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Shrivastava, Sachan, Sachan, and Mandloi: Survival analysis of triple negative breast cancer patients treated with Anthracycline based chemotherapy: A Retrospective Study from Central part of India


Introduction

Breast cancer is a heterogeneous disease with different characteristics such as age, tumor stage, lymph node involvement and pathologic grade which are associated with disease prognosis.3, 2, 1 With rising incidence and awareness, breast cancer has become the commonest cancer in urban Indian females and the second commonest in the rural Indian women.4 Over 100,000 new breast cancer patients are estimated to be diagnosed annually in India.5 With a rising trend in incidence reported from various registries of National Cancer Registry Program, presently India has become the country with the largest estimated number of breast cancer deaths worldwide.6

Triple negative breast cancers (TNBCs) are defined as the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2).7 These cancers occur in approximately 10% to 25% of all patients with breast cancer with significant heterogeneity existing within the group of patients diagnosed with TNBC. The primary goal of this study was to assess the response of anthracyclines based adjuvant chemotherapy in triple negative breast cancer.

Materials and Methods

The retrospective study was done on 100 post-operative patients, who were proven ductal carcinoma on histopathology. Patient identifier data were anonymized to preserve patient confidentiality. The study period of the study was from January 2016 to March 2017. All 100 patients were triple negative as assessed by immunohistochemistry and fluorescence in situ hybridization technique.

ER and PR positive were defined as positive immunohistochemical staining in more than 10% of tumor cells. HER-2 status was determined according to the guideline recommended by College of American Pathologists.8 Immunohistochemistry assay with anti-HER2 antibodies was used to identify HER negative (0 and 1+) or positive (2+ and 3+). HER2 gene amplification was determined by fluorescent in situ hybridization (FISH). Tumors with a positive FISH result were considered as HER2 positive. Parameters assessed included age at the time of diagnosis, tumor histology, nuclear grade, lymphovascular invasion, perineural invasion, tumor size, pathologic tumor (T) and nodal (N) score, OS and type of surgery.The immunostaining procedures were performed using formalin-fixed, paraffin-embedded tissue sections. The sections were immunohistochemically stained for ER, PR, HER2, HMWCKs, c-Kit and EGFR according to the protocols. Tumors negative for ER, PR and HER2 were considered as triple-negative.

Patients were planned for six cycles of Anthracycline based combination adjuvant chemotherapy. Data was analyzed using SPSS v 20. Disease free survival and overall survival durations were analyzed with the Kaplan-Meier method. Comparisons among clinical variables were performed with Person Chi-square test. All tests were 2-tailed and the statistical significance was set as P<0.05.

Results

A total of 100 patients were included in this study. Demographic profile of the study subjects are shown in Table 1. Most of the women belongs to rural area (53%). As far as age group is concerned, majority i.e. 48% are in age group of 40-50 years followed by 30-40 years age group.

Out of these, 18 patients (18%) were defaulted after chemotherapy, 29 patients (29%) were lost during subsequent follow ups. 49 patients (49%) had disease free survival (DFS)and 4patients (4%) survive with bone metastasis. The median survival was 18 months, disease free survival was 7.8 months and 3 year overall survival (OS) was 18.6 months.

Table 1
Profile
Rural 53
Urban 47
Age group
20-30 years 6
30-40 years 38
40-50 years 48
>50 years 8

Demographic characteristics of patients.

Table 2
Characteristics
Age (mean) 44.6 years
Menstrual history Pre menopausal 48
Peri menopausal 38
Post menopausal 14
Laterality Right 32
Left 65
Bilateral 3
Tumour size <2cm 1
2-5cm 6
>5cm 93
LN Status Negative 1
Positive 99
Stage I 1
II 1
III 94
IV 4
Surgery MRM 98
BCS 2
Axilla clearance Yes 5
NA 95
Histological grade I 13
II 23
III 64
LN status Positive 98
Negative 2
Extracapsular extension Present 56
Negative 33
NA 11
Lymph-vascular invasion Present 76
Absent 24

Clinicopathological Features of Triple-negative Breast Cancer.

Table 3
Event No.of Patients
Defaulted after chemotherapy 18
Lost during subsequent follow ups 29
Disease free survival 49
Bone metastasis 4

Showing the end result of events in survival analysis.

Discussion

Breast cancer is a heterogeneous disease comprising of distinct biological subtypes with diverse natural history, presenting with varied spectrum of clinical, pathological and molecular features with different prognostic and therapeutic implications. Increasing burden of breast cancer has led to enormous change in the treatment strategies due to discovery of specific prognostic and predictive biomarkers that enable the application of more individualized targeted therapies following hormone receptor testing.10, 9

Basal like cancer accounts for 15% of all breast carcinoma, 75% being triple negative. Studies have shown that this phenotype is more common in young African women facing worse prognosis compared to other ethnic group as observed by other researchers.12, 11 In 2009, a case control study showed 2.5 fold increased risk for Oral Contraceptive Pill (OCP) users using for more than one year than women using for less than a year or never.13 Other associations with the triple negative subtype include higher parity and lack of or shorter duration of breast feeding.14 As per the results of some studies, association of obesity is consistent with TNBC.[15-20]20, 19, 18, 17, 16, 15 Patients with triple negative breast cancers tend to present at younger age and with more advanced cancer.23, 22, 21

Earlier studies had reported that TNBC phenotype show significantly higher FDG uptake compared to ER, PR positive and HER2/NEU negative, probable explanation may be related to aggressive biology of the tumor.24 At the current time, TNBC lack any specific targeted therapy. Combined chemotherapy is the standard treatment like anthracycline, taxanes, ixabepitine and platinum agents. BRCA1 related TNBC appears to be particularly susceptible to chemotherapy involving Platinum based agents and Taxanes.26, 25

In the present study, TNBC is common in younger groups. This observation was concordant with many other studies conducted by many other people in the previous decade.30, 29, 28, 27 However few studies have shown higher incidence of TNBC in postmenopausal women32, 31, 29 In one published study in Turkey, no significant difference in age was found in both two groups.33

According to the literature, patients with TNBC present with relatively larger size compared to non TNBC group which is consistent with our results.34, 31, 30 Aggressive tumour biology and rapid growth and proliferation are possible explanations for these findings.

In our study a high rate of node positivity was found in TNBC. Comparing the histological subtypes, IDC NOS comprised maximum number of cases. Similar results were observed in other studies conducted over the other countries.38, 37, 36, 35, 34 The patients in our study were mostly diagnosed with grade III tumor, which is similar to the findings of other studies.36, 34, 31, 30 This finding is consistent with the explanation of aggressive tumour biology and high potential for visceral and bone metastasis.

Results from our study showed that 4% of the cases presented with bone metastasis during follow up. Approximately half of the cases had a disease free survival(DFS) of 7.8 months which is similar to the results obtained from other studies.34, 31

Some patients (29%) were lost during subsequent follow ups and 18% had defaulted after chemotherapy. This along with less number of cases in the study population are the main limitation of our study. Also, we did not directly assess tumors for molecular subtype. We did not have information on percent staining of ER or PR by IHC, nor did we have information on cytokeratin or epidermal growth factor receptor staining; these variables may influence the proportion of patients with true basal subtype, and separate triple-negative tumors into different prognostic groups. Another drawback is the short duration of follow-up as the longer follow-up may make clearer differences in OS and DFS between two subgroups.

Conclusion

The disease stage at presentation is an important prognostic factor influencing the treatment failure and survival among TNBC. The increasing tumor size is related to lymph node positivity. The adjuvant Anthracycline-based combination chemotherapy predict improved long term outcomes for TNBC. Future analyses will be needed on the prognostic significance of tumor size and nodal status in the triple-negative subset, and on variations in patterns of care.

Source of funding

None.

Conflict of Interest

None.

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