Outcome of breast cancer patients with low hormone receptor positivity: analysis of a 15-year population-based cohort.

BACKGROUND: Guideline recommendations for the treatment of breast cancer with low hormone receptor (HR) expression (1%-9%) are ambiguous and several studies showed more similarities with HR-negative tumors than with HR strongly positive tumors (≥10%). We used a population-based 15-year cohort to compare patient characteristics and outcome of HR low positive tumors with HR-negative and HR strongly positive tumors, respectively. PATIENTS AND METHODS: A total of 38  560 women diagnosed with early invasive breast cancer between 2004 and 2018 within the scope of the Munich Cancer Registry with 4.9 million inhabitants were included. Descriptive analyses of prognostic factors, treatment, and outcome analyses using the Kaplan-Meier method; cumulative incidence in consideration of competing risks; and multivariate analyses (Cox regression and Fine-Gray model) were conducted. Endpoints were time to local recurrence (TTLR), time to lymph node recurrence (TTLNR), time to metastasis (TTM), overall survival (OS), and relative survival (RS). RESULTS: A total of 861 patients (2%) had HR low positive, 4862 (13%) HR-negative, and 32  837 (85%) HR strongly positive tumors. Within the HER2-negative cohort (n = 33  366), survival of HR low positive tumors was significantly worse than that of HR strongly positive tumors [OS hazard ratio 0.66 (95% confidence interval 0.55-0.78)], whereas between HR low positive and HR-negative tumors no significant survival difference could be detected [OS hazard ratio 0.93 (95% confidence interval 0.78-1.11)]. TTLR, TTLNR, and TTM showed similar results. By contrast, within the HER2-positive cohort (n = 5194), no statistically significant differences between the three HR groups could be detected in multivariate analyses. CONCLUSION: Current definitions for HR positivity and its clinical relevance should be reconsidered. Patients with HR low positive/HER2-negative tumors could be regarded and treated similar to patients with triple-negative tumors.

Systematic analysis of parameters predicting pathological axillary status (ypN0 vs. ypN+) in patients with breast cancer converting from cN+ to ycN0 through primary systemic therapy (PST).

Optimization of axillary staging among patients converting from clinically node-positive disease to clinically node-negative disease through primary systemic therapy is needed. We aimed at developing a nomogram predicting the probability of positive axillary status after chemotherapy based on clinical/pathological parameters. Patients from study arm C of the SENTINA trial were included. Univariable/multivariable analyses were performed for 13 clinical/pathological parameters to predict a positive pathological axillary status after chemotherapy using logistic regression models. Odds ratios and 95%-confidence-intervals were reported. Model performance was assessed by leave-one-out cross-validation. Calculations were performed using the SAS Software (Version 9.4, SAS Institute Inc., Cary, NC, USA). 369 of 553 patients in Arm C were included in multivariable analysis. Stepwise backward variable selection based on a multivariable analysis resulted in a model including estrogen receptor (ER) status (odds ratio (OR) 3.916, 95% confidence interval (CI) 2.318-6.615, p < 0.001), multifocality (OR 2.106, 95% CI 1.203-3.689, p = 0.0092), lymphovascular invasion (OR 9.196, 95% CI 4.734-17.864, p < 0.001), and sonographic tumor diameter after PST (OR 1.034, 95% CI 1.010-1.059, p = 0.0051). When validated, our model demonstrated an accuracy of 70.2% using 0.5 as cut-point. An area under the curve of 0.81 was calculated. The use of individual parameters as predictors of lymph node status after chemotherapy resulted in an inferior accuracy. Our model was able to predict the probability of a positive axillary nodal status with a high accuracy. The use of individual parameters showed reduced predictive performance. Overall, tumor biology was the strongest parameter in our models.

German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients.

BACKGROUND: Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine. PATIENTS AND METHODS: Women (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4. RESULTS: From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10). CONCLUSION: Adding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.

The West German Study Group Breast Cancer Intrinsic Subtype study: a prospective multicenter decision impact study utilizing the Prosigna assay for adjuvant treatment decision-making in estrogen-receptor-positive, HER2-negative early-stage breast cancer.

PURPOSE: The West German Study Group (WSG) Breast Cancer Intrinsic Subtype (BCIST) study was designed to assess the influence of Prosigna gene signature assay results on physicians' adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians' confidence in their therapeutic recommendations and on patients' decisional conflict status, anxiety levels, and functional status. METHODS: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with estrogen-receptor (ER)-positive, HER2-negative, lymph-node-negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in a WSG central pathology laboratory following manufacturer's guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay result concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. RESULTS: The present study population consisted predominantly of low-to-intermediate risk patients (N = 198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna test results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna test results. CONCLUSIONS: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.

Endocrine sensitivity is decisive for patient outcome in small node-negative breast cancers (BC) (pT1a,b) - results from the Munich Cancer Registry.

PURPOSE: In clinical routine, adjuvant systemic therapy in small node-negative (N0) BC is controversial, in particular in HER2-positive disease. We aimed to evaluate outcome of consecutive patients with small N0 BC in a population-based cancer registry and thus consequently substantiate indications for chemotherapy in those patient subgroups at increased relapse risk or poor survival. METHODS: From 2002 to 2009 (median follow-up 6 years), 9707 primary breast cancer patients with N0 tumors <2 cm (pTis, pT1N0M0) were reported to the Munich Cancer Registry. Patients with pTis tumors (n = 1870) served as internal comparator. Time to progression, observed (OS) and relative survival rates (Kaplan-Meier estimates) are presented. Cox regression analysis was used to assess the influence of tumor size, age, HR-, and HER2-status. RESULTS: 10-year-OS for pTis was 94.0%. In HR-positive tumors it was 91.9% in pT1a, 90.6% in pT1b, and 86.8% in pT1c. In HR-negative tumors, rates were 91.7%, 86.8%, and 86.8%, respectively. In HER2-positive tumors it was 81.2%, 88.1%, and 86.7%, in HER2-negative 93.1%, 90.6%, and 86.0%, respectively. In the multivariate model, age, tumor size, and HR-status showed a significant impact on OS (HRneg. vs. HRpos.: hazard ratio 1.50 (95% CI; 1.12-1.99), while HER2-status was not an independent prognostic factor. CONCLUSION: Prognosis of N0 tumors <1 cm is excellent, especially if they are HR-positive, even in HER2-positive cases. Weighing potential benefits vs. side-effects, there seems to be no need for chemotherapy in tumors <0.5 cm. In pT1b chemotherapy may be considered, if tumors are triple negative or HER2-positive and HR-negative. In pT1c guideline-based adjuvant therapy using all therapeutic options seems to be warranted.

Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40--GeparQuattro).

BACKGROUND: The GeparQuattro study showed that adding capecitabine or prolonging the duration of anthracycline-taxane-based neoadjuvant chemotherapy from 24 to 36 weeks did not increase pathological complete response (pCR) rates. Trastuzumab-treated patients with HER2-positive disease showed a higher pCR rate than patients with HER2-negative disease treated with chemotherapy alone. We here present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1495) with cT ≥ 3 tumors, or negative hormone-receptor status, or positive hormone-receptor and clinically node-positive disease received four times epirubicin/cyclophosphamide and were thereafter randomly assigned to four times docetaxel (Taxotere), or four times docetaxel/capecitabine over 24 weeks, or four times docetaxel followed by capecitabine over 36 weeks. Patients with HER2-positive tumors received 1 year of trastuzumab, starting with the first chemotherapy cycle. Follow-up was available for a median of 5.4 years. RESULTS: Outcome was not improved for patients receiving capecitabine (HR 0.92; P = 0.463 for DFS and HR 93; P = 0.618 for OS) as well as for patients receiving 36 weeks of chemotherapy (HR 0.97; P = 0.818 for DFS and HR 0.97; P = 0.825 for OS). Trastuzumab-treated patients with HER2-positive disease showed similar DFS (P = 0.305) but a significantly better adjusted OS (P = 0.040) when compared with patients with HER2-negative disease treated with chemotherapy alone. Recorded long-term cardiac toxicity was low. CONCLUSIONS: Long-term results, similar to the results of pCR, do not support the use of capecitabine in the neoadjuvant setting in addition to an anthracycline-taxane-based chemotherapy. However, the results support previous data showing a benefit of trastuzumab as predicted by higher pCR rates.

Dose-dense intensified sequential versus conventionally-dosed anthracycline and taxane-containing neoadjuvant therapy in patients with inflammatory breast cancer.

BACKGROUND: This post-hoc analysis aimed to compare an intense dose-dense sequential chemotherapy (DD-CT) and a conventionally-dosed chemotherapy (CD-CT) in the neoadjuvant AGO-1 study, focusing on the subgroup with inflammatory breast cancer (IBC). PATIENTS AND METHODS: Out of 668 randomised patients, 101 patients presented with IBC. Patients received epirubicin followed by paclitaxel every 2 weeks (DD-CT) or simultaneously every 3 weeks (CD-CT). RESULTS: No differences in pathological complete response rates were observed [odds ratio (OR)=1.27, p=0.33]. Most patients were scheduled for mastectomy before starting therapy; however, in 21.7% breast-conserving surgery was performed. Disease-free survival rates [Hazard Ratio (HR)=0.65; p=0.597] and overall survival rates (HR=1.40; p=0.327) were similar for both treatment arms. Patients with breast-conserving surgery had a significantly better outcome than patients treated with mastectomy (disease-free survival: HR=0.41; p=0.034 and overall survival: HR=0.09; p=0.003). CONCLUSION: Patients with IBC benefited not from DD-CT but from breast-conserving surgery after neoadjuvant chemotherapy.

The high-grade endometrial sarcoma: a rare entity.

INTRODUCTION: With an estimated incidence of one to two per one million women, the endometrial stromal sarcoma (ESS) is a rare disease. It is subclassified into a high-grade and a prognostically better low-grade type. Evidence-based data for a standardized therapy is lacking. CASE REPORT: A 32-year-old obese nulligravida presented with persistent vaginal bleeding after the operation of an acute adnextorsion at another hospital. The repeat gynecological ultrasound examination showed a 5.3x5.3x3.6 cm vascularized, partially inhomogeneous mass in the uterus. A fractioned curettage yielded a differential diagnosis of malignant muellerian mixed tumor or a non-differentiated endometrial sarcoma. For completion of the operative treatment, laparotomy with hysterectomy, adnexectomy, and pelvine lymphonodectomy were performed. The final histological report described a 7 cm non-differentiated endometrial sarcoma with infiltration of the left ovary and 25 tumor-free lymph nodes. DISCUSSION: Standard therapy for resectable sarcoma is abdominal hysterectomy and bilateral adnexectomy. So far, there is little data from studies reporting radio- or chemotherapy treatment of small patient numbers in an adjuvant setting. CONCLUSION: The ESS is a very rare disease of the uterus. Due to missing clinical data, it remains a multidisciplinary therapeutic challenge requiring individual decisions. To receive more information on this rare disease, treatment should be performed according to international protocols.

[Breast cancer treatment during pregnancy - experiences in the department of OB/GYN Grosshadern-Munich and review of international data]. / Behandlung des Mammakarzinoms in der Schwangerschaft - Erfahrungen aus der Universitätsfrauenklinik Grosshadern und Internationale Datenlage.

With an incidence of 1 case in 3 000 to 10 000 pregnancies, breast cancer is the second common pregnancy associated malignancy besides cervical cancer. An analysis of 12 patients with pregnancy associated breast cancer, treated at the University Department of OB/GYN Grosshadern, and a review of the international literature is presented. Eight women underwent surgery during pregnancy (four radical mastectomies, four breast conserving procedures), four received CMF-chemotherapy during pregnancy (1 to 4 cycles). Three other patients were treated post partum. The tumor stages were advanced (> 2 cm: 10/11; N pos.: 8/11; G3: 7/11; ER/PR neg.: 5/11). One patient with metastatic breast cancer received palliative care only and died 1 week after diagnosis and emergency caesarean section in the 31 (st) gestational week. Median overall survival was 41 months with six patients dead of breast cancer. One pregnancy was terminated in the 20 (th) week of gestation by legal abortion, another because of intrauterine death in the 24 (th) gestational week. Of the other six pregnancies, four were terminated by elective caesarean section and two by induced vaginal delivery. One child died with trisomy 18 shortly after birth. The five healthy children (now aged 3 to 12 years) showed normal development up to now. The cases show the challenge and the opportunities associated with therapy of pregnancy associated breast cancer. Utmost attention should be turned to the psychological support of the woman and her family.

Reduction mammaplasty in granular cell tumour of the breast.

Granular cell tumour of the breast is a rare peripheral nerve tumour. A case in a 34-year-old woman is reported. The clinical and histological differentiation from invasive malignant neoplasm and the surgical management are discussed. Core needle biopsy preoperatively is able to establish the definite diagnosis and help to avoid surgical overtreatment.

[Neoadjuvant therapy of breast cancer]. / Neoadjuvante Chemotherapie bei Mammakarzinom.

Whereas in the past primary systemic therapy (PST) was rather used for other tumor entities or was limited to the use in inoperable breast cancer, treatment of operable stages is being increasingly investigated. After the proof of equivalency between PST and adjuvant chemotherapy, numerous trials have been conducted. PST enables testing of in vivo chemosensitivity; thus, treatment can be monitored by tumor response. Insufficient responders can be switched to non-cross-resistant concepts to avoid administration of ineffective drugs and try to achieve improvement of survival for these patients. The reduction of tumor size not only increases the rate of breast-conserving therapy, but has predictive value for the further course of the disease. Especially pathohistological complete remission is a good surrogate marker for improved survival and the goal of modern protocols in the preoperative setting. Actively recruiting trials (e.g. trials of the AGO PREPARE and TECHNO) integrate modern concepts of treatment like dose-dense, dose-intensified, sequential therapy and tumor targeting with trastuzumab in PST. Eligible patients should be recruited in ongoing trials to further elucidate the role of PST in primary breast cancer. Evaluation of predictive factors and correlation of therapy response to the genetic profile of the tumor with modern technologies will allow improved selection of patients with increasingly tailored therapy.

[Sonographically guided percutaneous needle aspiration of breast abscesses - a minimal-invasive alternative to surgical incision]. / Sonographisch gesteuerte Mammaabszesspunktion als minimal-invasive Alternative zur chirurgischen Inzision.

AIM: The current standard treatment of breast abscesses is surgical incision and drainage. This method, however, frequently yields poor cosmetic results. Sonographically guided percutaneous aspiration of breast abscesses and local antibiotic treatment need to be considered as an interesting alternative. The present study aimed to compare these treatment alternatives. METHOD: The patient population analysed comprised 24 patients with 28 breast abscesses who presented to the Department of Obstetrics and Gynaecology of Munich University Hospital Grosshadern between 12/1997 and 9/2002. 25 % of these patients (6/24) suffered from a puerperal and 75 % (18/24) from a non-puerperal breast abscess. The study group of surgically treated patients comprised 15 women (16 abscesses). Ten patients (10 abscesses) were treated with the novel, minimally invasive method. The treatment success was statistically analysed using chi (2)- and t-Tests (p < 0,05). RESULTS: The minimally invasive approach did not extend the length of intravenous antibiotic treatment or hospital stay and did not lead to an increase in the need for analgesic drugs. We encountered recurrent abscesses in 31 % (5/16) of the surgical treatment group, yet none in the group undergoing minimally invasive treatment. The aesthetic-cosmetic as well as the functional result in lactating patients was satisfactory in all cases. CONCLUSION: Sonographically guided percutaneous aspiration of breast abscesses represents a less invasive and very promising alternative to surgical incision, showing the following advantages: no general anaesthesia required, a superior cosmetic result and shorter hospitalisation. The method was highly accepted by all patients treated.

Chemosensitivity testing in gynecologic oncology--dream or reality?

Cell culture and animal models have played an essential role in the research of new principles of therapy. Many methods for the individualized testing of therapy sensitivity and resistance have been developed, for example, the clonogenic assay. Presently, the ATP-TCA is commercially available as a testing kit. This review gives an overview of the tumor samples that were tested in the oncologic laboratory in the Department of Obstetrics and Gynecology, Munich Grosshadern between 1993 and 2001. All target parameters show a clear trend in favor of sequential, dose-intensified Epirubicin/Paclitaxel therapy. If this trend remains valid for the total number of patients, a significant impact of this new principle of therapy can be expected. By individualized planning of therapy with ATP-TCA testing, therapy in the individual patient could already be performed by the examination of sensitivity in the preoperative biopsy specimen.

Intra-uterine fetal demise caused by amniotic band syndrome after standard amniocentesis.

The amniotic band syndrome represents a prime example of exogenous disruption of an otherwise normal fetal development. It may be a sequel of invasive diagnostic procedures such as amniocentesis or fetal blood sampling. A 38-year-old gravida II, para II delivered a morphologically normal male stillborn at term. The pregnancy history had been unremarkable but for an early 2nd-trimester amniocentesis. Cause of the intra-uterine fetal demise was noted to be an amniotic band constricting the umbilical cord. An amniotic band is a rare but potentially fatal condition which may be induced by, e.g., invasive prenatal procedures. Such bands are not usually diagnosed prenatally; however, selected patients with augmented risk may profit from intensive ultrasound evaluation including Doppler studies.

[An ectopic ureter with communication to the duct of Gartner and opening into the cervix--a rare cause of uncontrolled urine loss]. / Ektoper Harnleiter mit Verbindung zum Gartner-Gang und Mündung in die Zervix--eine seltene Ursache unwillkürlichen Urinverlusts.

This is a report of a 22-year-old woman who suffered from a loss of urine via the vagina of unknown origin since childhood. The diagnosis of a left ureteral and renal duplication with an opening of an ectopic ureter into the cervix was established. Due to the result of the retrograde pyelogram we came to the conclusion that the opening into the cervix must have been via a segment of a Gartner duct. The ectopic system and the Gartner duct were completely removed by a combined abdomino-vaginal operation. Genesis, diagnostics, differential diagnostics and therapy of ectopic ureters are described.