Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials.

BACKGROUND: The development of anti-HER2 antibody-drug conjugates opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. To characterise this new breast cancer subtype, we have compared the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer, including response to neoadjuvant chemotherapy and prognosis. METHODS: In this pooled analysis of individual patient data, we evaluated a cohort of 2310 patients with HER2-non-amplified primary breast cancer that were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, NCT01583426; GeparOcto, NCT02125344; GeparX, NCT02682693; Gain-2 neoadjuvant, NCT01690702) between July 30, 2012, and March 20, 2019. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Disease-free survival and overall survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46·6 months (IQR 35·0-52·3). Bivariable and multivariable logistic regression models and Cox-proportional hazards models were performed based on a predefined statistical analysis plan for analysis of the endpoints pathological complete response, disease-free survival, and overall survival. FINDINGS: A total of 1098 (47·5%) of 2310 tumours were HER2-low-positive and 1212 (52·5%) were HER2-zero. 703 (64·0%) of 1098 patients with HER2-low-positive tumours were hormone receptor positive, compared with 445 (36·7%) of 1212 patients with HER2-zero tumours (p<0.0001). HER2-low-positive tumours had a significantly lower pathological complete response rate than HER2-zero tumours (321 [29·2%] of 1098 vs 473 [39·0%] of 1212, p=0·0002). Pathological complete response was also significantly lower in HER2-low-positive tumours versus HER2-zero tumours in the hormone receptor-positive subgroup (123 [17·5%] of 703 vs 105 [23·6%] of 445, p=0·024), but not in the hormone receptor-negative subgroup (198 [50·1%] of 395 vs 368 [48·0%] of 767, p=0·21). Patients with HER2-low-positive tumours had significantly longer survival than did patients with HER2-zero tumours (3-year disease-free survival: 83·4% [95% CI 80·5-85·9] vs 76·1% [72·9-79·0]; stratified log-rank test p=0·0084; 3-year overall survival: 91·6% [84·9-93·4] vs 85·8% [83·0-88·1]; stratified log-rank test p=0·0016). Survival differences were also seen in patients with hormone receptor-negative tumours (3-year disease-free survival: 84·5% [95% CI 79·5-88·3] vs 74·4% [70·2-78.0]; stratified log-rank test p=0·0076; 3-year overall survival: 90·2% [86·0-93·2] vs 84·3% [80·7-87·3], stratified log-rank test p=0·016), but not in patients with hormone receptor-positive tumours (3-year disease-free survival 82·8% [79·1-85·9] vs 79·3% [73·9-83·7]; stratified log-rank test p=0·39; 3-year overall survival 92·3% [89·6-94·4] vs 88·4% [83·8-91·8]; stratified log-rank test p=0·13). INTERPRETATION: Our results show that HER2-low-positive tumours can be identified as new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours. HER2-low-positive tumours have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumours. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Treatment algorithm for women with endometriosis in a certified Endometriosis Unit.

INTRODUCTION: Endometriosis is a chronic hormone-dependent disease affecting approximately 25-30% of women in the third and fourth decade. Despite its frequency, it is often detected late. The aim of this overview article was to present a standardized treatment algorithm for an interdisciplinary endometriosis consultation considering conservative and surgical approaches. EVIDENCE ACQUISITION: Despite the frequency of endometriosis and a high number of publications dealing with the disease there is a lack of evidence in literature for standardized treatment algorithms allowing a rational diagnostic and therapeutic approach. In May 2019 we did a literature search in Medline. While finding 26702 publications under the term "endometriosis" there was only one publication for the search term "endometriosis consultation treatment algorithm." After screening the abstracts 144 publications in English, French or German language had been assessed as relevant for the diagnosis and therapy of endometriosis (143 overview articles and one guideline). EVIDENCE SYNTHESIS: Based on clinical evidence, we have developed a treatment algorithm for women with suspected endometriosis. The diagnosis includes a structured medical history with the identification of endometriosis-typical symptoms and a gynecological examination, if necessary additional examinations. The treatment algorithm is essentially divided into the phase of diagnosis and the phase of therapy as well as the prevention of recurrence or long-term treatment. A multi-professional team of visceral surgery, urology, nutritional medicine, physiotherapy and psychology can be consulted for support. CONCLUSIONS: The treatment of endometriosis should be multiprofessional, standardized and reproducible during specialized consultations at certified centers. So far, there are few publications on a standardized and clinically proven treatment algorithm for women with suspected endometriosis. The presented treatment algorithm could be helpful in the diagnosis and treatment of endometriosis patients, even at other centers.

Cytomegalovirus-specific T cells are detectable in early childhood and allow assignment of the infection status in children with passive maternal antibodies.

Serological identification of the cytomegalovirus (CMV) status in children less than 18 months of age is complicated by the variable persistence of maternal antibodies. As T cells are not passively transferred, we attempted to assess whether CMV-specific cellular immunity may be superior to determine the actual CMV status; we also performed a functional characterization of T-cell immunity in childhood. Antibodies from 59 mothers and 168 children were determined, and specific CD4(+) T cells were identified by induction of IFN-γ, IL-2, TNF-α, IL-4, and IL-17 after CMV-specific and polyclonal stimulation. Agreement between both tests was perfect for mothers and children more than 18 months. Among infants less than 18 months, 17/30 were concordantly negative. Interestingly, 8/13 seropositive children had detectable CMV-specific T cells, whereas only 5/13 were T-cell negative, indicating passive immunity. CMV-specific T cells from young infants differed in cytokine profiles from that of older age groups, and polyclonal effector T-cell frequencies were higher in young infants with detectable CMV-specific T cells compared with those without. In conclusion, the majority of young infants with CMV-specific antibodies show evidence of true infection, which indicates that passive immunity is overestimated. Our data may have important implications for improved risk stratification and CMV management in infants in the setting of transplantation.

Metastatic breast carcinoma mimicking a sebaceous gland neoplasm: a case report.

INTRODUCTION: Breast cancer is common in women and its metastases involve the skin in approximately one quarter of patients. Accordingly, metastatic breast cancer shown to be cutaneous through histology must be distinguished from a wide variety of other neoplasms as well as the diverse morphologic variants of breast cancer itself. CASE PRESENTATION: We report the case of a 61-year-old Caucasian woman with cutaneous metastases of a bilateral ductal breast carcinoma that in histopathological examination mimicked an adnexal neoplasm with sebaceous differentiation. CONCLUSION: Against the background of metastatic breast carcinoma, dermatopathological considerations of sebaceous differentiation of skin lesions are presented and discussed focusing on the rare differential diagnosis of sebaceous carcinoma of the breast.

Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells.

INTRODUCTION: The role of circulating tumor cells (CTCs) in blood of primary breast cancer patients is still under investigation. We evaluated the incidence of CTCs in blood, we evaluated the correlation between CTCs and disseminated tumor cells (DTCs) in the bone marrow (BM), and we characterized CTCs for the expression of HER2, the estrogen receptor (ER) and the progesterone receptor (PR). METHODS: Blood of 431 patients with primary breast cancer were analyzed for EpCAM, MUC1 and HER2 transcripts with the AdnaTest BreastCancer (AdnaGen AG, Germany). Expression of the ER and PR was assessed in an additional RT-PCR. BM aspirates from 414 patients were analyzed for DTCs by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. RESULTS: DTCs were found in 107/414 patients (24%), CTCs were detected in 58/431 (13%) patients. DTCs were associated with PR status of the primary tumor (P = 0.04) and CTCs significantly correlated with nodal status (P = 0.04), ER (P = 0.05), and PR (P = 0.01). DTCs in the BM weakly correlated with CTCs (P = 0.05) in blood. Interestingly, the spread of CTCs was mostly found in triple-negative tumors (P = 0.01) and CTCs in general were mostly found to be triple-negative regardless of the ER, PR and HER2 status of the primary tumor. CONCLUSIONS: (1) Due to the weak concordance between CTCs and DTCs the clinical relevance may be different. (2) The biology of the primary tumor seems to direct the spread of CTCs. (3) Since the expression profile between CTCs and the primary tumor differs, the consequence for the selection of adjuvant treatment has to be evaluated.

Reduced incidence of distant metastases and lower mortality in 1072 patients with breast cancer with a history of hormone replacement therapy.

OBJECTIVE: Substitution of estrogens (hormone replacement therapy [HRT]) is the most common therapy and prophylaxis of postmenopausal complaints. However, in most studies, long-term HRT has been associated with an increased risk for breast cancer, but the influence on a prognosis of breast cancer has been examined rarely. STUDY DESIGN: For further investigation, we analyzed 1072 patients aged 45-70 years at the time of first diagnosis of breast cancer with and without preoperative HRT with regard to the incidence of distant metastases and overall survival. Of these, 279 women were premenopausal (mean, 47.8 +/- 3.2 years); 793 women were postmenopausal (mean, 54.5 +/- 3.5 years); 320 women had received HRT over a minimum of 1 year (mean, 5.5 +/- 4.0 years; group HRT+); and 473 women had not received HRT (group HRT-). The median follow-up time was 73.2 months. RESULTS: Although body mass index, tumor size, and grading of group HRT- were significantly higher than in group HRT+, nodal status, S-phase fraction, hormone-receptor status, and local recurrence showed no significant differences. In regard to the incidence of distant metastases, women without HRT have significantly (P < .001) more metastases to bone (68 vs 20 women), lung (47:13 women), and liver (47:13 women). Overall survival was significantly lower in the HRT- group. CONCLUSION: We were able to show that the use of HRT before the diagnosis of breast cancer results in more favorable primary tumors, with a lower incidence of recurrences and a better overall survival rate. This might be due to normalized bone metabolism by the use of HRT, which may lower the conditions of tumor cell seeding.

Comparison of HER2 status between primary tumor and disseminated tumor cells in primary breast cancer patients.

BACKGROUND: The persistence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with poor prognosis. Preliminary studies indicated that these patients might benefit from secondary adjuvant targeted therapy. HER2 protein is suggested as one of the most promising targets. The aims of this study were (1) to determine the HER2 status of DTC in BM of breast cancer patients and (2) to compare the HER2 status of DTC and corresponding primary tumors. METHODS: BM aspirates from 137 primary breast cancer patients were included into the study. A double staining procedure was used for the identification of cytokeratin-positive (CK)/HER2 positive cells. HER2 status of the primary tumor was immunohistochemically assessed by the HERCEP-test. RESULTS: In 46 of 137 (34%) breast cancer patients CK-positive cells were detectable in BM. DTC with HER2 positivity were found in 20 (43%) of these patients. The HER2 expression on DTC was heterogeneous in 7 of 17 (41%) patients. Concordance rate of HER2 status between primary tumor and DTC was 62%. In 12 of 20 patients with HER2 negative tumors HER2 positive DTC were detected. CONCLUSIONS: HER2 positive DTC can be detected in patients with HER2 negative primary tumors. Therefore, the antigenic profile of DTC may be considered for treatment decision since these patients might actually benefit from trastuzumab. However, the HER2 overexpression on DTC is heterogeneous in individual patients which may reduce the efficacy of an immunotherapy based strategy directed against HER2-antigen only.