C. Jackisch

Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial

BACKGROUND The proliferation marker Ki67 has been suggested as a promising cancer biomarker. As Ki67 needs an exact quantification, this marker is a prototype of a new generation of tissue-based biomarkers. In this study, we have systematically evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort. PATIENTS AND METHODS We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial. We used the standardized cutoff-finder algorithm for three end points [response to neoadjuvant chemotherapy (pCR), disease-free (DFS) and overall-survival (OS)]. The analyses were stratified for hormone receptor (HR) and HER2 status by molecular subtype radar diagrams (MSRDs). RESULTS A wide range of Ki67 cut points between 3%-94% (for pCR), 6%-46% (for DFS) and 4%-58% (for OS) were significant. The three groups of Ki67 ≤ 15% versus 15.1%-35% versus >35% had pCR-rates of 4.2%, 12.8%, and 29.0% (P < 0.0005), this effect was also present in six of eight molecular subtypes. In MSRD, Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive, but not triple-negative tumors. CONCLUSIONS Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data-derived cut point optimization might not be possible. Ki67 could be used as a continuous marker; in addition, the scientific community could define standardized cut points for Ki67. Our analysis explains the variability observed for Ki67 cut points in previous studies; however, this should not be seen as weakness, but as strength of this marker. MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer. The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers.

Neoadjuvant bevacizumab and anthracycline–taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44)

BACKGROUND We evaluated the pathological complete response (pCR) rate after neoadjuvant epirubicin, (E) cyclophosphamide (C) and docetaxel containing chemotherapy with and without the addition of bevacizumab in patients with triple-negative breast cancer (TNBC). PATIENTS AND METHODS Patients with untreated cT1c-4d TNBC represented a stratified subset of the 1948 participants of the HER2-negative part of the GeparQuinto trial. Patients were randomized to receive four cycles EC (90/600 mg/m(2); q3w) followed by four cycles docetaxel (100 mg/m(2); q3w) each with or without bevacizumab (15 mg/kg; q3w) added to chemotherapy. RESULTS TNBC patients were randomized to chemotherapy without (n = 340) or with bevacizumab (n = 323). pCR (ypT0 ypN0, primary end point) rates were 27.9% without and 39.3% with bevacizumab (P = 0.003). According to other pCR definitions, the addition of bevacizumab increased the pCR rate from 30.9% to 41.8% (ypT0 ypN0/+; P = 0.004), 36.2% to 46.4% (ypT0/is ypN0/+; P = 0.009) and 32.9% to 43.3% (ypT0/is ypN0; P = 0.007). Bevacizumab treatment [OR 1.73, 95% confidence interval (CI) 1.23-2.42; P = 0.002], lower tumor stage (OR 2.38, 95% CI 1.24-4.54; P = 0.009) and grade 3 tumors (OR 1.68, 95% CI 1.14-2.48; P = 0.009) were confirmed as independent predictors of higher pCR in multivariate logistic regression analysis. CONCLUSIONS The addition of bevacizumab to chemotherapy in TNBC significantly increases pCR rates.

The Patient's Anastrozole Compliance to Therapy (PACT) Program: a randomized, in-practice study on the impact of a standardized information program on persistence and compliance to adjuvant endocrine therapy in postmenopausal women with early breast cancer

BACKGROUND Compliance and persistence are often overlooked in adjuvant breast cancer treatment. PATIENTS AND METHODS PACT was a prospective, multicenter, randomized, open, parallel-group study assessing whether educational materials (EMs) enhanced compliance with aromatase inhibitor (AI) therapy in postmenopausal women with early, hormone-receptor-positive (HR+) breast cancer. The primary end points were compliance (proportion taking ≥ 80% anastrozole) at 12 months and persistence (proportion reporting anastrozole intake during the study period). RESULTS Four thousand eight hundred and forty-four patients were randomly assigned 1:1 to receive standard therapy or standard therapy with EMs. There was no difference between arms in compliance (N = 2740; 88.5%/88.8%, respectively, P = 0.81) or persistence rates (N = 2740; 40.5%/43.0%, respectively, P = 0.18). Modified end point analyses found no differences in compliance between arms based on the classification of: (i) patients with missing documentation or follow-up visit <9 months as non-compliant (N = 4397, P = 0.15); (ii) patients with early (≤ 292 days) 12-month follow-up documentation excluded (N = 4091, P = 0.19); (iii) patients reaching ≥ 80% compliance during individual follow-up as compliant (N = 4397, P = 0.26). Modified persistence analyses found no difference between arms (N = 4397, P = 0.37). CONCLUSIONS Addition of EMs to standard therapy did not significantly affect compliance and persistence with adjuvant anastrozole. CLINICALTRIALS ID: NCT00555867.

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 S3-1: Lapatinib vs Trastuzumab in Combination with Neoadjuvant Anthracycline-Taxane-Based Chemotherapy: Primary Efficacy Endpoint Analysis of the GEPARQUINTO STUDY (GBG 44)

Background: The tyrosine-kinase inhibitor lapatinib (L) has shown to improve efficacy of cytotoxic and endocrine treatment in HER2-positive metastatic breast cancer (BC). Improved pathological complete response (pCR) rates were demonstrated by adding trastuzumab (T) to neoadjuvant chemotherapy. However, so far no head-to-head comparison of the two anti-HER2-agents is available. One primary aim of the GeparQuinto study was to improve the pCR rate by adding L instead of T to anthracycline-taxane-based neoadjuvant chemotherapy. We previously reported interim safety data of this study showing more diarrhea, skin changes, and hot flushes, but no cardiac events with L compared to T (von Minckwitz G et al, Ann Oncol 2010 in press). Patients and Methods: Patients (P) with untreated HER2-positive BC were eligible if they had cT3/4a-d; or estrogen (ER) and progesterone (PgR) receptor-negative; or ER/PgR-positive tumors with clinically N+ (for cT2) or pNSLN+ (for cT1) disease, and no increased cardiac risks. P were randomized to receive 4 cycles epirubicin/cyclophosphamide (EC) (90/600 mg/m2) q3w followed by 4 cycles docetaxel (D) (100mg/m2) given in combination with either T 6 (loading dose 8) mg/kg every 3 weeks or L 1000-1250 mg/d throughout all cycles. pCR was defined as no invasive or non-invasive tumor residuals in breast and nodes. We assumed a pCR rate of 26% with ECT-DT (based on GeparQuattro) and expected a pCR of 37% for ECL-DL (odds ratio 1.67). A two-sided Pearson9s Chi2 with α=0.05 and β=0.20 calculated a sample size of 613 P. Results: Between May ‘07 and June ‘10 597 P were randomized to ECT-DT (N=299) and ECL-DL (N=298). Median tumor size was 40/40 [T/L] mm (clinically) and 28/29 mm (sonographically); 4.7%/4.3% had T4a-c, 14.8%/14.2% T4d, 2.9%/1.8% bilateral, 17.0%/17.7% multifocal, and 9.0%/12.1% multicentric disease, 96.7%/97.9% had non-lobular, 45.6%/48.9% grade 3, 70.0%/67.7% node-positive, and 56.5%/56.0% ER and PgR-negative disease. Baseline characteristics were well balanced between the treatment arms. The last randomized P will have surgery early Dec910. Final results on histological response and surgical outcome will be reported. Conclusion: The GeparQuinto trial will provide for the first time randomized phase III efficacy data on the comparison of L and H in combination to chemotherapy for patients with early breast cancer. As pCR has been confirmed as being a surrogate marker for long-term outcome after T treatment, this result will give insight on the overall efficacy of L in patients with early breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-1.

COMPliance and Arthralgia in Clinical Therapy: the COMPACT trial, assessing the incidence of arthralgia, and compliance within the first year of adjuvant anastrozole therapy

BACKGROUND This prospective study evaluated the relationship between arthralgia and compliance during the first year of adjuvant anastrozole therapy in postmenopausal women with hormone receptor-positive early breast cancer. PATIENTS AND METHODS COMPliance and Arthralgia in Clinical Therapy (COMPACT) was an open-label, multicenter, noninterventional study conducted in Germany. Patients had started adjuvant anastrozole 3-6 months before the study start. The primary end points were arthralgia, compliance, and the relationship between compliance and arthralgia, assessed at specific time points. RESULTS Overall, 1916 patients received upfront anastrozole. Mean arthralgia scores were increased from baseline at each visit up to 9 months. Compliance with anastrozole therapy gradually decreased over time from baseline to 9 months (P<0.001). At 9 months, investigators estimated that >95% of patients were compliant versus patient reports of <70%. There was a significant association between arthralgia mean scores and noncompliance at 6 months (P<0.0001), 9 months (P<0.0001), and overall (P<0.0001). Over time, new events or impairment of existing arthralgias were reported in 14% (3 months), 11% (6 months), and 9% (9 months) of patients. CONCLUSION Arthralgia is important in the clinical management of women with early breast cancer and may contribute to noncompliance and clinical outcomes. CLINICALTRIALSGOV IDENTIFIER NCT00857012.

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

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

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.

S2-4: GAIN Study: A Phase III Trial To Compare ETC vs. EC-TX and Ibandronate vs. Observation in Patients with Node-Positive Primary Breast Cancer – 1st Interim Efficacy Analysis.

Background: We previously showed that intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) results in a superior DFS and OS compared to conventionally dosed EC-T in pts with primary breast cancer (PBC) and ≥4 involved lymph nodes (LN) (Mobus et al JCO 2010). In the GAIN study, the intense dose-dense strategy has been further investigated as well as the adjuvant application of ibandronate (I). We here report on the planned interim efficacy analysis after 50% (N>401) of the required events have occurred. Methods: A prospective, multi-center, controlled, non-blinded, randomized phase III trial investigating ETC (E: 150 mg/m 2 , T:225 mg/m 2 , C:2500–2000 mg/m 2 , i.v. day 1, q15 for 3 cycles each: A1); or EC→TX (E: 112.5 mg/m 2 + C: 600 mg/m 2 , i.v. day 1, q 15 for 4 cycles→T: 67.5 mg/m 2 i.v. day 1, q 8 for 10 weeks + X: 2000 mg/m 2 p. o. day 1–14, q 22 for 4 cycles: A2). Pts were further randomized in a 2:1 ratio to receive ibandronate: 50 mg/day p.o. for 2 years (B1) or observation (B2). Pts received a primary prophylaxis with either epoetin β or darbepoetin α and pegfilgrastim during ETC or EC. After recruitment of 1500 pts prophylactic ciprofloxacin was implemented and the dose of C was reduced to 2000 mg/m 2 . Eligibility : Females ≥18 and Primary objective:compare DFS A1 vs. A2 and B1 vs.B2. Secondary objectives: OS, safety, incidence of secondary primaries, and EFS in subgroups of hormone sensitivity and number of pos. LN between arms; assessment of compliance; determine prognostic factors. 3000 pts with 801 events were needed to show an increase of 5-year DFS from 75% to 79% for pts receiving EC→TX and 728 events to show an increase of 5-year DFS from 75% to 79.5% for pts receiving I, assuming a drop-out rate of 5%, α=0.05 (two-sided)and 1-β =80%. An interim analysis for both primary objectives was planned after 50% of the expected events occurred. Safety results have been reported previously (Mobus et al. SABCS 2009). Results: 3023 patients were randomized between 06/2004 and 08/2008.1512 received ETC and 1511 EC→TX. 29pts never started therapy, 14 in ETC, 15 in EC→TX. Median follow-up is 38.7 months. Median age was 50 years; pN1 (37.7%), pN2 (35.4%); pN3 (26.9%); 77.4% had ductal invasive carcinoma, 46.6% were grade 3; 76.7% had hormone receptor-positive tumors, 22% were HER2−positive. 405 events have occurred by 12.05.2011.380pts relapsed and 25pts. died w/o relapse. The interim futility boundary for chemotherapy was not crossed. For the ibandronate question the futility boundary was reached. There was no difference in DFS and OS between the patients with and without ibandronate (DFS log-rank p=0.593; HR 1.059; 95%CI 0.861−1.301; OS log-rank p=0.801 HR 0.961; 95% CI 0.705−1.31). Conclusion: The GAIN study demonstrated that adjuvant ibandronate does neither improve DFS nor OS in primary node positive breast cancer after treatment with dose-intensified chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-4.