S. D. Costa

S3-2: Neoadjuvant Chemotherapy Adapted by Interim Response Improves Overall Survival of Primary Breast Cancer Patients – Results of the GeparTrio Trial.

Background: The GeparTrio phase III trial investigated the concept of interim response-adapted neoadjuvant chemotherapy. Patients with an early response after 2 cycles chemotherapy were considered highly chemo-sensitive and randomized to additional 2 chemotherapy cycles compared to standard treatment. Patients with no early response were considered less chemo-sensitive and randomized to continue with a non-cross-resistant chemotherapy or with standard chemotherapy. Pathological complete response (pCR) rates were different between responders and non-responders but not between the randomized arms (von Minckwitz G, et al JNCI 2008+2008; Huober et al. BCRT 2010). We report here on the results of the secondary endpoints: disease-free (DFS) and overall survival (OS). Patients and Methods: 2072 patients with operable or locally advanced breast cancer were treated with 2 cycles TAC (docetaxel, doxorubicin cyclophosphamide) before interim response assessment. Responders were randomized to additional TACx4 (N=704) or TACx6 (N=686) and non-responders to TACx4 (N=321) or NXx4 (vinorelbine, capecitabine) (N=301). None of the HER2+ patients received Trastuzumab. Endocrine treatment was given postoperatively to ER+ and/or PgR+ patients. We observed 480 recurrences and 302 deaths during median 62 months of follow up. Results: Patients receiving the experimental treatments (TACx8 or TACx2-NXx4) showed a longer DFS (HR 0.71; 95%CI 0.60−0.86, p Conclusion: Adapting neoadjuvant chemotherapy according to interim response leads to better DFS and OS and represents therefore a unique advantage over adjuvant treatment. The investigated strategies to improve standard chemotherapy were most effective in the luminal A and B phenotypes. These phenotypes are usually considered less chemo-sensitive and pCR is not a prognostic factor. This might explain why the observed survival advantages could not be predicted by pCR. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-2.

Integrated meta-analysis on 6402 patients with early breast cancer receiving neoadjuvant anthracycline-taxane +/- trastuzumab containing chemotherapy.

Abstract #79 Background: An integrated meta-analysis on individual data has been performed on 7 prospective neoadjuvant trials containing doxorubicin (A) or epirubicin (E), docetaxel (D) or paclitaxel (P) (with or without trastuzumab (H)) conducted by the German Breast Group and the AGO Breast Group.
 Methods : Patients (Pts) with operable or locally advanced, non-metastatic breast cancer were included in trials between 1998 and 2002: GeparDo (dose-dense (dd) AD +/- tamoxifen (Tam), N=248), GeparDuo (ddAD+Tam vs AC-D+Tam;N=904), AGO 1 (EP vs ddE-ddP;N=666), Gepartrio-Pilot (DAC+/-vinorelbine/capecitabine(NX);N=284), and between 2003 and 2007: GeparTrio (DACx6 vs DACx8; DACx6 vs DAC-NX;N=2072); Prepare (EC-P vs ddE-ddP-CMF;N=733) and GeparQuattro (EC-D vs EC-DX vs EC-D-X;+H if HER2+),N=1495). Pathological complete response (pCR) is defined as no invasive residuals in the breast and lymphnodes (ypT0/is,ypN0).
 Results: Overall 1200 (18.7%) out of 6402 pts (13.7% before and 21.2% after 2003) had a pCR at surgery. pCR-rates according to treatment groups were: conventional dosed (N=5007): 20.1% vs dose-dense (N=1395): 13.9% (p = 50 yrs (N=3248): 15.9% (p 5cm (N=1358): 14.1% (p Conclusions: Findings of this meta-analysis might be used to better select patients and treatment for the neoadjuvant approach and development of new strategies to further improve pCR and breast conservation rate. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 79.

Abstract S3-1: Neoadjuvant Chemotherapy in the very young 35 years of age or younger

Background: In young women the course of breast cancer (BC) tends to be more aggressive. In several trials young age at diagnosis was an independent predictive factor for pathological complete response (pCR) after neoadjuvant chemotherapy. Here we investigate especially the rare entity of very young women at age 35 years or younger. Methods: 8949 patients from 8 neoadjuvant German studies with operable or locally advanced, non-metastatic breast cancer and follow-up were included (for details see von Minckwitz G et al, BCRT 2010 and NEJM 2012). A subgroup of 704 patients of age 35 years or younger was analyzed. All patients with endocrine responsive disease received adjuvant endocrine therapy according to institutional standard. We compared pathological complete remission rate (pCR) defined as ypT0, ypN0 and disease free survival rate (DFS) of this very young group with older patients in total and in different histopathological subgroups (as defined previously by von Minckwitz J Clin Oncol 2012). Results: From 8949/6561 had known ER, PR, HER2 and grading. There were less Luminal A and more TNBC in the very young women compared to the one >35 years of age: Luminal A: 131 (21%) vs. 2251 (27%); Luminal B HER2−: 50 (8%) vs. 783 (10%); Luminal B HER2+: 103 (17%) vs. 989 (14%); HER2+/HR−: 72 (11%) vs. 739 (10%); TNBC: 164 (26%) vs. 1415 (19%). The pCR rate was significantly higher in the very young than in the group older than 35 years (23.6% vs. 15.7.%; p 35 years, in the very young only hormone receptor status and grading had independent predictive information for pCR but not T-stage and nodal-stage. No difference in DFS according to age was seen when the patients had a pCR. Non-pCR patients had a significantly worse DFS when they were very young (DFS HR: 1.35; p = 0.001). Adjusting for T-stage, nodal-stage, age and pCR; within the TNBC pCR but not age had independent prognostic information for DFS (pCR: HR: 0.18 [95%CI 0.13–0.16]; p Conclusion: Very young women are more likely to achieve a pCR after neoadjuvant chemotherapy. This effect is driven mainly by triple negative BC, which is more common in the very young. Age did not influence DFS in TNBC when a pCR was achieved. It can be hypothesized that the very young pts with Luminal A tumors benefit from a pCR, whereas overall pCR is not a predictor in the Luminal A subgroup. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-1.

S5-4: pCR as a Surrogate in HER2−Positive Patients Treated with Trastuzumab.

Background: Patients with HER2−positive metastatic disease used to show a more unfavorable prognosis compared to patients with HER2−negative tumors. With the introduction of trastuzumab, patients with HER2−positive metastatic breast cancer show an improved survival compared to patients with HER2−negative tumors (Dawood et al. 2010). So far it has not been shown, if such a switch in prognosis is also achieved in early breast cancer. Methods: 6377 patients from 7 neoadjuvant German studies with operable or locally advanced, non-metastatic breast cancer were analyzed (for details see von Minckwitz G et al, BCRT 2010). In earlier studies patients (pts) with HER2−positive disease did not receive trastuzumab. Trastuzumab was given in 2 trials parallel to chemotherapy for 12–36 weeks and completed after surgery for up to one year of treatment. All patients with endocrine responsive disease received adjuvant endocrine therapy according to institutional standard. We compared the overall and disease free survival in three subgroups, HER2−negative patients, HER2−positive w/o trastuzumab and HER2−positive patients with trastuzumab according to pCR defined as ypT0, ypN0. Results: 6377 patients were evaluable. During a median follow up of 46.3 (0-127) months and observation of 22.869 patient years, 1466 (23%) relapses and 775 (12.2%) deaths were observed. 3060 had HER2−negative disease, 665 patients had HER2−positive disease w/o trastuzumab and 662 patients with HER2−positive disease received trastuzumab. No data on HER2 status were available in 1990 (31.2%) patients as measurement of HER2 was only implemented in the study procedures since 2001.Median age of patients at time of study entry was 50.1 (21-81) years. Median tumor size was 4.0 (range 1.2 − 33.0) cm. Overall 15% (955) of patients had a pCR. The pCR rate in HER2−positive pts was 24% in those with trastuzumab and 15.8% in those without. There was no difference in overall DFS in the three groups achieving a pCR (log rank p=0.251). There was a strong trend towards a better OS in pCR HER2+pts being treated with trastuzumab (overall log rank p= 0.067). Cox regression analysis revealed HER2 positive patients with trastuzumab had a better OS than HER2−positive pts w/o trastuzumab (HR: 7.44; 95%CI [0.92−60.1; p=0.06) and HER2negative pts (HR: 3.86; 95% CI [0.5−29.41], p=0.19). However, for non-pCR pts, DFS was significantly inferior for pts treated with trastuzumab compared to patients without trastuzumab (HR: 0.81, 95% CI [0.63−1.04), p=0.102) or pts with HER2−negative tumors (HR: 0.75; 95% CI [0.61−0.92] p=0.006.)(overall log-rank p=0.022). However, OS was not significantly different between the three groups of non-pCR pts. Conclusion: Patients with HER2−positive primary breast cancer treated with trastuzumab achieve a higher pCR rate. This higher absolute number of pCRs in trastuzumab-treated patients lead to a DFS at least as good as that of HER2−positive not trastuzumab treated and HER2−negative patients and OS even tended to be superior to the other two groups. This supports that pCR can be considered as a surrogate marker in HER2−positive disease. However, HER2−positive, trastuzumab-treated patients without a pCR are at high risk of relapse and are at high medical need for new treatment options. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-4.

Abstract S5-05: Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclines-taxane-based chemotherapy for primary breast cancer – The phase III NATAN study (GBG 36/ABCSG XX)

Background: Patients with residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemoresistant breast cancer. Adjuvant treatment with bisphosphonates is considered to reduce the relapse risk predominantly in estrogen-deprivated patients. Methods: Patients who had invasive tumor residuals (ypT1-4 or ypN+) after a minimum of 4 cycles of anthracycline-taxane-containing NACT were eligible to the NATAN study. Patients were randomized within 3 years after surgery to receive zoledronate 4 mg i.v. (plus 1000 mg Ca2+ and 880 I.U. vitamin D daily) for 5 years vs. observation. Zoledronate was given q 4 weeks for the first 6 months, q 3 months the following 2 years, and q 6 months for the last 2.5 years. Patients with hormone receptor (HR)-positive disease received letrozole for 5 years if postmenopausal, or tamoxifen, if premenopausal. Adjuvant trastuzumab for HER2-positive disease was allowed since an amendment in 2007. Stratification factors were HR, time since surgery, age, and center. Primary objective was event-free survival (EFS). 654 patients and 316 events were required to observe an increase of 5yr EFS from 58% to 67.2% (hazard ratio 0.73). Secondary objectives were to determine overall survival, EFS with respect to the interval between surgery and randomization, bone-metastasis-free-survival, toxicity of and compliance to zoledronate, the predictive value of breast tumor response to NACT on the effect of postoperative treatment and the prognostic impact of chemotherapy induced amenorrhea in premenopausal patients. An interim analysis for high efficacy at 158 observed events was planned in the protocol; in agreement with study IDMC a Bayesian analysis for futility with futility boundary of 15% will be performed at the same time. Results: Between 2/2005 and 5/2009 693 patients were enrolled. Time between surgery and randomization was Conclusion: This is the first post-neoadjuvant phase III study. Analysis of the primary endpoint will be presented in case the IDMC will release of the results of the futility analysis. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-05.

Combination of new biologic parameters as a prognostic index in epithelial ovarian carcinoma

&NA; In a total of 77 patients with epithelial ovarian carcinomas, new biologic parameters [estrogen and progesterone receptor (ER, PR), DNA‐ploidy (DP), S‐phase fraction (Spf), cycling index (Ki67), Her2b/neu oncoprotein, epidermal growth factor receptor (EGF‐R), cathepsin D and P170 glycoprotein] have been simultaneously detected and correlated to the clinical outcome [progression‐free (PFI) and overall survival (OAS)] in a preliminary study. Apart from conventional prognosticators (age, stage, grade, residual tumor) and the postoperative serum marker Ca125, DP (P = 0.01), Spf (P = 0.009), Ki67 (P = 0.05) and PR (P = 0.01) could predict a short OAS (log rank test), whereas cathepsin D was of borderline significance only. Prognostic significance could be improved by using combinations of different factors [two markers of differentiation (DP, PR), one marker of proliferation (Spf) and one marker describing local tumor spread (cathepsin D)]. The difference in prognosis between patients with either all or three favorable tumor factors and patients with two to four unfavorable tumor factors reached a similar significance as can be obtained using FIGO stage as a prognostic factor (P = 0.007 for PFI, P = 0.0005 for OAS). These results were similar if early stages (FIGO I and II) were excluded. However, in a Cox regression analysis, including stage and residual tumor, this combination was significantly independent for PFI and OAS and could give additional information. Therefore, the large number of new biologic tumor markers could be restricted to only a few significant prognosticators to predict prognosis in primary epithelial ovarian carcinoma. In the future tumor characterizations may allow more individualized treatment with more aggressive, or even without, cytotoxic therapy after primary surgery.

Abstract S5-06: BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study

Background: Mutations in BRCA1 and BRCA2 influence the molecular pathogenesis of breast cancer. However, little is known about the association between mutations, response to therapy, and prognosis. We therefore analysed these associations in triple negative breast cancer (TNBC) patients in the neoadjuvant GeparQuinto Study. Methods: The GeparQuinto study recruited 1956 patients with HER2 negative disease including a prespecified group of 671 TNBC patients with untreated breast cancer. Patients were randomized to receive four cycles EC (90/600 mg/m2; q3w) followed by four cycles docetaxel (100 mg/m2; q3w), with or without bevacizumab (15 mg/kg). Here we present the analysis for both randomization arms combined. Sufficient blood was available of 482 TNBC patients. BRCA1 and BRCA2 genotyping was successful in 469 patients with available germline DNA and was conducted by SureSelect custom capture and sequencing on HiSeq 2500. Mutation status was correlated with pathological complete response rates (pCR) and disease free survival (DFS). Results: A total of 74 (15.8%) mutations in BRCA1 (n=61) and BRCA2 (n=13) were detected after initial sequencing. A pCR (ypT0/ypN0) was observed in 50% (n=37) of mutation carriers but only 31.1% (n=123) of patients without mutations (p=0.002). Similar results were observed for pCR (pT0is/pN0) (52.7% vs. 36.5%; p=0.010). pCR (ypT0/ypN0) was predictive of disease free survival (DFS) in all patients (Hazard Ratio, HR=0.23; 95%CI: 0.15-0.37; p Conclusion: TNBC Patients with BRCA mutations showed a higher frequency of pCR than patients without BRCA mutations after treatment with epirubicin, cyclophosphamide and docetaxel (+/ bevacizumab), suggesting that BRCA mutations may influence pCR in response to treatment regimens that do not include platin chemotherapy. pCR as a surrogate marker for DFS was also confirmed in patients without BRCA mutations. In addition, the effect of pCR on prognosis seemed to be smaller among the mutation carriers, although the number of mutation carriers was too low to test for differences between mutation carriers and wildtype patients. The project has partly been funded within NIH-NIGMS U19 GM61388 and the Breast Cancer Research Foundation. Citation Format: Fasching PA, Loibl S, Eidtmann H, Tesch H, Untch M, Hilfrich J, Schem C, Rezai M, Gerber B, Costa SD, Blohmer JU, Fehm TN, Huober J, Liedtke C, Muller V, Nekljudova V, Weber K, Rack B, Rubner M, Wang L, Ingle JN, Weinshilboum RM, von Minckwitz G, Couch F. BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study. [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 S5-06.

CYCLINS AND BREAST CANCER

Proliferation of mammalian cells is controlled through interactions between extracellular agents and intrinsic control mechanisms, eventually resulting in either progression through the G1, S, G2 cell cycle phases followed by mitosis or, alternatively, in cell cycle arrest, quiescence, differentiation, or cell death. Three important cell cycle control points, sometimes referred to as checkpoints, have been described: G1/S, G2/M, and M checkpoint (fig. 1). The G1/S checkpoint, also called restriction point, is the most important in tumorigenesis because at this level interactions between extrinsic, mitogenic signals and cell cycle control mechanisms occur. Cell cycle control is exerted by both positive (cyclins, cyclin-dependent kinases) (Cdk) and negative signals (Cdk inhibitors (CKI) such as p16, p21 Cyclins and Breast Cancer Review Article · Übersichtsarbeit

Systemic Treatment of Bone Metastases: Review of Literature and Retrospective Analysis of 718 Breast Cancer Patients

One-half of all breast cancer patients develop metastases at some time during the course of their disease, and the skeleton is the most common site of distant recurrence. Bone metastases are identified clinically in approximately 70% of the patients with advanced breast cancer and most of these metastases will require therapy [2]. Once metastases have occurred, breast cancer is considered to be incurable. However, some patients with metastases confined to the bone survive for many years, demanding repeatedly palliative treatment.

Abstract P1-14-11: nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69)

Background: We previously reported that nab-paclitaxel (nP) increases the pathological complete response (pCR, ypT0 ypN0) rate when it replaces solvent-based paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for patients with early breast cancer (Untch et al. SABCS 2014). Here, we report efficacy and safety of patients being treated either with 150 mg/m2 nab-paclitaxel (nP150) before an amendment or with 125 mg/m2 nab-paclitaxel (nP125) thereafter in comparison to solvent-formulated paclitaxel at 80 mg/m2 (P80). Methods: In the GeparSepto study (NCT01583426), 1207 patients were randomized to either nP150 or P80 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w. The primary objective of the study was to compare the pCR rate (pCR, ypT0 ypN0). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Patients with HER2+ tumors received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly to all chemotherapy cycles. After a safety analysis showed a higher rate of dose reductions and treatment discontinuations with nP150 compared to P80, weekly dose of nP was reduced to 125 mg/m2. Results: nP was given for the majority of cycles at a dose of 150 mg/m2 to 179 patients and at a dose of 125 mg/m2 to 426 patients. Treatment characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for HER2 status (HER2-positive: nP150 22%, nP125 37% and P80 33%) and Ki67 ( Conclusions: Risk-benefit ratio of nP125 was improved over nP150 with better drug adherence and RTDI, lower frequency of PNP but a higher pCR rate. It should therefore be considered as the preferred schedule when nP is used as neoadjuvant treatment for primary breast cancer. The trial was financially supported by Celgene and Roche. Citation Format: von Minckwitz G, Untch M, Jakisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Weibringhaus H, Kummel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S. nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69). [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 P1-14-11.