Commentary: Eight Year Survival Analysis of Patients with Triple Negative Breast Cancer in India
Dinesh Chandra Doval1*, Atika Dogra2 3
Triple-negative breast cancer (TNBC) is clinically defined by the lack of expression of estrogen receptor, progesterone receptor and no overexpression of human epidermal growth factor receptor-2 (HER2). It accounts for approximately 15-25% of newly diagnosed breast cancer cases3. TNBC is an aggressive disease with outcomes inferior to those of other breast cancer subtypes. This group of breast cancer is only partially responsive to chemotherapy and presents a lack of targeted therapies.
Compared to other types of breast cancer, TNBC is seen more in premenopausal women than older women. In the article, the median age at the time of diagnosis was 49 years4 which may be considered as younger age and is comparable to many other Indian studies5. However, the majority of patients considered in this study were postmenopausal. This shows that TNBC is affecting younger population and most likely reflects the general trend of breast cancers occurring a decade earlier. This leads to another finding that menopause has been reached early in the women considered in this study. This is in line with the existing literature, the average age of menopause of an Indian woman is 46.2 years and is much less than their Western counterparts (51 years)6. Clinically stage II was the commonest stage at presentation. This reflects the awareness among population presenting to a private tertiary cancer care center located in a metropolis. Age group wise comparison showed that the pathological tumor size > 5 cm was observed more commonly in the patients with age group less the 50 years while patients > 50 years of age had a higher predominance of tumor size < 5 cm.
Interestingly, compared to the older patients’ group, the younger age (<50 years) group showed better overall survival (OS) despite having decreased relapse-free survival (RFS). Surprisingly, enhanced RFS was observed in patients with higher tumor grade and presence of lymph-vascular invasion (though not significant), while the reverse is expected concerning the observed trend. Similarly, improved OS was seen in patients with premenopausal status, higher tumor grade and presence of lymph-vascular invasion. Such findings are not usually found in the literature. This may indicate towards the heterogeneity of this disease. The subgroup of patients with no axillary lymphnode involvement showed better RFS (69%; p-value 0.001) as well as OS (86%; p-value 0.001) in comparison with the sub-group of patients with positive axillary lymphnodes.
Molecular profiling has provided biological evidence for heterogeneity of breast cancer through the identification of intrinsic subtypes. These subtypes consist of Luminal A, Luminal B, HER2 expressing, basal-like (BL) and normal breast-like. Further, it has also been observed that heterogeneity exists within TNBC. The majority of TNBCs show the expression of basal markers on gene expression profiling and most authors accept TNBC as BL. However, a smaller fraction lacks a BL phenotype despite being TNBC. Lately, the literature has reported that TNBC can be classified into 7 subtypes (6 defined subtypes and an unstable group) by gene expression microarray7,8. The subtypes were characterized as BL 1, BL 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor and unstable. These studies show that significant biological heterogeneity exists within a group of patients detected with TNBC.
The bias towards modified radical mastectomy (MRM) was highly significant in this study with all patients of neo-adjuvant chemotherapy undergoing only MRM. This reflects the social and cultural differences in the Indian population. No significant difference could be seen between RFS of surgical procedure groups, i.e., MRM vs. breast conservation surgery. Similarly, OS of surgical procedure groups showed no considerable difference. These observations are in collaboration with the known literature. The study observed that eight-years RFS and OS was 58% and 75%, respectively. Literature has pointed out that TNBC has higher chances of early recurrences and poor survival outcomes followed by treatment. Our results also represent this phenomenon, though the OS is better keeping in view the number of recurrences.
The current study has presented comprehensive eight-years survival data on the most aggressive type of breast cancer. There are many studies in the Western literature on the same, but the reliable data in the Indian setting on TNBC survival are scarce. TNBC have aggressive clinical behavior, distinct metastatic pattern and poor prognosis9 despite responding to conventional neoadjuvant and chemotherapy3. The main limitation of this study was the lack of testing for basal cytokeratins. Identification of basal markers positivity within this group of TNBC could identify a subgroup of tumors, BLBC. It has been shown that BLBC consistently over expresses HER1 or epidermal growth factor receptors (EGFR), hence EGFR inhibitors may have a role in the treatment of this tumor subtype10.
Prevalence of TNBC in India is considerably higher compared with Western populations11. The Triple-negative disease could affect one in three women with breast cancer11. This finding has significant clinical relevance as it may lead to poor outcomes in patients with breast cancer in India11. Further research is required to understand the determinants of TNBC in India. Identification of newer targets and development of targeted therapies are the need of the hour.
- World Health Organization [Internet]. Geneva: Breast cancer burden; 2017 [updated 2017; cited 09/21/ 2017]. Available from: http://www.who.int/cancer/detection/breastcancer/en/index1.html
- Cetin I, Topcul M. Triple negative breast cancer. Asian Pac J Cancer Prev. 2014; 15(6): 2427-31.
- Sharma B, Satyanarayan, Kalwar A, et al. Five year retrospective survival analysis of triple negative breast cancer in North-West India. Indian J Cancer. 2013; 50: 330-2.
- Doval D C, Suresh P, Sinha R, et al. Eight Year Survival Analysis of Patients with Triple Negative Breast Cancer in India. Asian Pac J Cancer Prev. 2016; 17(6): 2995-9.
- Thakur S, Grover RK, Gupta S, et al. Identification of Specific miRNA Signature in Paired Sera and Tissue Samples of Indian Women with Triple Negative Breast Cancer. PLoS ONE. 2016; 11(7): e0158946.
- Ahuja M. Age of menopause and determinants of menopause age: A PAN India survey by IMS. Journal of Mid-Life Health. 2016; 7(3): 126-31.
- Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selecction of targeted therapies. J Clin Invest. 2012; 121: 2750-67.
- Masuda H, Baggerly KA, Wang Y, et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res. 2013; 19: 5533-40.
- Anders CK, Carey LA. Biology, Metastatic Patterns, and Treatment of Patients with Triple-Negative Breast Cancer. Clinical Breast Cancer. 2009; 9(2): S73-S81.
- Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004; 10: 5367-74.
- Sandhu GS, Erqou S, Patterson H, et al. Prevalence of Triple-Negative Breast Cancer in India: Systematic Review and Meta-Analysis. J Glob Oncol. 2016; 2(6): 412-21.