C Denkert

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.

Abstract S1-06: Increased tumor-associated lymphocytes predict benefit from addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer in the GeparSixto trial (GBG 66)

Background: We have recently described a significantly increased pCR rate in triple-negative breast cancer with addition of carboplatin to a non-pegylated liposomal doxorubicin/taxane (MC) combination in the neoadjuvant Geparsixto study (von Minckwitz et al, ASCO, 2013). Here we report the results of prospective biomarker analyses performed in Geparsixto. Methods: Geparsixto investigates the effect of adding carboplatin to MC for the treatment of patients with HER2+ve and triple-negative (TN) primary BC. All HER2+ve patients received trastuzumab and lapatinib, all TN patients received bevacizumab. As part of the central pathology assessment, we prospectively evaluated tumor-associated lymphocytes (TILs) in 580 core biopsies. We used the parameters stromal lymphocytes (strLy) and lymphocyte-predominant breast cancer (LPBC, ≥60%TILs) as previously described (Denkert et al, JCO, 2010). In addition, Ki67 (n = 588) was measured by immunohistochemistry and p53 mutations in Exons 5-8 (n = 444) were evaluated by Sanger sequencing. Pathological complete remission (pCR) was defined as ypT0ypN0. Results: 24.7% of the 588 patients had a LPBC. These patients had an increased pCR rate of 60.3%, compared to 35.8% for the non-LPBC tumors (p Ki67>20% was associated with an increased pCR rate of 46.6%, compared to 27% in tumors with lower proliferation (p Conclusion: Our results show that the interaction with host immune response is relevant for response to chemotherapy, this effect is particularly strong with the addition of carboplatin. Tumor-associated lymphocytes as a continuous parameter as well as LPBC as a tumor subgroup are predictive for response to neoadjuvant chemotherapy. In particular with regard to the relevant toxicity of the MC+carboplatin combination, the integration of immunological biomarkers would be helpful to identify the patients with the highest benefit from the addition of carboplatin. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-06.

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.

Abstract S2-07: A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69

Background: Anthracycline/taxane based regimen are standard of care for neoadjuvant therapy in breast cancer. A reverse sequence of taxanes followed by anthracyclines was suggested to achieve higher pCR rates (H.Earl, Lancet Oncol 2014). Dual HER2 blockade was shown to be superior to trastuzumab alone increasing the pCR rate by 20%. Nab-paclitaxel (nP) is a solvent-free formulation of paclitaxel (P) encapsulated in albumin which might further improve the pCR rate in breast cancer patients receiving neoadjuvant treatment and cause lower toxicity. Methods: In the GeparSepto study (NCT01583426) patients were randomized to either nP (125 mg/m 2 ) q1w or P (80mg/m 2 ) q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E, epirubicin 90mg/m 2 ; C, cyclophosphamide 600 mg/m 2 ) q3w. The primary objective is to compare the pathological complete response rate (pCR, ypT0 ypN0). Further objectives are to compare the pCR rate in predefined subgroups, pCR by other definitions, clinical response rate, rate of breast conserving surgery and toxicity and compliance. Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. HER2+ patients received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly. HER2, estrogen receptor, progesterone receptor, Ki67 and SPARC status were centrally assessed prior to randomization for stratification. To increase the pCR rate from 33% with P to 41% with nP, corresponding to an odds ratio of 1.41 with an alpha of 0.05 and a power of 80%, 1200 patients would be needed. A window-of opportunity study was integrated to investigate response to anti-HER2 treatment without chemotherapy, HER2+ patients were randomized to receive 6 weeks of either trastuzumab, pertuzumab or the combination with biomaterial collection at the start and the end of the window. Results: A total of 1204/1229 (window study n=71) recruited patients (7/2012 - 12/2013) from 69 German centers were evaluable, 606 receiving nP. Baseline characteristics are well balanced; median age was 49/50 years (P/nP), 33/33% of the patients presented with HER2+ tumors, 23/23% triple negative breast cancer TNBC (ER and PR 20% 69/69%; SPARC positive 15.7/16%. 265 patients reported SAEs (119 P/146 nP) and 4 died on study (1 P: cardiac decompensation; 3 nP: accident at home, multiorgan failure, sepsis during EC). The pCR rate (ypT0 ypN0) is 29% with P and 38% with nP, OR 1.5; p Conclusions: GeparSepto showed that the pCR rate is significantly higher with nab-paclitaxel compared to solvent-based paclitaxel given weekly before anthracycline based chemotherapy. Subgroupanalyses and 2ndary endpoints will be presented at the meeting. The trial was financially supported by Roche and Celgene. The window-substudy was funded within the EU-FP7 project RESPONSIFY No 278659. Citation Format: Michael Untch, Christian Jackisch, Andreas Schneeweis, Bettina Conrad, Bahriye Aktas, Carsten Denkert, Holger Eidtmann, Hermann Wiebringhaus, Sherko Kummel, Jorn Hilfrich, Mathias Warm, Stefan Paepke, Marianne Just, Claus Hanusch, John Hackmann, Jens-Uwe Blohmer, Michael Clemens, Serban Dan Costa, Bernd Gerber, Valentina Nekljudova, Sibylle Loibl, Gunter von Minckwitz. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-07.

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 S4-06: PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer – Prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer (BC), PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2+ve BC. We therefore investigated the frequency and prognostic associations of PIK3CA mutations in HER2+ve and triple negative (TN) primary BC by treated with neoadjuvant therapy. Methods: We prospectively evaluated PIK3CA mutations in the 512 participants of the neoadjuvant Geparsixto (G6) study (von Minckwitz et al. ASCO 2013) and validated in 225 participants of the GeparQuinto (G5) study (Untch et al. 2012). The G6 study investigates the effect of adding carboplatin to a non-pegylated liposomal doxorubicin/taxane combination for the treatment of patients with HER2+ve and TN primary BC. All HER2+ve patients received trastuzumab and lapatinib, the TN patients received bevacizumab. The G5 study showed that trastuzumab added to EC-Doc results in a significantly higher pCR rate than lapatinib. HER2, hormone receptors (HR), and Ki67 were centrally assessed in both studies. PIK3CA was genotyped in tumor material from formalin-fixed, paraffin embedded core biopsies taken before therapy with a tumor cell content of ≥20% using classical Sanger sequencing of exon 9 and 20. Results: In the G6 study, 595 patients with HER2+ve or TN primary BC have been randomized from 09/2011 to 11/2012. Median age was 47 years (range 21-78); most tumors were cT2 (65%); cN0 (57%); ductal invasive (93%), grade 3 (65%); within the HER2+ve group 62% were HR-positive. Currently, PIK3CA genotype is available from 512 randomized patients - 240 with HER2+ve and 272 with TN disease. Overall, 13.1% were found to have at least one mutation, in HER2+ve: 19.2% and TNBC: 7.7%. PIK3CA mutations were numerically more frequent in the HER2+ve/HR+ve compared to the HER2+ve/HR-ve group: 21.5% vs 15.4% respectively (p = 0.245. Overall, pCR rate was significantly lower in the PIK3CA mutant compared to wt group (22.7% vs. 43.6%; p = 0.001).This effect was only significant within the HER2+ve group (17.8% vs. 36.8%; p = 0.015) compared to TNBC (33.3% vs. 49%; p = 0.168). Within the HER2+ve/HR+ subgroup the PIK3CA mutant pts had a pCR rate of only 6.5% compared to 30.8% in the wt group (p = 0.005). In contrast there was no difference in pCR (42.9% vs. 46.1%) according to PIK3CA mutation status in the HER2+ve/HR-ve (p = 0.825) group. In the G5 study, 225 of 620 HER2+ve pts have biomaterial available for PIK3CA genotyping and central confirmation of HER2 and hormone-receptor status. The analyses are ongoing and the results for the trastuzumab and lapatinib treated cohorts will be presented at the meeting. Conclusion: Pts with PIK3CA mutant HER2+ve/HR+ve breast cancer are resistant to chemotherapy and dual anti-HER2 treatment. Other treatment options are needed to be tested in this group. The project has been funded within the EU-FP7 project RESPONSIFY No 278659. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S4-06.

Abstract S1-09: Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy - A metaanalysis of 3771 patients

Background: Tumor-infiltrating lymphocytes (TILs) have been shown to be predictive for response to neoadjuvant therapy, in particular in triple-negative and HER2 positive breast cancer, suggesting that subtypes of breast cancer are immunogenic. The role of TILs in luminal breast cancer as well as the impact on prognosis in the different subtypes is less clear. In this study we evaluated TILs in a total of 3771 breast carcinomas from 6 prospective neoadjuvant clinical trials and evaluated their relevance for pCR, DFS and OS in different molecular subtypes. Methods: A total of 3771 tumors from the clinical studies GeparDuo, GeparTrio, GeparQuattro, GeparQuinto, GeparSixto, GeparSepto were evaluated for stromal TILs by standardized methodology. Data on pCR were available for all tumors, DFS and OS was available for 2560 tumors. Logistic regressions, Cox regressions and Kaplan-Meier analyses were performed. In addition, a combined analysis of pCR, survival and TILs in different subtypes was performed. Results: In the complete cohort of 3771 tumors, increased TILs (>=60%) were observed in 19% of tumors, these tumors with >=60% TILs had a pCR rate of 44% (p =60%) were observed in 30% of TNBC (n=906), in 19% of HER2+ tumors (n=1379) and in 13% of HR+/HER2- tumors (n=1366). In all three subtypes, increased TILs were significantly associated with increased pCR rates (p =60%) were associated with worse survival in Kaplan-Meier analysis in luminal tumors (DFS: p=0.04, OS: p Conclusion: Our results suggest that tumor-infiltrating lymphocytes are a strong predictive marker for response to neoadjuvant chemotherapy in all molecular subtypes, and this predictive effect is translated into a survival benefit in HER2+ BC and TNBC. In contrast, a survival benefit is not observed in luminal BC, suggesting a different biology of the immunological infiltrate in this subtype. Citation Format: Denkert C, von Minckwitz G, Darb-Esfahani S, Ingold Heppner B, Klauschen F, Furlanetto J, Pfitzner B, Huober J, Schmitt W, Blohmer J-U, Kummel S, Engels K, Lederer B, Schneeweiss A, Hartmann A, Jakisch C, Untch M, Hanusch C, Weber K, Loibl S. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy - A metaanalysis of 3771 patients [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 S1-09.

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.

Imatinib – eine mögliche Therapieoption beim Zervixkarzinom: Ergebnisse einer präklinischen Phase-I-Studie

BACKGROUNDnIn the last few years, the therapy of cervical carcinoma has progressed substantially due to the use of simultaneous platinum- containing radiochemotherapy. However, there are no data which evaluate an individualized treatment adapted to tumor biology, in spite of the fact that patients show remarkably different responses to chemotherapy. Therefore this preclinical phase I study aims at finding therapeutic alternatives to the current cytostatic drugs to treat cervical carcinoma.nnnMATERIAL AND METHODSnIn a tumor chemosensitivity assay, 8 drugs were tested on freshly isolated tumor cells of 16 patients [carbo- and cisplatin, topotecan, paclitaxel as well as the 2 tyrosine kinase inhibitors imatinib (Glivec) and gefitinib (Iressa (R) ) and the 2 monoclonal antibodies cetuximab (Erbitux) and trastuzumab (Herceptin (R) )].nnnRESULTSnOverall the test was evaluable for 16 specimens (100%). Ten of 15 tumor samples (66.6%) were sensitive to imatinib. A sensitive therapeutic response could be demonstrated in all tested FIGO stages. An interindividual comparison could establish sensitivity to cetuximab in 12.5% of cases, to gefitinib in 6.25%, to trastuzumab in 6.6%, to cisplatin in 13.3%, to carboplatin in 7.6%, to paclitaxel in 93.8% and to topotecan in 25%.nnnCONCLUSIONnImatinib seems to be an efficacious therapeutic option for patients with cervical carcinoma, independently of tumor subtype.BACKGROUND: In the last few years, the therapy of cervical carcinoma has progressed substantially due to the use of simultaneous platinum- containing radiochemotherapy. However, there are no data which evaluate an individualized treatment adapted to tumor biology, in spite of the fact that patients show remarkably different responses to chemotherapy. Therefore this preclinical phase I study aims at finding therapeutic alternatives to the current cytostatic drugs to treat cervical carcinoma. MATERIAL AND METHODS: In a tumor chemosensitivity assay, 8 drugs were tested on freshly isolated tumor cells of 16 patients [carbo- and cisplatin, topotecan, paclitaxel as well as the 2 tyrosine kinase inhibitors imatinib (Glivec) and gefitinib (Iressa (R) ) and the 2 monoclonal antibodies cetuximab (Erbitux) and trastuzumab (Herceptin (R) )]. RESULTS: Overall the test was evaluable for 16 specimens (100%). Ten of 15 tumor samples (66.6%) were sensitive to imatinib. A sensitive therapeutic response could be demonstrated in all tested FIGO stages. An interindividual comparison could establish sensitivity to cetuximab in 12.5% of cases, to gefitinib in 6.25%, to trastuzumab in 6.6%, to cisplatin in 13.3%, to carboplatin in 7.6%, to paclitaxel in 93.8% and to topotecan in 25%. CONCLUSION: Imatinib seems to be an efficacious therapeutic option for patients with cervical carcinoma, independently of tumor subtype.

Abstract S4-5: Ki67 levels in pretherapeutic core biopsies as predictive and prognostic parameters in the neoadjuvant GeparTrio trial

Background: Ki67 has been suggested as a marker for definition of luminal A and luminal B tumors by the 2011 St. Gallen consensus panel. However, the cutoffs for Ki67 are still under debate. In particular, it is not clear if one single cutoff is useful for prognostic and predictive information in the different molecular subtypes. It is an advantage of the neoadjuvant approach that predictive and prognostic outcome measurements can be separated in the same cohort. In this study, we evaluated a large cohort of core biopsies from the neoadjuvant GeparTrio trial to investigate the impact of pretherapeutic Ki67 levels as a predictive marker for response to neoadjuvant chemotherapy as well as a prognostic marker for progression-free and overall survival. The analysis was stratified for hormone-receptor positive and negative tumors as well as HER2 status. Methods: A total of 1166 pretherapeutic core biopsies from the neoadjuvant Gepartrio trial were evaluated for Ki67 by immunohistochemistry, a total of 200 cells were counted in each sample. Ki67 cutoffs were evaluated using web-based software Cutoff Finder (http://molpath.charite.de/cutoff/). The details of the GeparTrio study design have been described before (von Minckwitz, JNCI 2008). We compared pCR rate as well as the overall and disease free survival in the complete cohort as well as subgroups of patients based on hormone receptor and HER2 expression. Results: Using Ki67 as a continuous parameter, a wide range of cutoffs between 10% and 80% for Ki67 were predictive for pCR. For DFS and OS, a wide range of cutoffs between 10% and 45% was significant. For further analysis, the three groups of Ki67 0–15% vs. Ki67 15.1%–35% vs. Ki67 >35 were defined and were compared for different outcome parameters. The pCR rates in these three groups of Ki67 expression were 4.2%, 12.9% and 29.0% (p Conclusion: Ki67 is a valid predictive and prognostic marker in breast cancer. This marker is significant over a wide range of different cutoffs, which explains the different results of Ki67 cutoffs in different previous studies. Therefore, the variability observed in different studies evaluating Ki67 might reflect A) the wide range of valid cutoffs B) the different clinical endpoints of the studies and C) the different contribution of the molecular subtypes in the study cohorts. Based on our results we suggest three subgroups for Ki67 (0–15% vs. 15.1–35 vs. >35%) as a reasonable approach for further standardization of this marker. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-5.