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Simple Summary: In breast cancer patients in whom tumor cells overexpress the protein human epidermal growth factor receptor 2 (HER2), HER2-targeted therapy is the mainstay of neoadjuvant therapy (NAT). Two thirds of these patients respond so well to HER2-targeted therapy that during microscopic analysis of the surgically resected tissue, it becomes apparent there are no vital tumor cells left, classified as complete responders. These patients might not have needed surgery. However, with current imaging techniques such as MRI, it remains difficult to preoperatively assess whether there is residual tumor after NAT or not, so all patients still undergo surgery. This study investigated if a HER2-targeted PET/CT scan can reliably assess the response to NAT. In six patients, a HER2-targeted PET/CT scan was acquired before and after NAT. Two out of six patients had residual tumor at microscopic analysis. Visual assessment of the PET/CT scans correctly predicted the response in 66.7% of cases. When the PET/CT signal in both the scan before and after NAT was quantified and (percentual) changes were calculated, there was a difference in the change of signal between patients with and without residual tumor. This difference, although not statistically significant due to the limited patient number in this study, suggests that quantitative assessment of HER2-targeted PET/CT can be used for accurate response evaluation after NAT. Background: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. Methods: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. Results: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of −48% and −90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was −79% and −94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. Conclusions: NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy is a common and potentially debilitating side-effect of microtubule-stabilizing agents like docetaxel and is characterized by sensory symptoms like numbness, tingling and burning pain. Docetaxel induced neuropathy may occur in up to 37% of patients and can be dose limiting, thus potentially reducing its chemotherapeutic efficacy. Doxorubicine has occasionally been described to be associated with neuropathy. With this background we investigated the role of various single nucleotide polymorphisms (SNPs) to predict chemotherapy-induced neuropathy. The exploration of SNPs and an association with incidence or severity of neuropathy is important, because it can result in identifying individuals being at higher risk of neurotoxicity. Methods: The MATADOR study is a prospective, non-blinded randomized phase II/III trial for patients with invasive breast cancer, comparing TAC (docetaxel 75 mg/m² as 1 hour i.v. infusion q 3 weeks, in combination with doxorubicin and cyclophosphamide for 6 cycles) with AC dose dense (doxorubicin and cyclophosphamide q 2 weeks)(ISRCTN61893718 ). In total 180 interesting SNPs were selected that are involved in metabolism, distribution and excretion of drugs and tested on DNA that was isolated from tumor or from tumor surrounding tissue. We selected 20 SNPs for further analyses because of reported associations with chemotherapy-induced neuropathy (see table). In the first analysis DNA of 45 patients was analyzed as a pilot, comparing DNA of 23 neuropathy patients with that of 22 controls. The primary hypothesis was to identify SNPs associated with NCI-CTC grade ≥ 2 neuropathy. Results: Interim toxicity data from the MATADOR study demonstrated that 30 of 580 patients had grade ≥ 2 neuropathy. GSTP1 114Ala/114Val genotype was associated with grade ≥ 2 neuropathy. Twelve out of 14 (86%) patients with this genotype had chemotherapy-induced neuropathy compared to 11 out of 31 (35%) without this genotype (chi-square test p = 0.002). Conclusion: We found a correlation between GSTP1 114Ala/114Val genotype, involved in detoxification, and development of grade ≥ 2 neuropathy during treatment with chemotherapy. Updated results will be presented at the meeting. [ABSTRACT FROM AUTHOR]

Background: Dose-dense administration of chemotherapy and the addition of taxanes to anthracycline-based adjuvant chemotherapy have improved breast cancer survival substantially. However, clinical trials directly comparing the additive value of taxanes with dose-dense anthracycline-based chemotherapy are lacking., Patients and Methods: In the multicentre, randomised, biomarker discovery Microarray Analysis in breast cancer to Tailor Adjuvant Drugs Or Regimens (MATADOR) trial, patients with pT1-3, pN0-3 breast cancer were randomised (1:1) between six adjuvant cycles of doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 every 2 weeks (ddAC) and six cycles of docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks (TAC). The primary objective was to discover a predictive gene expression profile for ddAC and TAC benefit. Here we report the preplanned secondary end-point recurrence-free survival (RFS) and overall survival (OS)., Results: Between 2004 and 2012, 664 patients were randomised. At 5 years, RFS was 87% (95% confidence interval [CI] 83%-91%) in the ddAC-treated patients and 88% (84-92%) in the TAC-treated subgroup (hazard ratio [HR] 0.89, 95% CI 0.62-1.28, P = 0.53). OS at 5 years was 93% (90%-96%) in the ddAC-treated and 94% (91%-97%) in the TAC-treated patients (HR 0.89, 95% CI 0.57-1.39, P = 0.61). Anaemia was more frequent in ddAC-treated patients (62/327 patients [18.9%] versus 15/319 patients [4.7%], P < 0.001) and diarrhoea (21 [6.4%] versus 53 [16.6%], P<0.001) and peripheral neuropathy (15 [4.6%] versus 46 [14.4%], P < 0.001) were observed more often in TAC-treated patients., Conclusions: With a median follow-up of 7 years, no significant differences in RFS and OS were observed between six adjuvant cycles of ddAC and TAC in high-risk breast cancer patients., Trial Registration Numbers: ISRCTN61893718 and BOOG 2004-04., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A 68-year-old woman had had a TNM stage-III rectal carcinoma at the age of 54 for which she had undergone a low anterior resection followed by postoperative radiotherapy and adjuvant chemotherapy with fluorouracil and levamisol. More than 10 years later she presented with a swelling in the right groin, which turned out to be a metastasis; this was a poorly differentiated carcinoma with some of the characteristics of a transitional epithelial carcinoma, for which no primary tumour was found. The lymph node was excised. One year later, a swelling was detected on the labium majus, caused by a poorly differentiated transitional epithelial carcinoma of the glandula vestibularis major (Bartholin's gland). The patient was treated by means ofhemivulvectomy and postoperative radiotherapy.

Mucins, including MUC-1, are generally considered to be products of epithelial tissues and of their tumors. To examine the possible expression of MUC-1 in other cell types, a panel of human epithelial and non-epithelial tumor cell lines was studied by reverse transcriptase polymerase chain reaction (RT-PCR), Northern blot analysis, immunocytology and radioimmunoprecipitation. Using the highly sensitive RT-PCR method, products corresponding to the non-repetitive 5' and 3' MUC-1 sequences were detected in all the cell lines examined. Amplified products lacking the tandem repeat region of MUC-1, including a new short form (designated MUC-1/Z) different from the previously reported MUC-1/Y protein, were also detected in most cell lines tested. Northern blot analysis, using a probe to the variable number tandem repeat (VNTR) region, confirmed the presence of MUC-1 mRNA in the astrocytoma, melanoma and neuroblastoma cell lines studied. MUC-1 protein was detected by immunocytology in these cell lines using monoclonal antibody (MAb) 139H2. Immunoprecipitation analysis with [3H]-glucosamine-labeled cell lysates and MAb 139H2 or an antibody to the cytoplasmic domain, CT-1, detected MUC-1 protein in 2 epithelial cell lines, an astrocytoma cell line (SK-MG-4) but not in the melanoma and neuroblastoma cell lines studied. Northern blot analysis using a probe to the 3' end of MUC-1 mRNA, confirmed the presence of MUC-1 mucin and also identified short products corresponding to the size of the short variant forms. Protein products corresponding to the MUC-1/Y and MUC-1/Z variant forms were not observed using either [3H]-glucosamine-labeled OVCAR-3 cells or [3H]-amino acid-labeled MCF-7 cells and either CT-1 antibody or MAb 232A1, detecting an epitope to the C-terminal region. Thus, depending on the sensitivity of the assay used, varying amounts of MUC-1 mRNA and protein could be detected in non-epithelial tumor cell lines. Although the amounts of MUC-1 in these cell lines are much lower than in carcinomas, it is possible that MUC-1 mucin serves a similar function in non-epithelial as in epithelial cells. The possible role of MUC-1/Y and MUC-1/Z variant forms in these cell lines is not understood.

Vintriptol, a tryptophan ester of vinblastine, is a new vinca alkaloid derivative. Preclinical studies have demonstrated its antitumour activity in a large variety of animal models. In this phase I study, 47 patients with advanced cancer were exposed to escalating doses of vintriptol, starting at 6 mg/m2 and following a modified Fibonacci schedule. The drug was administered as an intravenous push on a weekly schedule. Myelosuppression was the dose-limiting toxicity and the maximum tolerated dose was 45 mg/m2. Other toxicities consisted of mild nausea and vomiting and the occurrence of fever and dryness of the mouth immediately after drug administration. Neurotoxicity, a major side-effect of other vinca alkaloids, was insignificant. 1 partial remission in a patient suffering from colorectal cancer and 1 minor response in a patient with a metastatic tumour of the cutaneous appendagous glands were documented. Pharmacokinetics of vintriptol were evaluated at the highest dose levels. A dose schedule of 40 mg/m2 vintriptol per week is recommended for phase II studies.