Spatial expression of claudin 18.2 in matched primaries and metastases of tubo-ovarian carcinoma of all subtypes.

Physiologically, claudin 18 splice variant 2 (CLDN18.2) expression is restricted to the gastric epithelium, but its expression has been detected in solid cancers. Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further. To date, little is known about CLDN18.2 expression in other histological subtypes of tubo-ovarian carcinoma (TOC) and their matching metastases.Using a cohort of all histological TOC subtypes, we investigated the immunohistochemical (IHC) CLDN18.2 expression in both TOCs (n = 536), their matching metastatic tissue (n = 385) and in 93 metastases without primary. Tissue microarrays comprised both the tumor center and periphery. IHC positivity was defined as biomarker expression of ≥ 75% in tumor cells with moderate-to-strong membranous staining.Overall CLDN18.2 positivity was 4.1% (21/515) in the TOC centers and 3.6% (18/498) in their peripheries. In primaries of mucinous tubo-ovarian carcinoma (MTOC), CLDN18.2 positivity rates were 45% (18/40) and 36.6% (15/41), respectively. Positivity rates for the corresponding metastases were 33% (4/12, center) and 27% (3/11, periphery). The expression was relatively homogenous throughout all tumor sites. With no expression in 99.5% of nonmucinous tumors, CLDN18.2 positivity was almost exclusively seen in the mucinous subtype.In tubo-ovarian carcinoma, CLDN18.2 expression was, with rare exceptions, restricted to the mucinous subtype. Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.

Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer-A Europe-Wide External Quality Assessment.

Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could offer a reliable alternative. In this first Europe-wide external quality assessment (EQA) study, we investigated performance of mRNA-based Xpert® Breast Cancer STRAT4 (CE-IVD) in five European laboratories. The cohort comprised ten pre-therapy IBC core biopsies diagnosed in the coordinating center (CC). STRAT4 binary (positive or negative) mRNA results of each marker (ESR1, PGR, ERBB2, MKI67) were compared with the gold standard IHC/ISH performed by the CC. Sensitivity, specificity, and accuracy of ESR1 and ERBB2 mRNA were 100% for all samples. In contrast, PGR expression was falsely negative for one case by two sites and MKI67 falsely negative for two cases (respectively by four and one sites). These cases had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. Our EQA shows that STRAT4 mRNA assay may be a reproducible method to evaluate ER, PgR, HER2, and Ki-67 status. However, cases with expression values close to assay cut-offs should be carefully reviewed.

Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): A randomised phase III trial.

BACKGROUND: GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC). PATIENTS AND METHODS: Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w for 3 cycles or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344. RESULTS: 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77-1.28, P = 0.979) with no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P < 0.001), mainly due to adverse events; two patients on PM(Cb) died. CONCLUSIONS: In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice.

Clinical Relevance of Serum HER2 and Circulating Tumor Cell Detection in Metastatic Breast Cancer Patients.

BACKGROUND/AIM: Presence of circulating tumor cells (CTCs) is associated with impaired survival in metastatic breast cancer (MBC). This study was designed to evaluate whether assessment of serum HER2 (sHER2) levels provide additional prognostic information in MBC. MATERIALS AND METHODS: Two hundred and fifty-three MBC patients were enrolled in this multicentre trial. CTCs were detected before the start of first- or later-line treatment using the CellSearch system. sHER2 was determined using ELISA. RESULTS: ≥5 CTCs were detected in 122 of 245 evaluable patients (49.8%). One hundred and nineteen of 251 patients (47%) had sHER2 levels above 15 ng/ml. Median overall survival (OS) was 16.3 months in patients with elevated sHER2; median OS in patients with non-elevated sHER2 has not been reached (p=0.001). Patients with ≥5 CTCs were more likely to present with elevated sHER2 (61% vs. 33% in those with <5 CTC; p<0.001). In patients with HER2-negative tumors, elevated sHER2 was associated with shorter OS and PFS; in HER2-positive patients with OS only. Including sHER2, CTC status and established prognostic factors into a multivariate analysis, only the presence of CTCs and higher-line of therapy remained independent predictors of OS. CONCLUSION: Elevated levels of sHER2 are associated with worse survival, irrespective of the HER2 status of the tumor. However, sHER2 does not provide additional prognostic information in patients with known CTC status.

Preoperative pain and recurrence risk in patients with peritoneal endometriosis.

OBJECTIVE: Pain symptoms in endometriosis patients do not necessarily correlate with the extent of the disease, and there is little evidence regarding the recurrence risk. Aim of this study was to assess the risk factors for the recurrence of endometriosis, with regard to preoperative and postoperative pain. DESIGN: Retrospective observational study. SETTING: Single institution study. POPULATION: A total of 150 patients were followed up for recurrence after surgical treatment for endometriosis. METHODS: The patients were interviewed retrospectively to obtain information about pain levels during the course of the disease. MAIN OUTCOME MEASURES: Disease free survival. RESULTS: High preoperative pain levels were associated with a higher risk of recurrence after 4 years of follow-up. The hazards ratio was 2.30 (95% CI, 1.22-4.31; p = 0.009). None of the other parameters assessed for medical history, reproductive history, or lifestyle was associated with the recurrence risk. CONCLUSIONS: The risk for recurrence after surgery for endometriosis may be substantially influenced by the patients' perception of pain. Risk classifications for the recurrence risk in endometriosis are nonexistent. Developing these is imperatively needed soon to improve further treatment and/or prophylaxis for patients after surgery. A classification might be improved by adding sensory testing before surgery.

Single nucleotide polymorphisms of the aromatase gene (CYP19A1), HER2/neu status, and prognosis in breast cancer patients.

PURPOSE: Estrogen exposure is involved in both breast cancer susceptibility and the prognosis in patients with breast cancer. Aromatase is involved in the production of estrogens, and altered expression of it might be associated with the prognosis. The aim of this study was to examine the effect of single nucleotide polymorphisms (SNPs) in the aromatase gene, CYP19A1, on the prognosis, and in relation to tumor and patient characteristics in a cohort of breast cancer patients. PATIENTS AND METHODS: The cohort analyzed in this study consisted of 1,257 patients with invasive primary breast cancer. Polymorphisms rs10046, rs4646 and rs700519 were genotyped within this group. RESULTS: The variant genotypes of rs10046 and rs4646 were associated with a lower percentage of HER2-positive tumors. There was no association of rs700519 and rs4646 with disease-free survival (DFS) or overall survival (OS). The variant genotype of rs10046 was significantly associated with a better 5-year DFS (hazards ratio 0.51; 95% CI, 0.32 to 0.81; P=0.004) adjusted for age, nodal status, tumor size grading, and hormone receptor status. This effect appeared to be determined in the subgroup of premenopausal patients. CONCLUSION: SNPs rs10046 and rs4646 may influence the HER2 status of breast cancer tumors, and rs10046 genotypes are associated with an altered DFS. Genotypes of aromatase polymorphisms may influence the prognosis for breast cancer patients not only by affecting the extent of estrogen exposure but also through an alteration in tumor characteristics.

Acceptance for preventive genetic testing and prophylactic surgery in women with a family history of breast and gynaecological cancers.

The fear of family members of patients with breast or gynaecologic cancer of developing a similar disease is often high. We investigated the acceptance for genetic testing of untested women with a positive family history and their attitude for prophylactic surgery. A total of 659 women with a familial history of breast or gynaecologic cancer were asked to answer a questionnaire regarding their interest in genetic testing for breast cancer as well as for gynaecologic carcinoma and their interest in prophylactic surgery. Genetic testing is seen to be accepted by the majority of participants: 85.0 and 77.8% chose a genetic test for breast and gynaecologic cancer, respectively. Prophylactic surgery was much less chosen; prophylactic mastectomy as well as prophylactic hysterectomy or bilateral prophylactic oophorectomy was an option only for a minority of women. Genetic testing for risk assessment of healthy women with a positive family history was observed to be accepted by a majority of participants. Prophylactic surgery was an option only for a minority and was not acceptable for most of the women.

Age of uptake of early cancer detection facilities by low-risk and high-risk patients with familial breast and ovarian cancer.

INTRODUCTION: Some 5-10% of all cases of breast cancer and ovarian cancer have a hereditary genesis. In the setting of an interdisciplinary cancer genetics clinic, a study of the age at which patients first take advantage of early cancer detection (ECD) facilities was conducted in order to assess the influence of familial risk on health issues. METHODS: The study included 556 women who fulfilled the inclusion criteria (IC) for genetic analysis of the BRCA1 and BRCA2 genes, as well as 205 who did not meet these criteria but attended the primary consultation. RESULTS: Consulters who met the inclusion criteria took advantage of nearly all methods of ECD at an earlier time than women who did not. A comparison of consulters with or without breast cancer showed that those without breast cancer participated in all methods of ECD at an earlier time. CONCLUSION: Methods of improving and increasing participation in ECD facilities, and of encouraging women who are at risk to start on such programs at a younger age, need to be discussed. In this study, familial risk already resulted in a younger age of uptake of ECD facilities.