Abstract

INTRODUCTION

Breast cancer is the most common cancer among females in urban India and is rapidly catching up with cervical cancer in rural India.[1] It has been long recognized that breast cancer is a heterogeneous disease and not a single entity. Gene expression studies using DNA micro arrays have identified subtypes of breast cancer[2] that were not apparent using traditional histopathologic methods. Four common subtypes have been identified; two of these are derived from estrogen receptor (ER) negative tumors [basal-like and Human epidermal growth factor receptor-2(HER-2) positive] and two are derived from ER-positive tumors (luminal A and B). A fifth subtype called the “Normal” has also been described of which the clinical relevance is not clear.

The definition of basal-like breast cancers has been evolving and though there are no universally agreed upon criteria to define it, the panel developed by Nielsen et al.[3] is generally accepted in practice – basal-like cancers are negative for hormone receptors (HRs) and HER-2, in addition to being positive for cytokeratin (CK) 5/6 or Epidermal growth factor receptor (EGFR). Basal like breast cancers have been found to be more common in younger women of African-American descent, are more aggressive cancers with shorter relapse free survival (RFS), a tendency to visceral rather than bone metastases and a significant likelihood of Breast Cancer (BRCA) susceptibility type-1 mutation.[4] To date, studies on patients with basal-like breast cancers have been limited by small sample sizes and short follow-up times and have been restricted to western literature. To some extent, this is because the basal-like phenotype is based on immunohistochemical staining of tumor slides using anti-keratin antibodies, and these are not yet in general clinical use. In the clinical setting, it has been found that this “basal-like” category of tumors is composed almost entirely of “triple negative breast cancers” (TNBCs)[4] (tumors that are negative for ER, progesterone receptor (PR) and HER2), which can be easily identified in the lab by immunohistochemistry (IHC)[5] and hence has been used as a surrogate for basal-like cancers in many studies all over the world. TNBCs constitute 12-24% of breast cancers[4,6,7] and have attracted the attention of pathologists and oncologists as an easily recognizable prognostic group of breast cancer with aggressive behavior that commonly lack the benefit of any specific targeted therapy. Reliable data on TNBC in Indian setting is scarce[8] and hence, we felt the need to study the clinical profile of these cancers in our setting.

MATERIALS AND METHODS

A total of 171 patients of TNBCs who were registered and treated at a tertiary care cancer hospital in North India between January 2005 and December 2008 were included in this study. All these patients had undergone their primary treatment from this institute and from the very beginning were under the care of a single unit. These patients were followed-up till December 2010. A detailed retrospective analysis was carried out according to a planned Performa. Diagnosis of breast cancer was primarily based on clinical presentation, imaging (mammogram, ultrasound or MRI of the breast when indicated) and cytopathological studies. Staging was done with X-ray chest, Ultrasound abdomen for localized disease with the addition of bone scan and computed tomography (CT) or positron emission tomography (PET) scan for locally advanced disease and metastatic disease. Patients were staged in accordance with American Joint Committee on Cancer (AJCC)-6-(TNM) staging system. TNBC was defined as ER negative, PR negative and HER2 neu negative cancers. These tests were carried out with standard Food and Drug Administration (FDA) approved kits by IHC. For each patient in the database, antibody staining of a set of paraffin embedded slides for ER and PR was carried out. This test was carried out using the BioGenex kit. Any positivity was taken as positive. The over expression of HER2 status was evaluated using the Hercep Test kit from Dako, Denmark. A HER2 report of 3 + by IHC was considered as positive. Confirmation by Flourescence in-situ hybridisation (FISH) was carried out for all those with receptor status 2+. HER2 score of 0 or 1 was considered negative. Patients with ambiguous marker status were excluded. Baseline epidemiological and tumor characteristics of triple negative cancers were analyzed for all 171 patients. Outcomes were analyzed for subgroups of early breast cancer (EBC), locally advanced breast cancer (LABC) and metastatic breast cancer (MBC) separately. EBC was defined as a T-stage ≤ T2 and/or N-stage ≤ N1, LABC was defined as T-stage ≥ T3 and/or N stage ≥ N2 without any evidence of distant metastasis. MBC was defined as any breast cancer with evidence of distant metastasis. However, for survival analysis 31 patients who were lost to follow-up for more than 1 year were excluded. Of these 31 patients, 27 were non metastatic at presentation and were disease free and 4 were metastatic and in remission at last follow-up. Attempts were made to contact these patients telephonically as well as through letters. However, no responses could be obtained. SPSS v. 16 (SPSS Inc.,) was used for statistical analysis. The consort diagram is illustrated in Figure 1.

DISCUSSION

Our study was designed to look at the demographic profile, clinical features and responses to various modalities of therapies and its correlations to the clinical outcomes in the Indian setting. To our knowledge, this is possibly the largest study on TNBC done in India.

Our population was slightly younger (median age 49 years) than the ones described in western data[4] (median age 53 years). The peak incidence was observed in the 5th decade (36.3%) in our study. This finding of younger median age most likely reflects the general trend of breast cancers occuring a decade earlier in India. None of the standard risk factors for breast cancer had any significant association as was noted in other studies also.[9]

Clinically and pathologically stage II was the most common stage (62%) followed by stage III (15%). The low number of stage IV patients (11%) in our study most probably reflects the bias in presentation to a private tertiary care cancer center. The bias towards MRM was highly significant in our study with all patients of NACT undergoing only MRM. This reflects the social and cultural differences in the Indian population. Irrespective of the type of surgery the relapses were predominantly systemic in our study and very rarely were systemic recurrences preceded by a local relapse. It is well-known that in hormone receptor positive breast cancers, there is a definite increase in the incidence of lymph node positivity with increasing size of the tumor. This has been aptly highlighted in the study by Dent et al.[4] where they have shown that in TNBCs even small tumors have a high chance of lymph node positivity. Our study also found a lack of correlation between tumor size and lymph node positivity, with 41% and 31% node positivity for T2 and T3 size tumors. The T1 size tumors had 17% incidence of lymph node positivity.

TNBCs are known to be highly chemosensitive with higher pCR rates than HR positive tumors. In our study, the pCR rates after NACT of 25% were similar to the results found by Liedtke et al.[10] where they reported 22% CR rates for TNBC. Thirty four out of 153 patients (22%) who underwent surgery (upfront/after NACT) and adjuvant therapy relapsed. Six were local relapses and the rest systemic with only 3 patients with bone only disease and 25 with visceral metastases. Very few local recurrences (16%) preceded a distant recurrence. Most of the recurrences occurred within 2-3 years (84%). The high predilection for visceral metastasis was evident in our study and it was similar to the data from western studies.[4]

CONCLUSIONS

Triple negative cancers are highly aggressive tumors that have distinct epidemiological, pathological and outcome characteristics.[4,6,7] This was evident in our study where we found higher grade tumors with a significant number of early relapses despite the short median follow-up. About 12.5% of breast cancers at this institute were TNBCs, and they affected younger females with no significant risk factors or family history, with no correlation between lymph node positivity and tumor size, had most of the recurrences distally in visceral organs within a period of 3 years. They responded well to NACT and the complete responders were relapse free at 3 years of follow-up. These data are still early findings and further follow-up for more mature data is on.

The main limitation of our study was the lack of testing for basal cytokeratins. Further, large scale prospective trials incorporating basal cytokeratin markers and gene expression profiling are required for complete characterization of these tumors and to identify a positive marker that can facilitate targeted therapy.

Footnotes