HER2 testing in metastatic gastric or gastroesophageal junction cancer (mGC/mGEJC) is standard practice. Variations in HER2-positivity rates suggest factors affecting test quality; however, the ...influence of patient-, tumor-, and laboratory-related factors on HER2-positivity rates remains unknown. This observational, prospective study collected routine HER2 testing data from 50 pathology centers in Germany (January 2013–December 2015). For each sample, HER2 status, primary tumor location, method of sample retrieval, and other patient- and tumor-related parameters were recorded. A model for predicting the probability of HER2-positivity was developed using stepwise multiple logistic regression to identify influencing factors. Documented positivity rates and corresponding predicted HER2-positivity probabilities were compared to identify institutes with deviations in HER2-positivity. Data from 2761 mGC/mGEJC routine diagnostic specimens included 2033 with HER2 test results (1554 mGC, 479 mGEJC); overall HER2-positivity rates across centers were 19.8% and 30.5%, respectively. HER2-positivity correlated most with Lauren classification, then HER2 testing rate, primary tumor location, sample type, and testing method (all
p
< 0.05). Three institutes had model-predicted HER2-positivity rates outside the 95% confidence interval of their documented rate, which could not be explained by sample and center characteristics. Results demonstrated the high quality of routine HER2 testing in the mGC/mGEJC cohort analyzed. This is the first study investigating parameters impacting on HER2-positivity rates in mGC/mGEJC in routine practice and suggests that assessment of HER2 testing quality should consider primary tumor location, testing method and rate, and tumor characteristics. Accurate identification of patients with HER2-positive mGC/mGEJC is essential for appropriate use of HER2-targeted therapies.
Aberrant promoter methylation is a fundamental mechanism of inactivation of tumor suppressor genes in cancer. The Ras association domain family 1A gene (RASSF1A) is frequently epigenetically silenced ...in several types of human solid tumors. In this study, we have investigated the expression and methylation status of the RASSF1A gene in hepatocellular carcinoma (HCC). In two HCC cell lines (HepG2 and Hep3B) RASSF1A was inactivated and treatment of these cell lines with a DNA methylation inhibitor reactivated the transcription of RASSF1A. The methylation status of the RASSF1A promoter region was analysed in 26 primary liver tissues including HCC, hepatocellular adenoma (HCA), liver fibrosis, hepatocirrhosis. Out of 15, 14 (93%) HCC were methylated at the RASSF1A CpG island and hypermethylation was independent of hepatitis virus infection. RASSF1A was also methylated in two out of two fibrosis and in three (75%) out of four cirrhosis; the latter carries an increased risk of developing HCC. Additionally, we analysed the methylation status of p16(INK4a) and other cancer-related genes in the same liver tumors. Aberrant methylation in the HCC samples was detected in 71% of samples for p16, 25% for TIMP3, 17% for PTEN, 13% for CDH1, and 7% for RARbeta2. In conclusion, our results demonstrate that RASSF1A and p16(INK4a) inactivation by methylation are frequent events in hepatocellular carcinoma, but not in HCA, which is in contrast to HCC without cirrhosis, viral hepatitis, storage diseases, or genetic background. Therefore, this study gives additional evidence against a progression of adenoma to carcinoma in the liver. Thus, RASSF1A hypermethylation could be useful as a marker of malignancy and to distinguish between the distinct forms of highly differentiated liver neoplasm.
Although breast cancer is the second most common cause of central nervous system (CNS) metastases with a notable increase of incidence, only few studies on brain-metastasizing breast cancer are ...available. In this immunohistochemical and fluorescence in situ hybridization (FISH) study, metastases to the CNS (n=85) and primary breast cancers, with known involvement of the CNS (n=44) including paired primary and metastasized tumours (n=23), were investigated retrospectively for the expression of oestrogen- (ER) and progesterone- (PR) hormone receptors, Her-2/neu, epidermal growth factor receptor (EGFR), Ki-67, and cytokeratins (CKs) 5/14. The majority of brain metastases were steroid hormone receptor negative (ER 66%, PR 82%) corresponding to the findings in primary tumours with known involvement of the CNS (68% ER-negative, 75% PR-negative). The frequency of HER-2/neu-overexpressing or -amplified cancers was increased in both groups (34 and 32%, respectively). EGFR expression was more frequent in metastases (41%) than in primary tumours (16%). The proportions of cases with a basal phenotype were 26 and 30%, respectively. In paired primary tumours and metastases to the CNS, constancy of Her-2/neu status was observed in 87% of cases with only one sample turning Her-2/neu-negative and two samples acquiring overexpression/amplification in brain metastases. In contrast, steroid hormone receptors exhibited more frequently a loss of expression (17%) than a gain (9%) with 74% revealing a constant phenotype. We conclude that brain-metastasizing breast cancer belongs predominantly to the basal type or Her-2/neu type. Primary and metastatic tumours differ from each other only in a minority of cases, leading rather to a loss of steroid hormone receptors and to a gain of EGFR and Her-2/neu.
Introduction: The AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, German Gynecological Oncology Group) Task Force on Diagnosis and Treatment of Breast Cancer as an interdisciplinary team consists ...of specialists from gynecological oncology, pathology, diagnostic radiology, medical oncology, and radiation oncology with a special focus on breast cancer. Methods: The updated evidence-based treatment recommendation 2022 for early breast cancer (EBC) and metastatic breast cancer of the AGO Task Force has been released. Results and Conclusion: This paper captures the update of EBC.
Valid HER2 testing is essential for optimal therapy of patients with HER2-positive gastric cancer and the correct use of first-line chemotherapy. While testing for HER2 status in breast cancer is ...routinely performed, this is not the case for HER2 testing in gastric cancer and it is usually only performed on clinician request. An interdisciplinary German expert group (pathologists and clinicians) took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication. The recommendations made in this manuscript reflect the consensus of all participants and reflect their opinions and long-term experience in this field.
Transcription factor AP-2β (TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated ...AP-2β in breast cancer (BC). This study characterizes AP-2β expression in the mammary gland and in BC. AP-2β protein expression was assessed in the normal mammary gland epithelium, in various reactive, metaplastic and pre-invasive neoplastic lesions and in two clinical BC cohorts comprising >2000 patients. BCs from various genetically engineered mouse (GEM) models were also evaluated. Human BC cell lines served as functional models to study siRNA-mediated inhibition of AP-2β. The normal mammary gland epithelium showed scattered AP-2β-positive cells in the luminal cell layer. Various reactive and pre-invasive neoplastic lesions, including apocrine metaplasia, usual ductal hyperplasia and lobular carcinoma in situ (LCIS) showed enhanced AP-2β expression. Cases of ductal carcinoma in situ (DCIS) were more often AP-2β-negative (P<0.001). In invasive BC cohorts, AP-2β-positivity was associated with the lobular BC subtype (P<0.001), loss of E-cadherin (P<0.001), a positive estrogen receptor (ER) status (P<0.001), low Ki67 (P<0.001), low/intermediate Oncotype DX recurrence scores (P<0.001), and prolonged event-free survival (P=0.003). BCs from GEM models were all AP-2β-negative. In human BC cell lines, AP-2β expression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2β diminished proliferation of lobular BC cell lines in vitro. In summary, AP-2β is a new mammary epithelial differentiation marker. Its expression is preferentially retained and enhanced in LCIS and invasive lobular BC and has prognostic implications. Our findings indicate that AP-2β controls tumor cell proliferation in this slow-growing BC subtype.
Background. Human T-cell lymphotropic virus type 1 (HTLV-1) screening of blood and organ donors is not mandatory in Germany because of its low prevalence (about 7/100 000). An HTLV-1 transmission ...event caused by a multiple organ donor was investigated. Validity of diagnostic procedures and HTLV-1 disease association in immunosuppressed organ recipients were analyzed. Methods. Two screening immunoassays and an immunoblot (confirmatory assay) were used for detection of HLTV-1/2 antibodies. Proviral DNA was quantified in blood and biopsies of organ recipients by HTLV-1 real-time polymerase chain reaction (PCR). Results. Proviral HTLV-1-DNA was detected in all blood samples of 3 organ recipients (1–100 copies/10 2 cells), but seroconversion was delayed for up to 2 years in screening assays and >6 years in the confirmatory assay. In 2 of 3 organ recipients, a cutaneous T-cell lymphoma was diagnosed 2 and 3 years after infection, respectively. Proviral HTLV-1 DNA concentration was almost 100 copies/10 2 cells in cutaneous lymphoma biopsies whereas in biopsies of other tissues ≤3.0 copies/102 cells were found. The third organ recipient did not suffer from lymphoma, but detailed clinical data on this patient were not available to us. Conclusions. Biopsy results support an etiological role for HTLV-1 in these cases of primary cutaneous T-cell lymphoma after solid organ transplant. HTLV-1–associated lymphoma can arise quickly in immunocompromised transplant recipients. The diagnosis of potentially HTLV-1–associated disease in organ recipients may require PCR because of delayed seroconversion.
Biallelic mutations of mismatch repair genes cause constitutional mismatch repair deficiency associated with an increased risk for childhood leukemia/lymphoma. We report on a case with constitutional ...mismatch repair deficiency caused by a novel MSH6 mutation leading to a T-cell lymphoma and colonic adenocarcinoma at six and 13 years of age, respectively. A review of the literature on hematologic malignancies in constitutional mismatch repair deficiency showed that in almost half of the 47 known constitutional mismatch repair deficiency families, at least one individual is affected by a hematologic malignancy, predominantly T-cell lymphomas. However, diagnosing constitutional mismatch repair deficiency may be difficult when the first child is affected by leukemia/lymphoma, but identification of the causative germline mutation is of vital importance: (i) to identify relatives at risk and exclude an increased risk in non-mutation carriers; (ii) to prevent hematopoietic stem cell transplantation from sibling donors also carrying a biallelic germline mutation; and (iii) to implement effective surveillance programs for mutation carriers, that may reduce constitutional mismatch repair deficiency-associated mortality.
Background:
Endocrine sensitivity, as determined by response of the proliferation marker Ki-67 to short-term preoperative endocrine therapy (ET), is currently not included in adjuvant treatment ...decisions in hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)− breast cancer (BC).
Methods:
The prospective WSG-ADAPT HR+/HER2− trial included patients with N0/N1 early BC who were candidates for adjuvant chemotherapy based on clinical–pathological criteria alone. The trial utilized a genomic assessment the Recurrence Score (RS) plus endocrine sensitivity testing to guide treatment. All patients received 3 (±1) weeks of preoperative induction ET. According to protocol, patients with RS 0–11 or RS 12–25 plus endocrine proliferation response (EPR, post-induction Ki-67 ⩽ 10%) were to be spared adjuvant chemotherapy.
Results:
The ADAPT HR+/HER2− trial run-in phase included 407 patients with baseline RS, of whom 386 (median age: 54 years) had complete data for Ki-67 at both baseline and post-induction. RS distribution: 23.1% RS 0–11, 58.3% RS 12–25, and 18.7% RS 26–100. EPR occurred in 84.3%, 76.0%, and 36.1% of these RS groups, respectively. Differences in EPR proportions (RS 26–100 versus others, RS 0–11 versus others) were significant (both p < 0.001); Ki-67 quotients were higher for RS 26–100 (p = 0.02, Mann–Whitney). In premenopausal women (n = 146, mostly tamoxifen-treated), median quotient of Ki-67 level (post/pre) was significantly higher than in postmenopausal women (n = 222, mostly aromatase-inhibitor treated; 0.67 versus 0.25, p < 0.001). EPR was significantly associated with baseline estrogen-receptor status as determined by immunohistochemistry (p = 0.002) or real-time polymerase chain reaction (p < 0.001). Also, a strong correlation was observed between RS measured pre- and post-ET (RS = 0.7, n = 181).
Conclusions:
This phase of the WSG-ADAPT HR+/HER2− trial confirms trial design estimates of RS and EPR. It indicates that the ADAPT concept of combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible using the EPR criterion post-induction Ki-67 ⩽ 10%.
Clinicaltrials.gov identifier:
NCT01779206.
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