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Background Current clinical criteria do not discriminate well between women who will or those who will not develop ipsilateral invasive breast cancer (IBC), or a DCIS recurrence after a ductal carcinoma in situ (DCIS) diagnosis. The 12-gene Oncotype DX® DCIS assay (RT qPCR gene-based scoring system) was established and shown to predict the risk of subsequent ipsilateral IBC or DCIS recurrence. Recent studies have shown that microRNA (miRNA) expression deregulation can contribute to the development of IBC, but very few have evaluated miRNA deregulation in DCIS lesions. In this study, we sought to determine whether specific miRNA expression changes may correlate with Oncotype DX® DCIS scores. Methods For this study, we used archived formalin-fixed, paraffin-embedded (FFPE) specimens from 41 women diagnosed with DCIS between 2012 and 2018. The DCIS lesions were stratified into low (n = 26), intermediate (n = 10), and high (n = 5) risk score groups using the Oncotype DX® DCIS assay. Total RNA was extracted from DCIS lesions by macro-dissection of unstained FFPE sections, and next-generation small-RNA sequencing was performed. We evaluated the correlation between miRNA expression data and Oncotype score, as well as patient age. RT-qPCR validations were performed to validate the topmost differentially expressed miRNAs identified between the different risk score groups. Results MiRNA sequencing of 32 FFPE DCIS specimens from the three different risk group scores identified a correlation between expression deregulation of 17 miRNAs and Oncotype scores. Our analyses also revealed a correlation between the expression deregulation of 9 miRNAs and the patient’s age. Based on these results, a total of 15 miRNAs were selected for RT-qPCR validation. Of these, miR-190b (p = 0.043), miR-135a (p = 0.05), miR-205 (p = 0.00056), miR-30c (p = 0.011), and miR-744 (p = 0.038) showed a decreased expression in the intermediate/high Oncotype group when compared to the low-risk score group. A composite risk score was established using these 5 miRNAs and indicated a significant association between miRNA expression deregulation and the Oncotype DX® DCIS Score (p Conclusions Our analyses identified a subset of 5 miRNAs able to discriminate between Oncotype DX® DCIS score subgroups. Together, our data suggest that miRNA expression analysis may add value to the predictive and prognostic evaluation of DCIS lesions.

Background A ductal carcinoma in situ (DCIS) Nomogram integrating 10 clinicopathologic/treatment factors and a Refined DCIS Score (RDS) that incorporates a genomic assay and three clinicopathologic factors (Oncotype DX DCIS Score) are available to estimate DCIS 10-year local recurrence risk (LRR). This study compared these estimates. Methods Patients 50 years of age or older with DCIS size 2.5 cm or smaller and a genomic assay available were identified. An RDS within 1-2% of the range of Nomogram LRR estimates obtained by assuming use and non-use of endocrine therapy (Nomogram ± ET) was defined as concordant. Assuming a 10-year risk threshold of 10% for recommending radiation, Nomogram ± ET and RDS estimates were compared, and threshold concordance was determined. Results For 54 (92%) of 59 patients, the RDS and Nomogram ± ET LRR estimates were concordant. For the remaining 5 (8%) of the 59 patients, the RDS LRR estimates were lower than the Nomogram + ET estimates, with an absolute difference of 3-8%, and thus were discordant. For these five patients, the RDS estimates of 10-year LRR were lower than 10% (range 5-8%) and the Nomogram + ET estimates were 10% or higher (range 11-14%). These five patients with both discordant and threshold-discordant estimates all had close margins (≤ 2 mm). Conclusions Among 92% of women 50 years of age or older with DCIS size 2.5 cm or smaller, free-of-charge online Nomogram 10-year LRR estimates were concordant with those obtained using the commercially available RDS (> $4600). Among the 8% with discordant risk estimates, the RDS appeared to underestimate the LRR and may lead to inappropriate omission of radiotherapy. Unless other data show a clinically significant advantage of the RDS (Oncotype DX DCIS Score), the study data suggest that for women 50 years of age or older with DCIS size 2.5 cm or smaller, its use is not warranted.

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m(2) every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo.

Tipifarnib (T) is a farnesyl transferase inhibitor (FTI) that enhances the antineoplastic effects of cytotoxic therapy in vitro, has activity in metastatic breast cancer, and enhances the pathologic complete response (pCR) rate to neoadjuvant doxorubicin-cyclophosphamide (AC) chemotherapy. We, therefore, performed a phase I-II trial of T plus neoadjuvant sequential weekly paclitaxel and 2-week AC chemotherapy in locally advanced breast cancer. Eligible patients with HER2-negative clinical stage IIB-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) followed by AC (60/600 mg/m(2) every 2 weeks and filgrastim), plus T (100 or 200 mg PO on days 1-3 of each P dose, and 200 mg PO on days 2-7 of each AC cycle). The trial was powered to detect an improvement in breast pCR rate from 15 to 35 % (α = 0.10, β = 0.10) in two strata, including ER and/or PR-positive, non-inflammatory (stratum A) and inflammatory carcinoma (stratum B). Of the 60 patients accrued, there were no dose-limiting toxicities among the first six patients treated at the first T dose level (100 mg BID; N = 3) or second T dose level (200 mg BID; N = 3) plus paclitaxel. Breast pCR occurred in 6/33 patients (18 %, 95 % confidence intervals (CI) 7-36 %) and 1/22 patients (4 %, 95 % CI 0-8 %) in stratum B. Combination of the FTI T with weekly paclitaxel-AC is unlikely to be associated with a breast pCR rate of 35 % or higher in patients with locally advanced HER2/neu-negative inflammatory or non-inflammatory ER- and/or PR-positive breast carcinoma.

The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.