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Background: Prediction of response and toxicity of chemotherapy can help personalize the treatment and choose effective yet non-toxic treatment regimen for a breast cancer patient. Interplay of variations in various drug-metabolizing enzyme (DME)-encoding genes results in variable response and toxicity of chemotherapeutic drugs. Generalized multi-analytical (GMDR) approach was used to determine the influence of the combination of variants of genes encoding phase 0 ( SLC22A16); phase I ( CYP450, NQO1); phase II ( GSTs, MTHFR, UGT2B15); and phase III ( ABCB1) DMEs along with confounding factors on the response and toxicity of chemotherapeutic drugs in breast cancer patients. Methods: In an Indian breast cancer patient cohort ( n = 234), response to neo-adjuvant chemotherapy ( n = 111) and grade 2-4 toxicity to chemotherapy were recorded. Patients were genotyped for 19 polymorphisms selected in four phases of DMEs by PCR or PCR-RFLP or Taqman allelic discrimination assay. Binary logistic regression and GMDR analysis was performed. Bonferroni test for multiple comparisons was applied, and p value was considered to be significant at <0.025. Results: For ABCB1 1236C>T polymorphism, CT genotype was found to be significantly associated with response to NACT in uni-variate and multi-variate analysis ( p = 0.018; p = 0.013). The TT genotype of NQO1 609C>T had a significant association with (absence of) grade 2-4 toxicity in uni-variate analysis ( p = 0.021), but a non-significant correlation in multi-variate analysis. In GMDR analysis, interaction of CYP3A5*3, NQO1 609C>T, and ABCB1 1236C>T polymorphisms yielded the highest testing accuracy for response to NACT (CVT = 0.62). However, for grade 2-4 toxicity, CYP2C19*2 and ABCB1 3435C>T polymorphisms yielded the best interaction model (CVT = 0.57). Conclusion: This pharmacogenetic study suggests a role of higher order gene-gene interaction of DME-encoding genes, along with confounding factors, in determination of treatment outcomes and toxicity in breast cancer patients. This can be used as a potential objective tool for individualizing breast cancer chemotherapy with high efficacy and low toxicity. [ABSTRACT FROM AUTHOR]

Introduction: Sentinel lymph node biopsy (SLNB) is the standard of care for staging N0 primary early breast cancers (EBC). Patients in developing countries mostly present with large (LOBC) or locally advanced cancers (LABC) and are treated with neo-adjuvant chemotherapy (NACT). Accuracy of SLNB in staging stage III N0 and post-NACT N0 patients is uncertain. This prospective validation study on LOBC/LABC patients compared the accuracy of SLNB between primary versus post-NACT surgery. Materials and methods: Fifty T3/T4, N0 patients undergoing primary surgery (Group I) and 70 LOBC/LABC (index stage) treated with NACT and N0 at the time of surgery (Group II) were inducted. Validation SLNB was performed using low-cost methylene-blue and Tc-Antimony colloid. SLN identification (IR) and false-negative (FNR) rates were compared between the groups. Sub-group analysis was done in Group II per index tumor and nodal stage to identify factors predicting SLN IR and FNR in post-NACT patients. SLN IR and FNR in both groups were compared with those in previously published SLN validation study and meta-analysis in EBC. Results: Using combination of blue-dye and radio-colloid, post-NACT SLN IR and FNR (82.9, 13.5 %) were far inferior to T3/T4 primary surgery group (94, 7.7 %; p values 0.034, 0.041) and in EBC. SLN IR using blue-dye alone was dismally low in post-NACT LABCs. Factors predicting unidentified post-NACT SLN and false-negative SLNB included young age, LVI, skin infiltration, extra-nodal spread or N2a stage, and UOQ tumors. Conclusions: Accuracy of SLNB in T3, N0 tumors undergoing primary surgery is comparable to that of SLNB for N0 EBC. In post-NACT patients, SLNB IR are lower and FNR are higher. Factors predictive of non-identification and false-negative SLNB include pre-NACT skin involvement (T4b), N2a stage or extra-nodal invasion and LVI, and to a lesser extent, young age and UOQ location of the tumor. [ABSTRACT FROM AUTHOR]

The lack of objective documentation of pre-neoadjuvant chemotherapy (NACT) margins after chemotherapy is a major constraint in performing safe breast-conserving surgery (BCS) in patients with locally advanced breast cancer (LABC). Using a novel method of marking pre-NACT tumor margins with indigenous silver wire markers, this prospective pilot study attempted to assess the feasibility of safe BCS in LABC patients by performing excision wide of the marked pre-NACT margins. LABC patients had sterile silver wire markers placed at all tumor margins percutaneously. Patients were then treated with NACT followed by wide local excision (WLE) incorporating pre-NACT margins (ex vivo on mastectomy specimen or in vivo in patients opting for BCS). The histology of the margins wide of the post-WLE cavity (pre-NACT) and post-NACT tumor was used to assess adequate disease clearance and safety of BCS. Altogether, 40 stage III breast cancer patients (mean tumor size 7.9 cm) were studied; none had marker-related complications. Following NACT, the tumor size assessed by markers showed average regression by 1.5 cm. The pre-NACT margins were histologically negative in 95% of the surgical specimens. In 2 (5%) patients both pre-NACT and post-NACT margins were positive; post-NACT margins were infiltrated in 14 (35%). The post-NACT WLE that is wide of the marked pre-NACT margins can achieve uninfiltrated margins in 95% of cases. If post-NACT margins are used to guide the WLE, 35% patients would have infiltrated margins, some of which would remain undetected, putting patients at high risk of local recurrence. This novel indigenous method of identifying tumor margins with sterile silver wire markers is safe, inexpensive, practical, and effective; and it may help perform safe BCS in a large proportion of LABC patients. [ABSTRACT FROM AUTHOR]