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Triple Negative Breast Cancer in India: What Is the Real Incidence?
CC BY 4.0 · Indian J Med Paediatr Oncol 2023; 44(04): 442-444
DOI: DOI: 10.1055/s-0042-1742612
The real incidence of triple negative breast cancer (TNBC) in India has always been a topic of debate. There has been considerable heterogeneity in the reporting of TNBC rates in India. A recent meta-analysis of 34 studies done till 2019 that included 20,678 patients reported a pooled prevalence of 27% (95% confidence interval [CI]: 24–31%).[1] Our previous work in which we collected data from 17 studies done between 1999 and 2015 involving 7,237 patients from all four regions of India reported a TNBC rate of 31% (95% CI: 27–35%).[2]
In this meta-analysis, substantial heterogeneity was observed across the studies (I2 of 91.2% [95% CI: 88–94%], p < 0.001). This was unexplained by study level characteristics like study location, definition of HER2 or estrogen receptor, age, proportion of patients who were premenopausal, grade 3 disease, or larger tumor size. We also found that the TNBC rate decreased as the quality of the study increased. Although the rates were not statistically significant, the TNBC rate of lower quality studies was higher when compared to higher quality studies (38% [95% CI: 27–48%] vs. 29% (95% CI: 25–33%]). Quality of studies were assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. One point was given to each parameter if the study described the setting and study participants, reported descriptive data, provided detailed outcome data, and discussed limitations. A good quality study had a score of ≥4 and a lower quality had a score of < 4 with a maximum score of 5.[2]
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Publication History
Article published online:
14 March 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
The real incidence of triple negative breast cancer (TNBC) in India has always been a topic of debate. There has been considerable heterogeneity in the reporting of TNBC rates in India. A recent meta-analysis of 34 studies done till 2019 that included 20,678 patients reported a pooled prevalence of 27% (95% confidence interval [CI]: 24–31%).[1] Our previous work in which we collected data from 17 studies done between 1999 and 2015 involving 7,237 patients from all four regions of India reported a TNBC rate of 31% (95% CI: 27–35%).[2]
In this meta-analysis, substantial heterogeneity was observed across the studies (I2 of 91.2% [95% CI: 88–94%], p < 0.001). This was unexplained by study level characteristics like study location, definition of HER2 or estrogen receptor, age, proportion of patients who were premenopausal, grade 3 disease, or larger tumor size. We also found that the TNBC rate decreased as the quality of the study increased. Although the rates were not statistically significant, the TNBC rate of lower quality studies was higher when compared to higher quality studies (38% [95% CI: 27–48%] vs. 29% (95% CI: 25–33%]). Quality of studies were assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. One point was given to each parameter if the study described the setting and study participants, reported descriptive data, provided detailed outcome data, and discussed limitations. A good quality study had a score of ≥4 and a lower quality had a score of < 4 with a maximum score of 5.[2]
Why Are Rates of TNBC So High in India? Is it a Precise Estimation of the Ground Reality?
Experts often cite referral bias as the reason why TNBC rates are higher in these studies. Most of the studies are done at a large referral center. Epidemiological studies can suffer from referral bias when patients are recruited from tertiary centers. Patients with TNBC have more severe disease and will probably get selectively referred to a tertiary center, which will spuriously raise the rate of TNBC in the tertiary centers.
However, in contradiction to the theory of “referral bias,” a recent study from a tertiary referral center in Chennai, which evaluated 2,137 patients with locally advanced breast cancer, reported that the incidence of TNBC was 12%.[3] This study was done from 2006 to 2013. Intuitively, one would think that in a study done among patients with locally advanced disease, the number of TNBCs would be higher than what is currently reported. Could it be that only patients who had less severe disease and who could afford to go to these centers were selectively referred to these institutions? Contrast that with the original assumption for a referral bias wherein patients with more severe disease gets referred to a higher center. If that is the case, is a more realistic estimate for the rate of TNBC somewhere between 12% and 27%?
Another possible reason for higher rates of TNBC is the poor quality of the pathological examination of the specimen. For instance, Chakraborty et al in their study of 925 patients collected from a single tertiary cancer center reported a TNBC rate of around 12%. The study population underwent testing during 2011 to 2015. Although the institution was a tertiary referral center, the rate of TNBC is lower than what was reported in the meta-analysis. The authors hypothesize that it is a more accurate reflection of the reality as their pathology laboratory adhered to the established guidelines.[4] For this study, methods for immunohistochemistry (IHC) testing were automated, peer-reviewed with internal and external quality assurance that was done mostly on core biopsies.
However, in contradiction to Chakraborty et al, a recent study done among 3,453 patients diagnosed with stage I, II, or III breast cancer from three different private institutions in India (two of which were in Chennai) during the years 2008 to 2014 reported that the TNBC rate was 24.2%.[5] All three institutions have implemented high-quality pathology reporting. Most vital factor to be noted is that the patients in this study were likely to be at a higher socioeconomic status than the patients treated in government centers.
Inconsistent IHC diagnostic methods are very prevalent in India. [Table 1] lists issues concerning the heterogeneity of TNBC rate in India and some suggested solutions. Improper fixation techniques, use of non-U.S. Food and Drug Administration approved assays and interpretative error due to the failure to use the revised American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines for estrogen receptor/progesterone receptor positivity can cause some of the errors in reporting.[6] The standardized tests are compromised for cheap nonvalidated tests that lead to nonuniformity of results nationwide.
|
Issues |
Suggested solution |
|---|---|
|
Choice of specimen[4] |
• Biopsy tissue preferred |
|
Improper fixation of tissue[6] |
• Avoid delay or refrigeration before fixation • Adequate formalin fixation time • Adequate formalin to be used |
|
Use of nonvalidated antibodies[6] |
• Automation of IHC • Participation in EQAS • Protocol optimization |
|
Interpretative error[6] |
• Strict implementation of ASCO-CAP guidelines for scoring • Compare core biopsy with excised specimen • FISH confirmation for HER2neu heterogeneity |
|
Lack of training[6] |
• Training of pathologists and technicians • Laboratory certification |
|
Lack of uniformity in results[6] |
• Centralized testing • Internal auditing |
|
Expensive tests[6] |
• Economize or proper insurance coverage of these tests |
|
Referral bias[9] |
• Population-based recruitment • Careful interpretation of results |
- Kulkarni A, Kelkar DA, Parikh N, Shashidhara LS, Koppiker CB, Kulkarni M. Meta-analysis of prevalence of triple-negative breast cancer and its clinical features at incidence in Indian patients with breast cancer. JCO Glob Oncol 2020; 6: 1052-1062
- Sandhu GS, Erqou S, Patterson H, Mathew A. Prevalence of triple-negative breast cancer in India: systematic review and meta-analysis. J Glob Oncol 2016; 2 (06) 412-421
- Dhanushkodi M, Sridevi V, Shanta V. et al. Locally advanced breast cancer (LABC): real-world outcome of patients from cancer institute, Chennai. JCO Glob Oncol 2021; 7: 767-781
- Chakraborty S, Wadasadawala T, Ahmed R, Coles C, Chatterjee S. Breast cancer demographics, types and management pathways: can western algorithms be optimally used in eastern countries?. Clin Oncol (R Coll Radiol) 2019; 31 (08) 502-509
- Doval DC, Radhakrishna S, Tripathi R. et al. A multi-institutional real world data study from India of 3453 non-metastatic breast cancer patients undergoing upfront surgery. Sci Rep 2020; 10 (01) 5886
- Shet T. Improving accuracy of breast cancer biomarker testing in India. Indian J Med Res 2017; 146 (04) 449-458
- Chen X, Yuan Y, Gu Z, Shen K. Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis. Breast Cancer Res Treat 2012; 134 (03) 957-967
- Kumar RV, Panwar D, Amirtham U. et al. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 status in breast cancer: a retrospective study of 5436 women from a regional cancer center in South India. South Asian J Cancer 2018; 7 (01) 7-10
- Collonnaz M, Erpelding ML, Alla F. et al; AEPEI Study Group. Impact of referral bias on prognostic studies outcomes: insights from a population-based cohort study on infective endocarditis. Ann Epidemiol 2021; 54: 29-37
- McDonald JA, Rao R, Gibbons M. et al. Symposium report: breast cancer in India-trends, environmental exposures and clinical implications. Cancer Causes Control 2021; 32 (06) 567-575
- Holm J, Humphreys K, Li J. et al. Risk factors and tumor characteristics of interval cancers by mammographic density. J Clin Oncol 2015; 33 (09) 1030-1037
Reference
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Publication History
Article published online:
14 March 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
- Kulkarni A, Kelkar DA, Parikh N, Shashidhara LS, Koppiker CB, Kulkarni M. Meta-analysis of prevalence of triple-negative breast cancer and its clinical features at incidence in Indian patients with breast cancer. JCO Glob Oncol 2020; 6: 1052-1062
- Sandhu GS, Erqou S, Patterson H, Mathew A. Prevalence of triple-negative breast cancer in India: systematic review and meta-analysis. J Glob Oncol 2016; 2 (06) 412-421
- Dhanushkodi M, Sridevi V, Shanta V. et al. Locally advanced breast cancer (LABC): real-world outcome of patients from cancer institute, Chennai. JCO Glob Oncol 2021; 7: 767-781
- Chakraborty S, Wadasadawala T, Ahmed R, Coles C, Chatterjee S. Breast cancer demographics, types and management pathways: can western algorithms be optimally used in eastern countries?. Clin Oncol (R Coll Radiol) 2019; 31 (08) 502-509
- Doval DC, Radhakrishna S, Tripathi R. et al. A multi-institutional real world data study from India of 3453 non-metastatic breast cancer patients undergoing upfront surgery. Sci Rep 2020; 10 (01) 5886
- Shet T. Improving accuracy of breast cancer biomarker testing in India. Indian J Med Res 2017; 146 (04) 449-458
- Chen X, Yuan Y, Gu Z, Shen K. Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis. Breast Cancer Res Treat 2012; 134 (03) 957-967
- Kumar RV, Panwar D, Amirtham U. et al. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 status in breast cancer: a retrospective study of 5436 women from a regional cancer center in South India. South Asian J Cancer 2018; 7 (01) 7-10
- Collonnaz M, Erpelding ML, Alla F. et al; AEPEI Study Group. Impact of referral bias on prognostic studies outcomes: insights from a population-based cohort study on infective endocarditis. Ann Epidemiol 2021; 54: 29-37
- McDonald JA, Rao R, Gibbons M. et al. Symposium report: breast cancer in India-trends, environmental exposures and clinical implications. Cancer Causes Control 2021; 32 (06) 567-575
- Holm J, Humphreys K, Li J. et al. Risk factors and tumor characteristics of interval cancers by mammographic density. J Clin Oncol 2015; 33 (09) 1030-1037