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Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients

BACKGROUNDnThe presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations.nnnPATIENTS AND METHODSnPatients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured.nnnRESULTSnDTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated.nnnCONCLUSIONSnTreatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit.BACKGROUNDnThe presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations.nnnPATIENTS AND METHODSnPatients with EBC and DTC-positive bone marrow were randomized (N=96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured.nnnRESULTSnDTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P=0.009). At 12 months, DTC counts decreased to a mean of 0.5±0.8 DTCs in the ZOL group and to 0.9±0.8 DTCs in the control group. In addition, ZOL was generally well tolerated.nnnCONCLUSIONSnTreatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit.

Clinical Utility of Serial Serum c-erbB-2 Determinations in the Follow-up of Breast Cancer Patients

To evaluate the ability of serum c-erbB-2 protein to (1) indicate occult and manifest metastases and (2) reflect response to first-line therapy, serial serum c-erbB-2 measurements were performed in a retrospective series of 52 primary breast cancer patients who had developed metastatic disease during follow-up. The results were compared with CA 15-3. Preoperatively, 31% (16/52) of the primary breast cancer patients had elevated c-erbB-2 concentrations. The CA 15-3 positivity rate was 13% (7/52). After surgery, 10 of the 52 patients showed either stable but highly elevated or rising c-erbB-2 serum levels indicating serum c-erbB-2 producing minimal residual disease. Increasing CA 15-3 concentrations were seen in only three patients. Elevated serum c-erbB-2 levels predicted manifest metastases in 27 and 50% of the patients at 6 and 3 months, respectively, prior to clinical diagnosis. CA 15-3 was less sensitive. Only 16 and 32% of the patients had increased CA 15-3 serum concentrations at 6 and 3 months, respectively, prior to clinical detection. The positivity rates of c-erbB-2 and CA 15-3 were similar when metastases were clinically diagnosed. Elevated c-erbB-2 concentrations were found in 62% (32/52). The sensitivity of CA 15-3 was 56% (29/52). The association between serum profiles and response to first-line therapy was evaluated in detail for 45 patients. Serial c-erbB-2 and CA 15-3 measurements reflected disease course in 24 and 27 patients, respectively. The serum profiles of c-erbB-2 and CA 15-3 were similar in 17 patients. In summary, our results suggest that serial determinations of serum c-erbB-2 are useful to monitor breast cancer patients.

Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study

BACKGROUNDnApproximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited.nnnMETHODSnClinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis.nnnRESULTSnA total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS.nnnCONCLUSIONSnDespite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.BACKGROUNDnApproximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited.nnnMETHODSnClinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis.nnnRESULTSnA total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS.nnnCONCLUSIONSnDespite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.

Surgical staging and prognosis in serous borderline ovarian tumours (BOT): A subanalysis of the AGO ROBOT study

Background:Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure.Methods:Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS).Results:For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66–2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06–3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22–4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15–3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation.Conclusion:Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.

Abstract S2-03: Persistence of circulating tumor cells in high risk early breast cancer patients during follow-up care suggests poor prognosis – Results from the adjuvant SUCCESS A trial

Background: Recent data suggest that circulating tumor cells (CTCs) are of prognostic relevance in early as well as metastatic breast cancer (BC). While persisting CTCs immediately after chemotherapy are known to indicate poor prognosis, there is a lack of data regarding the prognostic role of CTCs assessed during long-term follow-up care. Hence the prognostic value of CTCs two years after chemotherapy was analyzed. Methods: The SUCCESS A trial is a randomized, open-label, 2x2 factorial design Phase III study in high-risk breast cancer patients (≥N0 or T2–T4 or grade 3 or age ≤ 35 or hormone-receptor negative). Patients were first randomized to adjuvant chemotherapy treatment with 3 cycles of epirubicin-fluorouracil-cyclophosphamide followed by either 3 cycles of docetaxel or 3 cycles of gemcitabine-docetaxel. In addition, patients were randomized to 2 vs. 5 years of zoledronate treatment. Presence of CTCs was assessed using the FDA-approved CellSearch System (Janssen Diagnostics, LLC). CTC positivity was defined as ≥ 1 CTC in 7.5 ml whole blood. To investigate if CTC status 2 years after chemotherapy is of prognostic relevance independent from CTC status before chemotherapy and to evaluate the prognostic relevance of changed CTC status, only patients with data on CTC status before and 2 years after chemotherapy were included. Patient outcomes in terms of overall survival (OS) and disease-free survival (DFS) were analyzed by univariate log-rank tests and multivariate Cox regressions adjusted for age, menopausal status, tumor stage, nodal stage, grading, histological type, hormone receptor status and HER2 status. Survival time was measured beginning with the date of follow-up CTC assessment two years after chemotherapy. Results: Data on CTC status before and 2 years after chemotherapy were available for 1103 (29.4 %) of 3754 randomized patients. The CTC status 2 years after chemotherapy was positive in 204 (18.5%) patients. The median follow-up time was 37 months. Multivariate Cox regressions including CTC status before chemotherapy showed significant independent prognostic role for CTC status 2 years after chemotherapy on OS (hazard ratio (HR) 3.95, 95% confidence interval (CI) 2.13 – 7.32, p Conclusion: The presence of CTCs two years after chemotherapy analyzed during routine breast cancer follow-up care was associated with decreased survival. According to these results, persisting CTCs during long term follow-up independently predict patients9 outcome and may serve as surveillance marker. Citation Format: Janni W, Rack B, Fasching P, Haeberle L, Friedl T, Tesch H, Lorenz R, Neugebauer J, Koch J, Jaeger B, Fehm T, Mueller V, Schneeweis A, Lichtenegger W, Beckmann M, Scholz C, Pantel K, Trapp E. Persistence of circulating tumor cells in high risk early breast cancer patients during follow-up care suggests poor prognosis – Results from the adjuvant SUCCESS A trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-03.

Abstract PD6-6: A pooled analysis of the prognostic relevance of circulating tumor cells in early breast cancer

Background: While there is unequivocal evidence regarding the prognostic relevance of circulating tumor cells (CTCs) in peripheral blood of patients (pts.) with metastatic breast cancer (BC), less data is available for the prognostic relevance at time of primary diagnosis.nnMethods: We conducted a pooled analysis with individual data of 3172 pts with non-metastatic (Stage I-III) BC from five academic institutions. Prevalence and number of CTCs in the peripheral blood were assessed at time of primary diagnosis using the FDA-approved CellSearch System (Veridex, USA). Patient outcomes were analyzed using univariate log-rank tests and multivariate Cox regressions. The median follow-up time was 61 months.nnResults: At least one CTC was detected in 20.2% of the pts. The presence of CTCs was associated with larger tumors, more axillary lymph node metastases, and higher histological tumor grade (all p < 0.005). The presence of CTCs was significantly related to poor progression-free (PFS, log-rank test, p < 0.001, hazard ratio [HR] 2.0) and overall survival (OS, p < 0.001, HR 2.6). Multivariate Cox regressions, including tumor size, nodal status, histological tumor grade, hormone receptor status and HER2 status, and CTC prevalence confirmed that the presence of CTCs was an independent prognostic factor for both poor PFS (HR 1.8) and OS (HR 2.1, both p < 0.001). In the univariate subgroup analysis concerning OS, the HR for pts. with positive HRS was 3.1 (p< 0.0001), and 2.0 (p = 0.001) for pts. with a negative HRS. The prognostic relevance of CTC status was similar for patients with HER2 negative and HER2 positive tumors (HR 2.6 and 2.5, respectively). The HR in CTC-positive pts. with HRS positive/HER2 positive tumors was 3.4 (p = 0.003). For patients with more than 3 CTCs, the hazard ratio for death was increased to 5.2 (1.5 - 2.8) in univariate and to 4.0 (2.6 - 6.2) in multivariate analysis.nnView this table:nnCox Regression Analysis for Overall SurvivalnnnnnnConclusions: In patients with early breast cancer, the presence of CTCs in peripheral blood is an independent predictor of poor progression-free and overall survival.nnCitation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-6.

The Value of Antiangiogenics in Breast Cancer Therapy

Tumor-induced angiogenesis supplies the tumor with nutrients and oxygen necessary to grow and provides tumor cells with a possibility to intravasate into blood vessels as first step of metastatic spread. In the last two decades, evidence has been accumulating that controlling tumor-associated angiogenesis might be a promising strategy against cancer growth. In breast cancer, a number of angiogenesis inhibitors have been investigated in clinical trials. The antibody against vascular endothelial growth factor (VEGF) bevacizumab has been approved for treatment of metastatic breast cancer in Europe. Although the mechanism of action is still under study, bevacizumab was also tested in other clinical settings of breast cancer treatment such as neoadjuvant and adjuvant therapy, as maintenance therapy, and in combination with both chemotherapy and other targeted agents. Other antiangiogenic agents, such as oral tyrosine kinase inhibitors sorafenib, sunitinib, and pazopanib, were tested and have not yielded as promising results. In this chapter, we will review the current evidence and clinical relevance of antiangiogenic treatment in early and metastatic

Discordance in Human Epidermal Growth Factor Receptor 2 (HER2) Phenotype Between Primary Tumor and Circulating Tumor Cells in Women With HER2-Negative Metastatic Breast Cancer

PurposeDiscordance in human epidermal growth factor receptor 2 (HER2) status between primary tumor and metastases might have important implications for treatment response and therapy decisions. Here, we evaluate both the frequency of circulating tumor cells (CTCs) and the factors predicting HER2 discordance between primary tumor and CTCs as a potential surrogate for tumor biology and tumor heterogeneity in patients with metastatic breast cancer.Patients and MethodsThe number of CTCs in 7.5 mL of peripheral blood and HER2 status were evaluated in 1,123 women with HER2-negative metastatic breast cancer. HER2 discordance was defined as the presence of at least one CTC with a strong immunocytochemical HER2 staining intensity. Factors predicting discordance in HER2 phenotype were assessed using multivariable logistic regression.ResultsOverall, 711 (63.3%) of 1,123 screened patients were positive for CTCs (≥ one CTC). Discordance in HER2 phenotype between primary tumor and CTCs was observed in 134 patients (18....

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.

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, pu2009<u20090.001), multifocality (OR 2.106, 95% CI 1.203–3.689, pu2009=u20090.0092), lymphovascular invasion (OR 9.196, 95% CI 4.734–17.864, pu2009<u20090.001), and sonographic tumor diameter after PST (OR 1.034, 95% CI 1.010–1.059, pu2009=u20090.0051). 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.