The risk of endocrine interventions in carriers of a genetic predisposition for breast and gynecologic cancers: recommendations of the German Consortium for Hereditary Breast and Ovarian Cancer.

PURPOSE: To support doctors in counselling women with genetic predisposition for breast or gynecologic cancers on endocrine interventions. METHODS: Evidence on the safety of endocrine interventions for fertility treatment, contraception, hormone replacement therapy after risk-reducing salpingo-oophorectomy (RRSO) or treatment of symptoms during peri- and postmenopause was analysed for carriers of probably pathogenic and pathogenic variants in BRCA1 or BRCA2 (BRCA1/2-pV), in other breast and ovarian cancer genes and the Lynch Syndrome. Cancer risks were compared with data on risks for the general population. RESULTS: Data on risk modulation of endocrine interventions in women with genetic predisposition is limited. Ovarian hyperstimulation for fertility treatment may be performed. Oral contraceptives should not be used to reduce ovarian cancer risk in BRCA1/2-pV carriers. Premenopausal BRCA1/2-pV carriers and carriers of pV in Lynch Syndrome genes should be offered hormone replacement therapy (HRT) after RRSO, to prevent diseases caused by estrogen deficiency. CONCLUSION: Effect direction and strength of risk modulation by endocrine interventions is similar to the general population. Participation of individuals at risk in prospective registries is recommended.

Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: analysis of individual data from 94,638 patients treated in 55 breast cancer centers.

Neoadjuvant chemotherapy (NACT) is frequently used in patients with early breast cancer. Randomized controlled trials have demonstrated similar survival after NACT or adjuvant chemotherapy (ACT). However, certain subtypes may benefit more when NACT contains regimes leading to high rates of pathologic complete response (pCR) rates. In this study we analyzed data using the OncoBox research from 94,638 patients treated in 55 breast cancer centers to describe the current clinical practice of and outcomes after NACT under routine conditions. These data were compared to patients treated with ACT. 40% of all patients received chemotherapy. The use of NACT increased over time from 5% in 2007 up to 17.3% in 2016. The proportion of patients receiving NACT varied by subtype. It was low in patients with HR-positive/HER2-negative breast cancer (5.8%). However, 31.8% of patients with triple-negative, 31.9% with HR-negative/HER2-positive, and 26.5% with HR-positive/HER2-positive breast cancer received NACT. The rates of pCR were higher in patients with HR-positive/HER2-positive, HR-negative/HER2-positive and triple-negative tumors (36, 53 and 38%) compared to HR-positive/HER2-negative tumors (12%). PCR was achieved more often in HER2-positive and triple-negative tumors over time.This is the largest study on use and effects of NACT in German breast cancer centers. It demonstrates the increased use of NACT based on recommendations in current clinical guidelines. An improvement of pCR was shown in particular in HER2-positive and triple-negative breast cancer, which is consistent with data from randomized controlled trails.

Does cavity margin shaving reduce residual tumor and re-excision rates? A systematic review.

PURPOSE: Cavity shaving (CS) is a surgical technique used in the treatment of breast cancer (BC). It may reduce margin positivity in histologic assessment and consequently reduces re- excision rates in breast conserving surgery (BCS). The evidence for this assumption is described in the present review. METHODS: A systematic review of relevant literature in English from January 1999 to April 2019 was conducted. The analysis included studies on CS and its effects on re-excision rates and margin positivity. We searched PubMed databases for relevant publications. In total, 22 studies were included in the present review. RESULTS: The benefit from CS on re-excision rates and histologic margin positivity was variable. Out of 22 studies, 17 reported a reduction in both re-excision rates and histologic margin positivity in margin shaved patients. Four studies could not find a significant reduction of second surgeries and residual tumor rates. One study suggested that CS after BCS was superior to single BCS only in subgroup analysis in IDC tumors. CONCLUSION: CS is a surgical technique that was shown to reduce re-excision and margin positivity rates in most of the studies. Furthermore, it can be a useful tool to assess specimen margins and detect multifocality.

Hormone replacement therapy in BRCA mutation carriers and risk of ovarian, endometrial, and breast cancer: a systematic review.

PURPOSE: BRCA mutation carriers have an increased risk of developing breast or ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is associated with a decrease in risk for tubal and ovarian cancer. Hormone replacement therapy (HRT) may increase breast, ovarian, and endometrial cancer risk in the general population. This review analyses the published data on HRT and risk of cancer in BRCA mutation carriers with and without RRBSO. METHODS: We included all relevant articles published in English from 1995 to October 2020. Sources were identified through a search on PubMed and Cochrane Library. RESULTS: We included one case-control and one retrospective cohort study on ovarian and one case-control study on endometrial cancer risk and HRT in BRCA mutation carriers. Regarding breast cancer risk, one case-control study on BRCA mutation carriers with and without RRBSO and one case-control study, one Markov chain decision model, two prospective cohort studies, and one metaanalysis on carriers after RRBSO were included. For ovarian cancer, results were ambiguous. For breast cancer, most studies did not find an adverse effect associated with HRT. However, some of the studies found a risk modification associated with different formulations and duration of use. CONCLUSION: Although data are limited, HRT does not seem to have a relevant effect on cancer risk in BRCA mutation carriers. RRBSO should not be postponed to avoid subsequent HRT in this population. Adequate HRT after RRBSO should be offered to avoid chronic diseases resulting from low estrogen levels. However, further data on the safety of different formulations are needed.

Use of fertility treatments in BRCA1/2 mutation carriers and risk for ovarian and breast cancer: a systematic review.

PURPOSE: Mutations in the genes BRCA1 and BRCA2 represent a significant risk factor for ovarian and breast cancer. With increasing number and success rates, fertility protection and treatment are gaining importance also for BRCA1/2 mutation carriers. However, the effect on primary cancer risk and risk for recurrence remains unclear. This review analyses the published data on fertility treatment and risk of ovarian and breast cancer in BRCA1/2 mutation carriers. METHODS: In this review, we included all relevant articles published in English from 1995 to 2018. Literature was identified through a search on PubMed and Cochrane Library. RESULTS: We identified one retrospective cohort and one case-control study regarding the association of fertility treatments and ovarian cancer risk in BRCA mutation carriers. The studies show no increase in ovarian cancer risk. Furthermore, one case-control study on the association between fertility treatment and breast cancer risk in BRCA mutation carriers and one prospective cohort study on the long-term safety of medication used for fertility preservation in women with a history of breast cancer were identified. One of the studies shows a possible adverse effect for gonadotropin-containing medication. CONCLUSION: Possible increases in cancer risk associated with fertility treatments in BRCA1/2 mutation carriers cannot be excluded at this time. Based on the existing studies, BRCA1/2 mutation carriers should not be generally excluded from fertility treatments. However, they have to be informed about limited data and possible increases in cancer risk.

Knowledge transfer as a tool towards improvement of cancer care in low- and middle-income countries. 6th European Roundtable Meeting (ERTM), June 14th, 2019, Berlin, Germany.

PURPOSE: To identify key factors for the best practice of knowledge transfer from high-income settings to low- and middle-income settings. RESULTS: Interactive sessions led to the identification of European learnings that can and should be shared beyond Europe. Furthermore, methods were characterised which may lead to successful knowledge transfer with subsequent quality improvement. CONCLUSION: To ensure successful implementation of knowledge and new methods, political support is extremely important. A strong focus should be an improvement of collaboration and network development. Rehabilitation, early and late pallative care, cost effectiveness and long-term follow-up are priorities. Limitations are budget constraints which limit the execution of NCCPs.

Use of oral contraceptives in BRCA mutation carriers and risk for ovarian and breast cancer: a systematic review.

PURPOSE: BRCA mutation carriers have an increased risk of developing breast or ovarian cancer. Oral contraception (OC) is known to increase breast cancer and reduce ovarian cancer risk in the general population. This review analyses the published data on OC and risk of cancer in BRCA mutation carriers. METHODS: We included all relevant articles published in English from 1995 to 2018. Literature was identified through a search on PubMed and Cochrane Library. RESULTS: We included four meta-analyses, one review, one case-control study and one retrospective cohort study on the association between ovarian cancer and OC in BRCA mutation carriers. All report a risk reduction for the OC users and several also describe an inverse correlation with duration of use. Regarding breast cancer, we included four meta-analyses, one review, one case-control study, two case-only studies, one prospective and one retrospective cohort study. Some studies report a risk elevation, while others did not find an association between OC use and breast cancer in BRCA mutation carriers. In other studies, the association was limited to early-onset breast cancer and/or associated with young age at first start of OC. CONCLUSION: Oral contraception leads to a risk reduction of ovarian cancer also in BRCA mutation carriers. An increase in breast cancer risk due to OC cannot be excluded. Women with BRCA mutation who consider OC use have to be informed about possible increase in breast cancer risk and alternative contraceptive methods. OC should not be used for the prevention of ovarian cancer in this population.

Recommendation of adjuvant trastuzumab treatment in HER-2-positive breast cancer patients: insights from quality indicator data collected in certified breast cancer centers in Germany, Italy, Austria, and Switzerland.

PURPOSE: In 2003, a certification system was introduced to ensure high standards of oncological care in breast cancer patients in Germany. Certified breast cancer centers (BCCs) must fulfill specific requirements including quality indicators (QI) derived from the clinical guidelines that are evaluated in annual audits. When target values for QIs are not fulfilled, centers need to give explanations. We analyzed data from BCCs for a selected indicator: the recommendation of trastuzumab for patients with early HER-2-positive invasive breast cancer. We investigated explanations given in cases when trastuzumab was not recommended to see whether this was justified. METHODS: Patient data from 274 BCCs treating 53,777 primary cases in 2015 were analyzed using descriptive statistics. RESULTS: In the 274 BCC sites, 5700 primary patients with early HER-2-positive breast cancer were treated in 2015. 128 sites (46.7%) did not reach the target value of 95% trastuzumab recommendation and thus had to give explanations. In these 128 sites, 2663 primary HER-2-positive breast cancer patients were treated, 343 (12.9%) of whom did not receive a recommendation for adjuvant trastuzumab treatment. All 128 sites delivered explanations. Overall, 450 explanations were given, allowing multiple explanations for single patients. No explanation was given for 8 of the 343 patients (2.3%). The most common given explanation was multi-/comorbidity (45.5%). CONCLUSIONS: The analysis suggests thorough decision-making when quality indicator target values for a trastuzumab recommendation were not fulfilled. Our data do not provide information on whether such decisions have an impact on treatment outcome for these patients.

Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review.

In recent years, a vast quantity of clinical data has been accumulated on the pathophysiology of symptomatic vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause (GSM) in peri- and postmenopausal women and on the treatment options for these conditions. Guidelines from several societies have recently been updated in favor of VVA/GSM vaginal therapy with the lowest possible doses of estrogens. The combination of a vaginal ultra-low dose of 0.03 mg of estriol (E3) and lyophilized, viable Lactobacillus acidophilus KS400 (0.03 mg-E3/L) is a unique product with a dual mechanism of action supporting not only the proliferation and maturation of the vaginal epithelium, but also restoration of the lactobacillary microflora. It has been demonstrated efficiently to establish and maintain a healthy vaginal ecosystem. Use of this combination considerably improves the clinical signs and symptoms as well as the quality of life of menopausal women suffering from vaginal atrophy. This combination therapy is well tolerated with a low overall incidence of side-effects and negligible estriol absorption. Based on recent scientific evidence and current treatment guidelines, the 0.03 mg-E3/L combination could be considered one of the options for the treatment of symptomatic vaginal atrophy in aging menopausal women.

Screening-relevant age threshold of 70 years and older is a stronger determinant for the choice of adjuvant treatment in breast cancer patients than tumor biology.

PURPOSE: The 70-year threshold determines whether patients are eligible or not for the breast cancer screening program in Germany. It is not known whether this age threshold also influences the choice of adjuvant treatment and ultimate outcome. METHODS: 3463 patients were analyzed from the clinical cancer registry Regensburg (Germany) with primary, non-metastatic invasive breast cancer diagnosed between 2000 and 2012. The distribution of tumor biological subtypes was evaluated in breast cancer patients both in those eligible for screening (ESG, 50-69 years) and those not eligible for screening (NESG, ≥70 years). Local and systemic therapies in different subtypes as well as overall survival (OS) were analyzed. RESULTS: 2171 patients (62.7%) pertained to the ESG and 1292 patients (37.3%) referred to the NESG. The distribution of the common subtypes Luminal A, Luminal B, HER2-like, and Basal-like was comparable in both groups. Treatment varied considerably with less systemic therapies in all subtypes in patients in the NESG. Regarding local therapies, patients in the NESG also received less surgery and less radiotherapy. As to Luminal A patients, best OS was seen in patients receiving endocrine therapy (ET) (7-year OS of 95.6%) and CHT plus ET (7-year OS of 93.1%) in the ESG. In the NESG, best OS was seen in patients receiving CHT plus ET (7-year OS of 95.2%), whereas patients receiving only ET had a 7-year OS of 73.9%. CONCLUSIONS: Despite similar tumor biology, elderly patients are undertreated regarding both systemic and local therapies compared to younger patients, leading to reduced OS.

Current developments in cancer care: including the patients' perspective-3rd European Roundtable Meeting (ERTM) June 17, 2016, Berlin, Germany.

PURPOSE: National Cancer Control Plans (NCCP) are necessary to improve cancer care and reduce mortality. We have reported previously on European institutional health structures and transformation of theoretical health care standards into a practical approach. For the latter consideration of the patients' perspective was considered as highly important and chosen as subject for this meeting. RESULTS: Several European organizations have realized deficits in this area. They promote equal and timely access to cancer care since current inequities lead to disparities in cancer survival across Europe. Patients' support working groups are focussing on employment issues, financial services, psychosocial screening and support, palliative care and rehabilitation. They also identified cancer research including patients' views as highly important. Workshops during the 3rd European Roundtable Meeting (ERTM) covered the issues transparency in patient care, implementation of new knowledge and decision making in partnership with the patient. CONCLUSIONS: It was concluded that patient views and perspectives have to be considered during the whole continuum of cancer care. Access to treatment, transparency and including patients into the development process are relevant aspects.

[Screening for cervical and breast cancer]. / Krebsfrüherkennung des Zervix- und des Mammakarzinoms.

Screening programs for cervical cancer and breast cancer lead to a clear reduction of mortality. Starting in 2018 screening for cervical cancer will be structured as an organized program as already exists for breast cancer. In future screening for cervical cancer will be primarily performed by human papillomavirus (HPV) testing at intervals of 5 years while cytological examination (Pap smear) will also be available as an additional or alternative procedure. For breast cancer screening in Germany an annual clinical examination with palpation and mammography screening at 2­year intervals is provided for women aged between 50 and 69 years. In Germany only approximately 50 % of invited women have used the opportunity to participate in screening in recent years. Weighing the benefits against the harms of cancer screening programs is always important in the process of evaluation of different strategies.

Antenatal Diagnosis of Dizygotic, Monochorionic Twins Following IVF/ICSI.

Monochorionic twins are usually monozygotic and thus usually have the same sex. A case of monochorionic diamniotic twins following IVF/ICSI and laser treatment of the zona pellucida ("assisted hatching") is presented in which partial embryo amalgamation appears to have occurred. Discordant sex between the twins was suspected on detailed antenatal ultrasound at 13 + 3 weeks gestation and was confirmed on subsequent examinations. The sexual phenotype at birth was female for one twin and male for the other. Placental histology confirmed the monochorionic, diamniotic situation. Cytogenetic analysis of both twins was carried out postpartum on various tissues. On karyotyping of blood lymphocytes the male and female twins each had one mosaic of male and female cells. Oral mucosal cells showed normal male and female karyotypes respectively. Analysis of urothelium showed a normal result for the male infant, and a weak gonosomal mosaic with an XX and XY constellation for the female infant. At least for blood lymphocytes, a diagnosis of chimerism was proven.

Effects of morcellation on long-term outcomes in patients with uterine leiomyosarcoma.

OBJECTIVES: Clinical long-term outcomes of women with uterine leiomyosarcoma (ULMS) with different types of hysterectomy (open abdominal, vaginal, laparoscopic and switch from laparoscopic to open abdominal) were compared according to morcellation and other factors. MATERIALS: The clinical cancer registry Regensburg (Germany) registered 64 patients between 2004 and 2013 with ULMS. A retrospective cohort analysis was performed using the Kaplan-Meier method to estimate 5-year overall survival (OAS), recurrence-free survival (RFS) and recurrence rates. To compare surgery with or without morcellation log rank test was used. To adjust for age, FIGO stage, grading and other factors multivariable Cox regression models were applied to estimate hazard ratios (HR). RESULTS: In the cohort of 64 patients 15 underwent morcellation, preferably during laparoscopic surgery. Although numbers were small we performed analysis for OAS and RFS. Median OAS for morcellation was 10.6 vs. 6.4 years for non morcellation. 5y-OAS was 76.0 % for morcellation compared to 54.8 % in patients without morcellation (p = 0.115). Cox regression models rendered an unadjusted (univariable) HR 0.428 for morcellation vs. non-morcellation (p = 0.125) and an adjusted (multivariable) HR 0.644 (p = 0.406). 5y-RFR was 64.0 % compared to 42.8 % in patients without morcellation (p = 0.104; unadjusted HR 0.484, p = 0.111; adjusted HR 0.607, p = 0.306). CONCLUSION: In general, the prognosis of patients with ULMS is poor. In our cohort, women who underwent hysterectomy with morcellation had a better cumulative OAS and RFS than women without morcellation. Although we adjusted for differences between women with and without morcellation regarding age, grading and stage, there were no statistically significant differences between the groups.

Statement of the AGO Kommission Ovar, AGO Study Group, NOGGO, AGO Austria and AGO Switzerland Regarding the Use of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer.

The AGO Kommission Ovar already published a statement in 2013, warning about the uncritical use of hyperthermic intraperitoneal chemotherapy (HIPEC) outside controlled studies. This statement has now been updated after the most recent literature was reviewed by AGO Kommission Ovar, the AGO Study Group, NOGGO, AGO Austria and AGO Switzerland. The authors conclude that HIPEC remains experimental. Its use is not recommended and should be rejected outside of prospective controlled trials.

Improving structural development in oncology: transformation of theoretical health care standards and knowledge into a practical approach -- 2nd European Roundtable Meeting (ERTM), May 8, 2015, Berlin, Germany.

PURPOSE: It is widely accepted that National Cancer Control Plans (NCCPs) are essential to improve cancer care. They often describe the structural requirements such as cancer centers, clinical cancer registries and quality control. During the 2nd European roundtable meeting, the implementation processes were analyzed and discussed. RESULTS: Communication strategies between cancer registries and cancer centers need to be developed. Analyses and discussion of collected data have to be performed by multidisciplinary teams. This has to be followed by appropriate actions to improve quality of care. It is essential to describe the clinical procedures, organizational processes and communication between individuals and professional teams. The patients' perspectives have to be included in the development of cancer care networks. The patients' feedback on cancer care is a routine quality indicator. CONCLUSION: NCCPs that include the description of structural requirements are important. In addition, it is essential to develop cancer care networks including multidisciplinary organizational processes to guarantee high quality. These have to consider patients preferences.

4-IHC classification of breast cancer subtypes in a large cohort of a clinical cancer registry: use in clinical routine for therapeutic decisions and its effect on survival.

The aim of the present study was to evaluate to what extent the combination of standard histopathological parameters determines the biology of breast cancer and the effect on therapy and prognosis. The Clinical Cancer Registry Regensburg (Bavaria, Germany) included n = 4,480 female patients with primary, non-metastatic (M0) invasive breast cancer diagnosed between 2000 and 2012. Immuno-histochemical analyses, i.e., estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 (4-IHC), defined the tumor biological subtypes Luminal A, Luminal B, HER2-like, and Basal-like. Subtype-related differences in therapies and overall survival (OS) were analyzed using multivariable statistical methods. 4344 patients (97.0 %) could be classified into the four common tumor biological subtypes. The two most frequent entities were Luminal A (48.4 %), Luminal B (24.8 %), HER2-like (17.8 %), and Basal-like subtype (9.0 %). A multivariable Cox regression model showed that the best 7-year OS was seen in Luminal A patients and that OS of Luminal B and HER2-like patients was comparable (HR = 1.59, P < 0.001 versus HR = 1.51, P = 0.03). Lowest OS was seen in patients with Basal-like tumors (HR = 2.18, P < 0.001). In conclusion, the classification of tumor biological subtypes by the ER, PR, HER2, and Ki-67 biomarkers is practical in routine clinical work. Providing that quality assurance of these markers is ensured, this classification is useful for making therapy decisions in the routine clinical management of breast cancer patients.