in women who are at an increased risk of the disease in randomized controlled trials.[29] At present, there is little difference between the management of patients with hereditary breast cancers and those with non-hereditary ones. BRCA carriers have around 30%–40% risk of developing breast carcinomas in the contralateral breast and 10%–15% risk of developing ovarian cancer. Therefore, RRBSO and/or prophylactic contralateral mastectomy can also be considered as initial treatment options.[30]
Figure 1: Management strategies for hereditary breast cancer (high-risk)

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Early detection remains the cornerstone for breast cancer care, concerning which many expert groups have issued clinical recommendations for breast cancer screening [Table 3].[31],[32],[33],[34],[35] However, there is equipoise in the oncology community regarding the optimal age to start screening, its frequency, techniques, and variations depending on the underlying risk involved.[36],[37],[38]
Table 3: Screening recommendations for average-risk population

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  Conclusion Top

This case is important as it emphasized the issue of risk stratification of breast cancer with rare mutations, for which good quality guidelines are not available. There are concerns about psychosocial implications associated with offering radical surgeries, especially in young patients, with an impact on the quality of life.[39] There are many clinical situations with dilemmas; however, one must be careful in balancing risk-benefit and treating a patient in entirety.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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