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Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 81-84

Molecular-based screening and therapeutics of breast and ovarian cancer in low- and middle-income countries

Oncology and Radiotherapy Centre, Square Hospitals Limited, Dhaka, Bangladesh

Date of Submission02-Jan-2020
Date of Decision10-Jan-2020
Date of Acceptance26-Jan-2020
Date of Web Publication24-Feb-2020

Correspondence Address:
Syed Md Akram Hussain
Oncology and Radiotherapy Centre, Square Hospitals Limited, Dhaka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_2_20

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How to cite this article:
Akram Hussain SM. Molecular-based screening and therapeutics of breast and ovarian cancer in low- and middle-income countries. Cancer Res Stat Treat 2020;3:81-4

How to cite this URL:
Akram Hussain SM. Molecular-based screening and therapeutics of breast and ovarian cancer in low- and middle-income countries. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Mar 30];3:81-4. Available from: http://www.crstonline.com/text.asp?2020/3/1/81/279097

Breast cancer is the most prevalent cancer and the second most common cause of death from cancer among women worldwide with an age-standardized incidence rate of 46.3/100,000 and a mortality rate of 13/100,000 as per data from GLOBOCAN 2018.[1] Approximately 45% of breast cancer cases and 55% of breast cancer deaths occur in low- and middle-income countries (LMICs).[2] Breast cancer patients are increasing in the Indian subcontinent with 162,468 new breast cancer patients in India, 12,764 in Bangladesh, and 3091 in Sri Lanka in 2018. In India, it is still the most common cancer among women with a mortality rate of 12.7/100,000 women.[3] Even though the overall survival (OS) of breast cancer patients has increased in the developed world, it is about 60% in India.[4]

Molecular biology of breast cancer is based on mutations of a number of genes. Mutations in BRCA1 and BRCA2 genes account for 5%–10% of all female breast cancers and 15%–20% of all familial breast cancers.[5],[6] Most BRCA1-related breast cancers have low expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2.[7],[8] Hence, BRCA1 mutation carriers are more likely to have triple-negative breast cancer (TNBC) than BRCA2 mutation carriers or noncarriers,[9] whereas BRCA2-associated cancers are mainly ER positive.[10],[11]

BRCA1/2 mutation is different from 'BRCAness,' which describes tumors that harbor a homologous recombination defect but have no detectable germline mutation in BRCA1 or BRCA2. It describes patients who do not have a pathogenic germline variant in BRCA1/2 but who have developed a tumor with an impaired ability to perform homologous recombination.[12] Recent estimates suggest that the proportion of breast cancer patients who fall into this category may be as high as 20%.[13]

Other genes are involved such as tumor suppressor genes, p53 and PTEN. Alterations in the Ras/Raf/MEK/ERK signal transduction pathway are often associated with breast cancer as well.[14] HER2/neu is amplified in 18%–20% of breast cancer patients, indicating a close correlation between its expression and prognosis in breast cancer.[15] This makes HER2 an attractive therapeutic target. Targeted therapies such as trastuzumab interfere with a specific molecular target and inhibit cancer progression.

Managing breast cancer in LMICs poses challenges including access to screening and availability and cost of therapeutic interventions.[2],[16] Screening for BRCA1 and BRCA2 (BRCA1/2) mutations helps to predict prognosis, make therapeutic decisions, and take preventive actions, but its high cost is a limiting factor. In a recent survey done in SAARC countries, only 15% of the participants routinely performed BRCA testing in their patients with ovarian cancer.[17] Meeting one or more of these criteria warrants germline testing for BRCA1/2 as per the National Comprehensive Cancer Network (NCCN) guidelines as follows:[18]

  • An individual from a family with a known BRCA1/2 pathogenic/likely pathogenic variant, including such variants found on research testing

  • Personal history of breast cancer plus one or more of the following:

    • Diagnosed ≤45 years
    • Diagnosed 46–50 years with:

      • An additional breast cancer primary at any age
      • ≥1 close blood relative with breast cancer at any age
      • An unknown or limited family history.

    • Diagnosed ≤ 60 years with:

      • TNBC.

    • Diagnosed at any age with:

      • ≥1 close blood relative with:

        • Breast cancer diagnosed ≤50 years or
        • Ovarian carcinoma.

      • ≥ 2 additional diagnoses of breast cancer at any age in patients and/or in close blood relatives.

  • Ashkenazi Jewish ancestry
  • Personal history of ovarian carcinoma.

Adjuvant trastuzumab with chemotherapy has significantly improved the outcome in HER2-positive early breast cancer patients, but the added cost of trastuzumab with chemotherapy means that few people can afford it. HER2-directed therapy is expensive, and <5% of the eligible population in India can afford it.[19] In a report from China, only 30% out of about 5000 patients from multiple centers could receive trastuzumab due to lack of proper insurance coverage.[20] As a result, breast cancer is either the leading or the second most common cause of cancer deaths among women in LMICs. Although early-stage breast cancer is potentially curable, mortality-to-incidence ratios for breast cancer are significantly worse in LMICs than in developed countries.[21]

In the current issue of the journal, Chheda et al. report their findings from a study conducted in India in which 160 women fulfilling the NCCN guidelines for genetic testing for BRCA1 and BRCA2 mutations were screened using Sanger sequencing and next-generation sequencing (NGS) methods.[22] Among them, 73 had breast cancer, 43 had ovarian cancer, and the rest were unaffected at the time of screening but had a family history of cancer. DNA was extracted from ethylenediamintetraacetic acid (EDTA) whole blood using Qiagen QIAamp DNA mini kit. Deleterious variants of BRCA1 or BRCA2 genes were found in 31.9% of the patients. BRCA1 mutation (70.6%) was higher than BRCA2 (29.4%) in this study as well, and this finding has been reported in other studies as well.[23] Pathogenic variants were found among 34.5% of cancer-affected patients and 25% in cancer-unaffected female relatives with hereditary breast and ovarian cancer (HBOC) family history. Pathogenic variants in breast cancer cases (31.5%) were lower than ovarian cancer cases (39.5%). BRCA1 mutations were almost five times higher than BRCA2 mutations in stand-alone cases of ovarian cancer. A spectrum of 20 different pathogenic variants was identified in BRCA1 and 14 in BRCA2. In both BRCA1 and BRCA2, the majority were frameshift variants (13 in BRCA1 and 10 in BRCA2). Eleven different Variants of uncertain significance (VUS) were identified in 6.3% of the patients. Four distinct VUS were found in BRCA1 and seven in BRCA2, among which three were novel variants.

Differentiating between clinically significant changes and benign nonpathogenic variations, termed as variants of unknown significance (VUS) in BRCA1/2, is one of the difficulties faced in clinical practice. Genetic testing has revealed that approximately 13% of BRCA1 and BRCA2 mutations are VUS, implying clinical uncertainty and ambiguity in risk assessment of tested individuals. The task of accurately identifying carriers of BRCA mutations is complicated by our lack of understanding of the significance of various polymorphisms in these genes.[24] The molecular profile of selective cohort (HBOC probands) shows that the prevalence of pathogenic variants in BRCA1 and BRCA2 is high in the Indian population. The spectrum of BRCA variants is diverse, and it is very important to correctly classify them as pathogenic, VUS, or benign. The knowledge of the pathogenicity and likely pathogenic mutations are useful to predict prognosis, make therapeutic decisions, apply risk reduction strategies in patients, and carry out cost-effective screening in the first-degree relatives.[25] It will also aid in management and surveillance focusing on reducing the risk of breast cancer and may also influence surgical decision-making in newly diagnosed breast cancer and ovarian cancer patients.

HER2 is amplified or overexpressed in 18%–20% of all breast cancer patients.[15] Trastuzumab has resulted in significant improvement in both disease-free survival (DFS) and OS in women with HER2-positive breast cancer when given in combination with standard chemotherapy, as confirmed in the Cochrane meta-analysis of randomized controlled trials in the FinHer trial, where it reduced mortality by one-third and the risk of relapse by 40%.[26] Although the recommended duration of 12 months of adjuvant trastuzumab remains the standard in HER2-positive breast cancer, the Phase III SOLD trial showed that the margin of difference, compared with just 9 weeks of the drug, was slim.[27] The Phase III SOLD trial compared outcomes for 9 weeks versus 12 months of adjuvant trastuzumab in patients, where the DFS and 5-year OS were 90.5% and 95.9%, respectively, in the 12-month arm compared with 88% and 94.7% in the 9-week arm. In the PERSEPHONE trial, the 4-year DFS in the 12-month group was 89.8% and 89.4% in the 6-month group, showing that 6-month trastuzumab treatment was noninferior to 12-month treatment in patients with HER2-positive early breast cancer.[28]

The current issue of the journal includes a study that has investigated whether the 9-week trastuzumab course with chemotherapy can be adapted in India to improve the outcome of HER2-positive breast cancer patients.[29] It was designed keeping in mind that the 12-month duration is often not feasible for patients due to financial limitation in LMICs. Majority of the 129 patients in this study were postmenopausal (64%). The most common histology was infiltrating ductal carcinoma; 57% had Grade 2 disease. Over 90% of the patients had T1 or T2 disease, and about 50% had node-negative disease. Trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) was started after four cycles of doxorubicin + cyclophosphamide in 110 patients along with weekly paclitaxel. The remaining patients were given docetaxel + cyclophosphamide. After completion of 9 weeks of trastuzumab, they received the remaining chemotherapy and radiation or hormonal therapy depending on the stage, receptor status, and menopausal status. At a median follow-up of 29 months, the 3-year OS was 98% and DFS was 97.4%. This is similar to or better than other studies using short-course trastuzumab in patients with early-stage breast cancer.[30] None of the patients experienced any symptomatic cardiotoxicity. Overall, trastuzumab was generally well tolerated by the patients.

Both the studies are limited by their retrospective design and small number of patients. Similar studies conducted in other countries have included a larger number of patients.[20],[31] The studies were conducted in a single institution, which may have introduced selection bias. In addition, there is no indication that ethnicity of the patients was taken into consideration. This may have caused some mutations to be over- or underrepresented. A study comprising a larger number of patients from all the ethnic backgrounds carried out across India will address these limitations.[32]

Unlike the FinHer trial, the study by Manuprasad et al. lacks a control group without trastuzumab or any comparator group with 3- or 12-weekly trastuzumab. In a study conducted in another tertiary cancer center in India, the 5-year OS was only 42% in patients who did not receive trastuzumab compared to 90% in those who received 3-weekly trastuzumab along with chemotherapy.[30] The FinHer trial showed that 9 weeks of trastuzumab is more effective than none at all (control). At 5 years, the trastuzumab-treated patients had a DFS rate of 83.3% and an OS rate of 91.3%. In patients who received chemotherapy alone, the 5-year DFS and OS rates were 73% and 82.3%.[33] Two different chemotherapy regimens were used in the current study; the OS and DFS of the individual regimens with trastuzumab were not mentioned, and there is no indication how the patients were chosen for each regimen. In addition, asymptomatic patients on the 9-week schedule did not undergo periodic echocardiographic evaluation; thus, the true incidence of asymptomatic decline in ejection fraction is not known. Although this is the largest study of 9-week adjuvant trastuzumab from India, the follow-up was short. This study was modeled after the FinHer trial, which itself is not a dedicated study, rather it provided a subgroup analysis on adjuvant 9-week trastuzumab. A study with a much larger patient pool conducted across the country with a single chemotherapy regimen and multiple comparators and control groups with random patient assignment will provide a better picture on the outcome and toxicity of short-course adjuvant trastuzumab on HER2-positive early breast cancer patients.

Short-course trastuzumab (9 weeks) is a feasible option in a resource-limited setting and can produce favorable outcomes, especially in early breast cancer. The regimen is well tolerated and can be combined with standard chemotherapy protocols in LMICs. Since the use of trastuzumab is limited in LMICs due to economic constraints and the 6-month or 1-year schedule of trastuzumab is not accessible to a majority of patients, governments can ensure that patients receive a 9-week schedule of trastuzumab through support schemes such as subsidy, government-sponsored insurance, or health assurance. Ideally, trastuzumab should be offered to all patients with HER2-positive breast cancer, but since its cost is beyond the range of most patients, government support to ensure access to trastuzumab can potentially save many lives.

Poly (ADP-ribose) polymerases, also called PARP inhibitors, are a new class of chemotherapeutic agents directed at targeting cancers with defective DNA damage repair and has been approved by the US Food and Drug Administration and European Medicines Agency for the treatment of BRCA mutation-positive breast and ovarian cancers. Thus, PARP inhibitors can play an important role in the treatment of HBOC if BRCA mutations are detected at an early stage.[34],[35]

NGS is now considered the method of choice for diagnostic gene panel testing. Although both Sanger and NGS were used in the study by Chheda et al. and the patients were not chosen randomly for each test, NGS can yield additional genomic information and increases the rate of mutation detection of risk-associated genes in HBOC. Identifying deleterious BRCA mutations can help both the patients and their relatives.[17] More awareness should be created among citizens and physicians about HBOC and BRCA1/2 mutation testing. This can be made a mandatory part of the current clinical practice for women with a familial history of breast and ovarian cancer. It must be ensured that citizens understand that screening for BRCA mutations is a part of preventive counseling. The test is unaffordable for a large proportion of the population because of its high cost; however, insurance coverage and government-provided subsidy can bring down the cost substantially.

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