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Belizario et al. Cancer Drug Resist 2019;2:527-38 I http://dx.doi.org/10.20517/cdr.2018.009 Page 535
[67]
to have an anti-inflammatory and anti-tumoral roles in a variety of tumors . A comprehensive analysis of
microbiota of 668 breast tumors indicated that H. influenza and Listeria spp inhabiting the stromal breast
cancer tissue significantly influence the expression of genes in the proliferative pathways: G2M checkpoint,
[68]
E2F TFs, and mitotic spindle assembly . Additionally, one study identified that Lactobacillus fleischmannii
[69]
was associated with epithelial mesenchymal transition . Oral supplementation with A. muciniphila
probiotic restore the efficacy of PD-1 blockade against epithelial tumors by increasing the recruitment of
[69]
CCR9+CXCR3+CD4+ T lymphocytes in an interleukin-12-dependent manner . With the approval of the
first chemo- immunotherapy combination for metastatic TNBC , we expect that future studies correlating
[70]
traditionally clinicopathological parameters with additive predictive valor of commensal bacteria will find
best cancer response signatures to combination chemotherapy and immunotherapy.

Breast cancer canonical risk factors include age at diagnosis, age at menarche, nulliparity, age at first birth,
number of children, months of breastfeeding, race, body mass index, menopausal status, absorption,
combined oral contraceptives, age at menopause, prior benign breast disease, and family history (BRCA 1
[71]
and 2 and PTEN mutations) of breast cancer . The hypothesis that estrogens and estrogen metabolites are
implicated in female breast cancer etiology and progression has been confirmed for luminal A and luminal
[71]
B breast cancer subtypes . Environmental factors such as endocrine disruptors compounds (xenobiotics,
pesticides and pollutants) may influence mammary and gut microbiota [72,73] . However, there is no data to
support that a putative disease-causing microorganism or if altered microbial pattern of women could have
a role in the development and progression of the breast cancer disease [72,73] . The molecular pathological
epidemiology (MPE) is a new discipline for investigating specific risk estimative for endogenous and
exogenous factors controlling the etiologic heterogeneity of carcinogenic process, as well as environmental
and inherited factors leading to failures to pharmaceutical treatment or prevention [74,75] . MPE incorporates
large multi-omic and epigenomic datasets to estimate the impact of genome-wide association studies
on disease entity in population-based cohorts [74,75] . MPE methodologies can provide novel insights into
mechanistic pathways of common diseases and contribution of medications (pharmaco-MPE), immune
[75]
mediators, and microorganism (microbial-MPE) on their risk expectative . In this way, standardized
pathological methods for breast cancer molecular subtyping (whole-tissue specimens or TMA), antibodies
for immunohistochemistry, and imaging digital analytical repertories will have great value to establish the
multidisciplinary framework for MPE investigations on definitive biomarkers to subtype breast cancers
and genotype-phenotype relationships.

CONCLUSION
Breast cancer is a highly heterogeneous disease with differences in histopathological and biological
characteristics, variable prognoses, and response to therapy. All breast tumor subtypes display different
types of clonal subpopulations and this intratumoural and metastatic heterogeneity contribute to different
drug sensitivities and resistance characteristics. Since the first study by Sorlie and colleagues in 2003,
knowledge about genetic, epigenetic and endogenous and exogenous factors associated with the five
subtypes of breast cancers (Luminal A, Luminal B, HER2-enriched, Basal-like and Claudin-low) and their
associated aberrant signaling pathways extensively increased and become extremely complex. The multi-
omics and MPE methods for large comprehensive molecular cataloguing of cancer patient cohorts will
help to establish and predictive biomarkers essential for new therapeutic agents and patients’ responses. A
systematic stratification of tumors based on therapeutically actionable mutated gene, TME immune cell
profile, mammary microbial profile and epigenetic functional signatures may better predict those patients
that will benefit from (neo) adjvuvant multi-agent chemotherapy, targeted and combination therapies,
including immunotherapies.