Premenopausal women with breast cancer in the early post-partum period show molecular profiles of invasion and are associated with poor prognosis.

PURPOSE: Young premenopausal women develop breast cancer (BC) within 5-10 years of the last childbirth, known as post-partum breast cancers (PPBC), often present with aggressive disease. The exact mechanisms that lead to poor prognosis in these patients are largely unknown. METHODS: We have evaluated the association of clinical and reproductive factors with BC in a cohort of women ≤ 45 years (N = 155) with long-term follow-up. Based on duration since last childbirth (LCB), grouped patients into PPBC1 (LCB ≤ 5 years), PPBC2 (LCB between 6 and 10 years), PPBC3 (LCB > 10 years), and NPBC (age-matched nulliparous BC patients). We compared disease-free survival and hazard associated with recurrence/metastasis between the groups. RNA sequencing of tumor samples was performed from three parous groups (n = 10), and transcriptomic data were analyzed for differentially expressed genes and altered pathways. RESULTS: Women in the PPBC1 group had an early menarche and late age at first and last childbirth compared to other groups. Survival analysis within lymph node-positive tumors showed that PPBC1 tumors had a worse prognosis than PPBC2 and NPBC tumors (p = 0.015 and p = 0.026, respectively). Clustering of the differentially expressed genes between the groups showed distinct expression in early PPBC (E-PPBC) tumors. Pathway analysis revealed upregulation of invasive-related pathways along with T cell exhaustion, extracellular matrix remodeling, angiogenesis, and epithelial-to-mesenchymal transition in E-PPBC tumors. CONCLUSION: Early PPBC is a unique subtype with aggressive clinical features and distinct biology. Further research is needed to accurately project the risk of recurrence and optimal treatment strategies in these young patients.

A comparative analysis of clinicopathological features and survival between pre and postmenopausal breast cancer from an Indian cohort.

Breast cancer (BC) among premenopausal women is an aggressive disease associated with poor outcome despite intensive treatment. Higher burden is observed in southeast Asian countries attributed to younger population structure. We compared the reproductive and clinicopathological characteristics, distribution of subtypes and survival between pre and postmenopausal women from a retrospective cohort of BC patients with median follow up over 6 years to examine the differences. In our cohort of 446 BC patients, 162/446 (36.3%) were premenopausal. Parity and age at last childbirth were significantly different between pre and postmenopausal women. Premenopausal BC had a higher proportion of HER2 amplified and triple negative breast cancer (TNBC) tumors (p = 0.012). Stratified analysis by molecular subtypes showed TNBC had significantly better disease free (DFS) and overall survival (OS) among premenopausal group (mean survival, pre vs. post, DFS = 79.2 vs. 54.0 months, OS = 72.5 vs. 49.5 months, p = 0.002 for both). Analysis on external datasets (SCAN-B, METABRIC) confirmed this finding for overall survival. Our data confirmed the previously observed association of clinical and pathological features between pre and postmenopausal BC. Exploration of better survival among premenopausal TNBC tumors is warranted in larger cohorts with long term follow up.

The Impact of Breast Cancer on the Patient and the Family in Indian Perspective.

PURPOSE: To understand the role played by the immediate family in treatment decision and support in patients diagnosed with breast cancer, the influence of demographic factors on psychosocial roles of women within the family. METHODS: A mixed method design used for data collection on family support, financial arrangement and psychosocial impact of cancer from 378 women with breast cancer recruited at first diagnosis between 2008 and 2012, during multiple counseling sessions. The median follow-up is 7 years with only 2% lost to follow-up. RESULTS: Most patients (99%) had support from family members. 57% of patients met the costs of treatment through personal savings and health insurance. The rest (43%) had difficulty and had to resort to desperate measures such as selling their property or taking on high-interest personal loans. Patients with higher education and urban settings had better financial management. A male member of the family (husband or son) was the main decision maker in half of the cases. Concerns over women's responsibilities within the family varied by the age of the patient. The vast majority of women (90%) experienced social embarrassment in dealing with the disease and its aftermath. CONCLUSION: In India, it is the family that provides crucial support to a woman with breast cancer during her ordeal with the disease and its treatment. This study has implications on the psychosocial support beyond the cancer patients alone, to include the immediate family and consider aspects of finance and social adjustments as critical in addition to the routine medical aspects of the disease.

HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells.

Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor-stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF-7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin ß6) versus those with low levels. Within the epithelial-to-mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin ß6 and growth factor receptors-human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan-Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin ß6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin αvß6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin ß6 could mediate epithelial-to-mesenchymal transition and migration in a subset of luminal breast cancers and lapatinib might be effective in disrupting this interaction.

High expression of integrin ß6 in association with the Rho-Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers.

Integrin αvß6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin ß6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvß6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens (N = 460) for the expression of integrin ß6 (ITGB6) mRNA by qPCR. In addition, we have examined a subset (N = 147) for the expression of αvß6 integrin by immunohistochemistry (IHC). The expression levels of members of Rho-Rac pathway including downstream genes (ACTR2, ACTR3) and effector proteinases (MMP9, MMP15) were estimated by qPCR in the HER2+ subset (N = 59). There is a significant increase in the mean expression of ITGB6 in HER2+ tumors compared to HR+HER2- and triple negative (TNBC) subtypes (P = 0.00). HER2+ tumors with the highest levels (top quartile) of ITGB6 have significantly elevated levels of all the genes of the Rho-Rac pathway (P-values from 0.01 to 0.0001). Patients in this group have a significantly shorter disease-free survival compared to the group with lower ITGB6 levels (HR = 2.9 (0.9-8.9), P = 0.05). The mean level of ITGB6 expression is increased further in lymph node-positive tumors. The increased regional and distant metastasis observed in HER2+ tumors with high levels of ITGB6 might be mediated by the canonical Rho-Rac pathway through increased expression of MMP9 and MMP15.

Estrogen Receptor Negative Breast Cancer in India: Do We Really Have Higher Burden of this Subtype?

ER negative and Triple negative breast cancers carry a poorer prognosis and are not amenable to hormone therapy. It has been previously observed that Indian patients with breast cancer have a higher tendency to have these tumours. Whether this is due to inherent biological differences in the tumours of our patients is a matter of much debate. We have analysed 250 patients of breast cancer for hormone receptor status, compared them with western series, and attempted to support the hypothesis that the higher ER negativity and triple negativity is indeed due to different tumour biology.