In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical).

Women with triple-negative breast cancer (TNBC) do not benefit from endocrine therapy or trastuzumab. Chemotherapy is the only systemic therapy currently available. To reduce the elevated risk of disease progression in these patients, better treatment options are needed, which are less toxic and more targeted to this patient population. We performed a comprehensive analysis of potential targetable genetic aberrations affecting the receptor tyrosine kinase/RAS/MAPK pathway, which are observed at higher frequencies in adenocarcinomas of other organs. Sixty-five individual TNBCs were studied by sequence analysis for HER2 (exon 18-23), EGFR (exon 18-21), KRAS (exon 2), and BRAF (exon 15) mutations. In addition, a tissue microarray was constructed to screen for EGFR gene copy gain and EML4-ALK fusion by FISH. Triple-negative status was confirmed by immunohistochemistry and FISH on tissue microarray sections. EGFR and CK5/6 immunohistochemical analyses were performed for identification of the basal-like phenotype. In addition, mutation analysis of TP53 (exon 5-8) was included. Sequence analysis revealed HER2 gene mutation in only one patient (heterozygous missense mutation in exon 19: p.L755S). No mutations were found in EGFR, KRAS, and BRAF. High polysomy of EGFR was detected in 5 of the 62 informative cases by FISH. True EGFR gene amplification accompanied by strong membranous EGFR protein expression was observed in only one case. No rearrangement of the ALK gene was detected. Basal-like phenotype was identified in 38 of the 65 TNBCs (58.5 %). TP53 gene mutation was found in 36/63 (57.1 %) tumors. We conclude that targetable genetic aberrations in the receptor tyrosine kinase/RAS/MAPK pathway occur rarely in TNBC.

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Overexpression of class III β-tubulin (TUBB3), a factor that confers dynamic properties to microtubules, is a candidate biomarker for resistance to microtubule-targeting chemotherapeutics in breast and other types of solid cancer. Discrepant results from previous studies, with respect to the association of TUBB3 expression levels with breast cancer phenotype and patient prognosis, prompted the present study to investigate TUBB3 expression in a large cohort of breast cancer cases, with available clinical follow-up data. A preexisting breast cancer prognosis tissue microarray, containing a single 0.6 mm tissue core from each of 2,197 individual patients with breast cancer, was analyzed for TUBB3 expression by immunohistochemistry. The results of the present study revealed that TUBB3 expression was less frequent in lobular breast cancer cases (34%), compared with that of cancer cases of alternative histologies, including breast cancer of no special type (60%; P<0.0001). High TUBB3 positivity was associated with high tumor grade (P<0.0001), negativity for estrogen (P<0.0001) and progesterone receptors (P<0.004), as well as the presence of human epidermal growth factor 2 amplification (P<0.0001) and a triple-negative phenotype (P<0.0001). TUBB3 overexpression was additionally associated with reduced patient survival if all breast cancer cases of any histology were jointly analyzed (P=0.0088); however this link was not evident in the subset of breast cancer cases of no special type, or in a multivariate analysis including the established prognostic factors of tumor stage, grade and nodal stage. In conclusion, the present study demonstrated that TUBB3 overexpression was associated with adverse features of breast cancer, and that TUBB3 may possess a distinct role in lobular breast cancer cases, compared with alternative histological subtypes. The results of the present study do not support a clinically relevant role for TUBB3 as a prognostic marker in breast cancer.

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