Amelie Schramm

Therapeutic intervention based on circulating tumor cell phenotype in metastatic breast cancer: concept of the DETECT study program

AbstractPurpose The aim of the ongoing DETECT study program is to evaluate therapeutic intervention based on phenotypes of circulating tumor cells (CTC) in patients with metastatic breast cancer (MBC). Currently (as of July 2015) more than half of the projected about 2000 patients with MBC have already been screened for CTC.MethodsWomen with HER2-negative primary tumor and presence of CTC are recruited into different DETECT trials according to the HER2-phenotype of CTC. Patients with HER2-positive CTC are randomized to treatment with physicians’ choice therapy (standard chemo- or endocrine therapy) with or without additional HER2-targeted therapy with lapatinib in the DETECT III trial. In DETECT IVa, postmenopausal patients with hormone-receptor positive primary cancer and HER2-negative CTC receive everolimus and standard endocrine therapy. For women with HER2-negative CTC and triple negative MBC or hormone-receptor positive tumor and indication for chemotherapy, a treatment with eribulin is offered (DETECT IVb). The clinical efficacy is investigated by CTC-Clearance and progression-free survival (PFS). The DETECT V/CHEVENDO trial extends the DETECT study program for women with HER2-positive and hormone-receptor positive MBC. The primary objective of this trial is to compare safety and quality of life (QoL) as assessed by the occurrence of adverse events in patients treated with dual (trastuzumab plus pertuzumab) HER2-targeted therapy plus either endocrine or chemotherapy. The translational research projects of the DETECT study program focus on further molecular characterization of CTC and evaluation of markers for their suitability to predict treatment response and to facilitate the development of more personalized treatment options.

Targeted Therapies in HER2-Positive Breast Cancer – a Systematic Review

About 20% of all breast cancer patients have a human epidermal growth factor receptor 2 (HER2)-positive breast tumor. This entity underwent an impressive change in prognosis, with notable improvement of progression-free survival and overall survival. Due to more aggressive tumors and no specific therapy, HER2 overexpression was historically seen as a negative prognostic marker, with worse prognosis and increased risk of recurrent disease. Trastuzumab, the first anti-HER2 antibody, revolutionized the systemic therapy options in HER2-positive breast cancer and initiated several targeted therapies and more personalized treatment strategies. Over the years, multiple HER2-targeting drugs stepped into clinical practice, for the curative as well as the metastatic situation. This review summarizes the targeted treatment options in HER2-positive breast cancer and their current impact in the clinical routine. Results of the most outstanding trials in HER2-targeted therapies and important ongoing trials are subsequently described for an up-to-date overview.

Liquid Biopsy in Metastasized Breast Cancer as Basis for Treatment Decisions.

According to current guidelines, the additional biopsy of breast cancer metastases to analyze the receptor status for phenotype assessment is recommended. However, due to clinical difficulties in performing biopsies of metastatic lesions, the phenotype of the primary tumor most often determines the treatment decisions in metastatic breast cancer. Liquid biopsy allows the analysis of several circulating biomarkers like circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) in peripheral blood samples of cancer patients. Thus, it is an elegant and easily practicable technique that delivers information on the current disease status. Determination of the CTC phenotype regarding the hormone receptor and human epidermal growth factor receptor 2 (HER2) status might replace additional tissue biopsy for planning further therapy strategies. Liquid biopsy is a crucial step towards a more individualized cancer therapy. In contrast to the conventional concept of tissue biopsy, it offers an easy, less invasive acquisition of biomaterial. In addition, it allows multiple repetitions and real-time monitoring of metastasized disease in the clinical routine. However, the clinical utility of liquid biopsy still needs to be evaluated.

Prevalence of Circulating Tumor Cells After Adjuvant Chemotherapy With or Without Anthracyclines in Patients With HER2-negative, Hormone Receptor-positive Early Breast Cancer

Background Use of anthracycline‐based chemotherapy in patients with early breast cancer (EBC) has been well‐established but is often associated with cardiotoxicity. Based on data suggesting a limited benefit of anthracyclines in human epidermal growth factor receptor 2 (HER2)‐negative patients, the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C study randomized patients to either anthracycline‐containing or anthracycline‐free chemotherapy. Given the proven prognostic value of circulating tumor cells (CTCs) in EBC, we compared the prevalence of CTCs after chemotherapy between both treatment arms for a preliminary efficacy assessment. Methods The SUCCESS C trial (NCT00847444) is an open‐label, phase III study randomizing 3547 patients with HER2‐negative EBC to either 3 cycles of epirubicin, 5‐fluorouracil, and cyclophosphamide followed by 3 cycles of docetaxel (FEC‐DOC) or 6 cycles of docetaxel and cyclophosphamide (DOC‐C). CTC status was prospectively evaluated in hormone receptor‐positive patients at the time of last chemotherapy cycle using the US Food and Drug Administration‐approved CellSearch System (Janssen Diagnostics). Results Data on CTC status were available for 1766 patients. Overall, CTCs were found in 221 (12.5%) patients. Univariate analyses revealed that presence of CTCs at time of last chemotherapy cycle was not significantly associated with tumor or patient characteristics (all P > .1). There was no significant difference with respect to presence of CTCs between patients randomized to FEC‐DOC or DOC‐C (11.5% vs. 13.6%; P = .18). Conclusions The comparable prevalence of CTCs at the time of last chemotherapy cycle may indicate that anthracycline‐free chemotherapy is equally effective to anthracycline‐containing chemotherapy in HER2‐negative, hormone receptor‐positive EBC. However, efficacy data from the final survival analysis of SUCCESS C have to be awaited to confirm these preliminary findings. Micro‐Abstract The prevalence of circulating tumor cells (CTCs) in patients with human epidermal growth factor receptor 2‐negative, hormone receptor‐positive early breast cancer after adjuvant chemotherapy was compared between anthracycline‐free and anthracycline‐containing treatment cohorts within the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C trial and showed no significant difference. Though CTCs have been established as an early treatment monitoring tool, comparison of CTC prevalence after therapy may have clinical implications with respect to equal effectiveness of both treatment regimens.

Abstract OT1-02-04: The DETECT V-study – Comparison of dual HER2-targeted therapy with trastuzumab plus pertuzumab in combination with chemo- or endocrine therapy in patients with HER2-positive and hormone-receptor positive metastatic breast cancer

Background: Maintenance of quality of life (QoL) is one of the main aims of treatment of incurable diseases such as metastatic breast cancer (MBC). In patients with HER2-positive MBC, taxan-based chemotherapy in combination with dual HER2 targeted therapy with trastuzumab and pertuzumab has shown promising efficacy results in terms of prolonged survival. However, cytostatic treatment is often accompanied by adverse events of grade 3 or higher, seriously impacting the patients9 QoL. In patients with HER2-positive and hormone-receptor positive MBC, the combination of trastuzumab with aromatase inhibitors was shown to be a safe and effective treatment option. The synergistic combination of dual HER2-targeted therapy with trastuzumab and pertuzumab plus endocrine therapy might offer an even better treatment option for these patients. DETECT V is the first prospective randomized phase III clinical trial comparing the safety and efficacy of the dual HER2-targeted therapy in combination with either endocrine therapy or chemotherapy. Trial design and eligibility criteria: Women with HER2-positive and hormone-receptor positive MBC with first to third line therapy are 1:1 randomized either to a dual HER2-targeted therapy with Pertuzumab and Trastuzumab plus endocrine therapy or to the dual HER2-targeted therapy plus chemotherapy. Specific aims: The primary objective of this study is to compare the safety and QoL in both arms, as assessed by the occurrence of AEs during the treatment period. We developed a modified adverse event score - including all adverse events grade 3 or higher, except neutropenia, which is included only if rated grade 4, and alopecia, rash, hand-foot-syndrome and peripheral neuropathy which are included if rated grade 2 or higher – in order to better reflect the clinical, physiological and psychological impact of AEs on patients9 QoL. Key secondary endpoint, besides the efficacy endpoints progression free survival (PFS) and overall survival, is to compare quality-adjusted survival (QAS), as measured using the quality-adjusted time without symptoms and toxicity (Q-TWiST) method, between both treatment arms. QAS as measured using the Q-TWiST method provides a single metric value that is a composite measure of quantity of survival time and quality of survival as assessed by the patients themselves. Q-TWiST analyses account for possible trade-offs between quantity and quality of life (e.g. prolonged time to progression at the cost of higher toxicity, which adversely affects QoL), and provide an excellent tool to evaluate whether two treatment options differ with regard to the overall perceived value to the patients. Translational research projects focus on Circulating Tumor Cell(CTC)-enumeration (the presence of CTCs is not obligatory in DETECT V), prognostic role of CTC dynamics, and the assessment of marker expression on CTCs in order to calculate an endocrine responsiveness score which will be evaluated regarding its suitability to predict treatment success. Contact: For further information on the DETECT V study please contact www.detect-studien.de or studienzentrale.ufk@uniklinik-ulm.de. Citation Format: Polasik A, Schramm A, Friedl TWP, Rack B, Trapp E, Tzschaschel M, Fasching PA, Taran F-A, Hartkopf A, Schneeweiss A, Muller V, Aktas B, Pantel K, Meier-Stiegen F, Wimberger P, Janni W, Fehm T. The DETECT V-study – Comparison of dual HER2-targeted therapy with trastuzumab plus pertuzumab in combination with chemo- or endocrine therapy in patients with HER2-positive and hormone-receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-02-04.

Comparison of Fetomaternal Outcome between 47 Deliveries Following Successful External Cephalic Version for Breech Presentation and 7456 Deliveries Following Spontaneous Cephalic Presentation.

Background: Achieving a cephalic position after a successful external cephalic version (ECV) is desired to result in delivery and fetal outcomes that are similar to those of deliveries following spontaneous cephalic presentation. Methods: We performed a retrospective cohort study including patients with successful ECV following fetal breech position (ECV cohort, n = 47) or with a singleton spontaneous cephalic pregnancy at ≥37 weeks of gestational age (control group, n = 7,456) attempting a vaginal delivery between 2010 and 2013 at the University Hospital Ulm. The mode of delivery and fetal outcome parameters were compared between these 2 groups using nonparametric statistics. Results: ECV cohort and control group did not differ with respect to maternal age, parity, gestational age at birth, and fetal gender. There were no significant differences between the 2 groups with regard to all parameters indicating fetal outcome. However, the rate of cesarean sections was higher after successful ECV compared to spontaneous cephalic presentation (27.7 vs. 12.8%, OR 2.615). Conclusion: While vaginal delivery is less likely to happen after a successful ECV compared to spontaneous cephalic singleton pregnancies, fetal outcome parameters showed no difference between the 2 groups. Physicians should be counseling and encouraging women to attempt ECV, as it is a safe and effective procedure.

Comparison of Outcome after Sentinel Lymph Node Biopsy or Inguinal Lymph Node Dissection in Patients with Nodal Negative Squamous Vulvar Cancer

Sentinel lymph node biopsy (SLNB) can reduce postoperative morbidity in women with vulvar cancer but data on long-term outcome of SLNB compared to inguinal lymph node dissection (ILND) is rare. Recurrence rates, disease-free survival (DFS) and overall survival (OS) from pT1/T2 pN0 squamous vulvar cancer from 1992 2011 were retrospectively compared between patients with SLNB (n=56) or ILND (n=56). PT2 tumors (59% vs. 11%; p<0.001) and complete vulvectomy (39% vs. 4%; p < 0.001) occured more often in the ILND than the SLNB group with no difference in lymph node recurrence rate. Multivariate survival analysis considering the year of primary diagnosis, tumor stage and surgery revealed no significant effect of treatment on DFS (p=0.062) or OS (p=0.924). SLNB seems to be a safe treatment for women with pT1/T2 nodal-negative vulvar cancer with no difference in DFS or OS compared to ILND. Those results confirm the results of the GROINSS-V Study and other literature with the longest follow-up data reported within a real-life collective.

Abstract OT3-04-02: DETECT III and IV – Individualized CTC-based therapy of metastatic breast cancer

Background: Circulating tumor cells (CTCs) are found in patients with early and metastatic breast cancer (MBC), and both their prognostic and predictive value has been described already. There is growing evidence that CTC phenotype may differ from the primary tumor. However, CTC targeted therapy is not used in clinical routine, and treatment decisions often still are based on the primary tumor9s phenotype without considering CTC-characteristics. The aim of the DETECT studies is to investigate and evaluate the role of presence and phenotype of CTC for guiding therapeutic decisions in women with HER2-negative MBC. Trial design and eligibility criteria: In a joint screening for DETECT III and IV, women with HER2-negative MBC are tested for CTCs and their HER2-phenotype. CTC detection is performed by the FDA-approved CellSearch System® (Janssen Diagnostics, Raritan, USA). Patients with HER2-positive CTCs are randomized in the multicenter Phase III study DETECT III to a physician9s choice chemo- or endocrine therapy with or without additional HER2-targeted treatment with lapatinib. Women with only HER2-negative CTCs are recruited to the multicenter open-label phase II study DETECT IV. Postmenopausal women with hormone-receptor positive MBC are treated with everolimus and a physician9s choice endocrine therapy in DETECT IVa. Patients with hormone-receptor positive MBC and an indication for chemotherapy and patients with triple-negative MBC receive mono-chemotherapy with eribulin in DETECT IVb. Treatment efficacy will be evaluated based on the early available CTC clearance rate (in DETECT III and DETECT IVa) and progression-free survival (in DETECT IVb) respectively, as the primary endpoint; secondary objectives will be to estimate disease control rate, progression-free (DETECT III and IVa) and overall survival, toxicity and tolerability of treatments with lapatinib, everolimus and eribulin, and quality of life. Specific aims: Changes in CTC-dynamics during therapy and their HER2-phenotype may influence following therapy decisions. The DETECT studies evaluate the prognostic and predictive role of CTCs as well as the efficacy of CTC based therapy to enable the establishment of a more personalized therapy for patients with MBC that might lead to prolonged progressive free survival and/or improved quality of life. The accompanying translational research programs investigate various markers for molecular characterization of CTCs and prediction of therapy response. Present accrual and target accrual: More than 1550 patients with HER2-negative MBC have already been screened within the DETECT study program. Thus, it is the worldwide largest study concept with therapy decisions resulting from CTC-testing and CTC-phenotypization. Contact: For further information on the DETECT study program please contact www.detect-studien.de or studienzentrale.ufk@uniklinik-ulm.de. Citation Format: Polasik A, Schramm A, Friedl TWP, Rack B, Trapp E, Fasching PA, Taran F-A, Hartkopf A, Schneeweiss A, Muller V, Aktas B, Pantel K, Meier-Stiegen F, Wimberger P, Janni W, Fehm T. DETECT III and IV – Individualized CTC-based therapy of metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-04-02.

Erratum to: Current role of liquid biopsy in metastatic breast cancer and future perspectives

Gynäkologe 2016 · 49:970–972 DOI 10.1007/s00129-016-3970-6 Published online: 26 September 2016

Assoziationen zwischen Lymphknotenbefall und Tumoreigenschaften beim Endometriumkarzinom – eine Single-Center Erfahrung

Zielsetzung: Beim Endometriumkarzinom stellt der Lymphknotenbefall einen entscheidenden Prognosefaktor dar; nach aktueller Leitlinie sollte bei allen Stadien – auser T1a, G1 oder G2 – die komplette pelvine und paraaortale Lymphonodektomie Teil des operativen Stagings sein. Die Datenlage hinsichtlich operativer Morbiditat und therapeutischem Nutzen einer kompletten Lymphonodektomie bleibt jedoch letztlich kontrovers. Ziel unserer Untersuchung war es, Subgruppen mit niedrigem Risiko fur einen Lymphknotenbefall zu identifizieren. Materialien/Methoden: In einer retrospektiv beschreibenden Studie wurden die Daten von Patientinnen mit Endometriumkarzinom analysiert, welche an der Universitatsfrauenklinik Ulm zwischen 2000 und 2013 mittels totaler Hysterektomie, bilateraler Salpingo-Oophorektomie und pelviner sowie paraaortaler Lymphonodektomie operiert wurden. Ergebnisse: Es standen Datensatze von 134 Patientinnen fur die Auswertung zur Verfugung. Bei insgesamt 35 (26%) Patientinnen wurde ein Befall pelviner und/oder paraaortaler Lymphknoten festgestellt. Lymphknotenbefall war signifikant mit dem Tumorstadium assoziiert (Chi-Quadrat Test: p < 0,001), wobei pT1a G1/G2 Tumore und pT1a G3 Tumore mit 7% bzw. 5% am seltensten und pT3 Tumore mit 67% am haufigsten befallene Lymphknoten aufwiesen, wahrend pT1b und pT2 Tumore mittlere Haufigkeiten von Lymphknotenbefall zeigten (26% bzw. 19%). Bei 84 (63%) der Patientinnen lag eine Invasion ins Myometrium vor; eine Invasionstiefe von mehr als der Halfte der Myometriumsdicke war signifikant haufiger mit einem positiven Lymphknotenbefall assoziiert als darunter liegende Invasionstiefen (25% vs. 8%; Chi-Quadrat Test: p = 0,048). Zusammenfassung: 7% in der pT1a G1/G2 Gruppe (endometrioide Histologie) wiesen Lymphknotenbefall auf. Diese Patientinnen waren ohne Lymphonodektomie prognostisch unterschatzt worden. Eine Sentinelbiopsie konnte bei geringerer Morbiditat das Staging in diesen Fruhstadien deutlich verbessern.