Von Minckwitz Research Articles

Abstract OT1-2-01: MINT I: Multi-institutional neo-adjuvant therapy, MammaPrint project I

Abstract Background: Women with locally advanced breast cancer (LABC) are often treated with neo-adjuvant chemotherapy to reduce the size of the tumor prior to surgery, to enable breast conserving surgery and to observe the clinical effect of therapy in real time. Studies have shown that the 25–27% of individuals who have a pathologic complete response (pCR) to neoadjuvant therapy have a survival advantage of 80% in 5 years, which is double the expected survival of the remaining patients without pCR. If patients who are likely to show a pCR could be identified prior to initiation of therapy, it would enable more informed treatment decisions – patients likely to respond would be served well by current neoadjuvant chemotherapy protocols, while those unlikely to respond may be better suited to innovative new strategies for drug discovery [von Minckwitz et al. JCO 2006]. Genomic assays, which are widely used to provide prognostic and predictive information in early breast cancer, have the potential to provide information on the likelihood of a patient with LABC responding to neo-adjuvant therapy [Glück et al. ASCO 2012]. Trial design: MINT I is a prospective study designed to test the ability of molecular profiling, as well as traditional pathologic and clinical prognostic factors, to predict response to neo-adjuvant chemotherapy in patients with LABC. MammaPrint risk profile, BluePrint molecular subtyping profile, TargetPrint estrogen receptor (ER), progesterone receptor (PR) and HER2 single gene readout, and TheraPrint Research Gene Panel will be analyzed on a fresh tumor specimen using the whole genome array. Patients will receive neo-adjuvant chemotherapy pre-specified in the protocol. Response will be measured centrally. pCR is defined as the absence of invasive carcinoma in both the breast and axilla at microscopic examination of the resection specimen, regardless of the presence of carcinoma in situ. Eligibility: The study will include women ≥18 years with histologically-proven invasive breast cancer T2 (≥3.5cm)-T4, N0M0 or T2-T4N1M0, adequate bone marrow reserves and normal renal and hepatic function who signed an IRB approved informed consent. Objectives: The objectives of the study are to: 1. Determine the predictive power of MammaPrint and BluePrint for sensitivity to neo-adjuvant chemotherapy as measured by pCR. 2. Compare TargetPrint ER, PR and HER2 with local and centralized IHC and/or CISH/FISH assessment. 3. Identify correlations between TheraPrint and response to neo-adjuvant chemotherapy. 4. Identify and/or validate predictive gene expression profiles of clinical response or resistance to neo-adjuvant chemotherapy. 5. Compare BluePrint with IHC-based subtype classification. Statistical methods: Standard statistical tests such as the Pearson Chi-square test will be used to characterize and evaluate the relationship between chemoresponsiveness and gene expression patterns. Accrual: A total of 226 eligible patients will be enrolled from multiple institutions. To date (June 06, 2013), 57 patients have been enrolled. Clinical trial registry number: NCT01501487. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-2-01.

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

Abstract 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.

Insight or Confusion: Survival After Response-Guided Neoadjuvant Chemotherapy in Breast Cancer

In current clinical practice, the use of neoadjuvant chemotherapy for the treatment of breast cancer is well established. Once reserved for the treatment of locally advanced inoperable tumors, the neoadjuvant treatment strategy has been increasingly employed in operable breast cancer with good reason. This strategy offers a number of advantages over adjuvant therapy, with in vivo assessment of tumor response ranking among the most important. The neoadjuvant strategy has shown great potential as a platform for drug development, and this has led the US Food and Drug Administration to recently strongly consider pathologic response to neoadjuvant therapy as an end point to support accelerated drug approval in high-risk early-stage breast cancer. 1 Historical results from a series of important neoadjuvant trials have shaped our current thinking. It has been clearly established that long-term outcomes are similar whether treatment is given preoperatively or postoperatively and that a pathologic complete response (pCR) at the time of surgery is associated with a favorable outcome in all patients who achieve it. 2-4 Failure to achieve a pCR is clearly associated with worse long-term outcomes in triple-negative and human epidermal growth factor receptor 2 (HER2) –positive breast cancer, though this negative prognostic association is not observed for the majority of hormone receptor–positive breast cancers. 5-7 Rates of pCR following neoadjuvant chemotherapy in hormone responsive breast cancer are uniformly low and because these patients arguably receive their most important therapy, endocrine therapy, after chemotherapy, the focus of current neoadjuvant chemotherapy trials has shifted away from this group of patients in large part. Instead, neoadjuvant endocrine therapy strategies have been increasingly investigated for these patients and the field has moved more generally toward strategies to omit chemotherapy in hormone receptor–positive patients unlikely to derive benefit based on results of multiplex gene expression assays. In the article that accompanies this editorial, von Minckwitz et al 8 report survival outcomes after response-guided neoadjuvant chemotherapy in the German Breast Group GeparTrio study. In the German Breast Group tradition, this phase III study represents an enormous effort that tests an interesting strategy of response-guided chemotherapy treatment. More than 2,000 patients with stage II/III breast cancer were treated with an initial two cycles of docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , and cyclophosphamide 500 mg/m 2 on day 1 every 21 days (TAC). Patients achieving clinical response were then randomly assigned to continuing the same therapy for four or six additional cycles and nonresponders were randomly assigned to continue the same therapy or sequence to an alternate chemotherapy combination of navelbine 25 mg/m 2 days 1 and 8 and capecitabine 1,000 mg/m 2 orally twice per day on days 1 through 14 of a 21-day cycle (NX) for four cycles. Patients were accrued from 2002 to 2005 and the patient characteristics and therapies are reflective of the times. Notably, HER2 status was unknown in approximately 20% and no patient received neoadjuvant or adjuvant trastuzumab. The primary end points of the study were to compare pCR rates in early responders and clinical response in early nonresponders. The previously reported primary results showed a nonstatistically significant difference in pCR among early responders treated with TAC 6 compared with TAC 8 (21% v 23.5%; P .27) 9 and similar clinical responses were observed among early nonresponders with TAC 6 compared with TAC NX (50.5% v 51.2%; P .008 for noninferiority). 10 In the article accompanying this editorial, von Minckwitz et al 8 report on the predefined secondary end points of disease-free survival (DFS) and overall survival (OS). At a median follow-up of 62 months, DFS was significantly longer in early responders treated with TAC 8 compared with TAC 6 (hazard ratio [HR], 0.78; 95% CI, 0.62 to 0.97; P .026) and in early nonresponders treated with TAC NX compared with TAC 6 (HR, 0.59; 95% CI, 0.49 to 0.82; P .001). No significant difference in OS was observed in these two groups, though there was a trend toward improved OS in responders receiving TAC 8 compared with TAC 6 (HR, 0.76; 95% CI, 0.57 to 1.01; P .060). As the sample size was calculated to provide adequate power for the primary end point, the study is underpowered for the end points of DFS and OS. In addition, though the groups were reasonably balanced in terms of baseline characteristics, there were fewer patients with grade 3 tumors in the nonresponder group treated with TAC NX (25%) compared with TAC 6 (36%), and this difference was statistically significant. The unexpected finding, namely, that response-guided therapy influences disease-free survival only in hormone receptor– positive and not hormone receptor–negative breast cancer, rests on a secondary exploratory subgroup analysis and therefore needs to

Liposome-encapsulated doxorubicin plus cyclophosphamide followed by trastuzumab plus docetaxel as neoadjuvant therapy for HER2-positive breast cancer (BC): A multicenter single-arm phase II study.

641 Background: Trastuzumab combined to sequential chemotherapy with taxanes and anthracyclines as primary treatment achieved high rates of pathologic complete response (pCR) in HER2 positive BC. Liposome-encapsulated doxorubicin (DLNP) shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab associated with chemotherapy for early or locally advanced HER2 positive BC. Methods: Primary objective of the study was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Preoperative treatment included DLNP (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Patients (pts) were scheduled to receive adjuvant trastuzumab (8 mg/mq loading dose, then 6 mg/mq iv) every 3 weeks for 12 cycles and radiation and hormonal therapy according to guidelines. Results: From December 2005 to September 2011, 43 pts were treated at 3 centers in Italy. 39 out of 43 pts were evaluable for the purpose of the study. Median age was 53 years (range: 31-78). The majority of pts had cT2 (63%), grade 3 (93%), N+ (77%) ER positive (56%) and MIB-1 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. The histological regression score (Von Minckwitz G, J Clin Oncol 2012) is shown in the Table. A significant correlation between MIB-1 ≥20% at baseline and pCR was observed (p=0.018). Pts with pCR had a time to response (29.4 weeks, 95% CI 28-31) lower than pts without pCR (32.9 weeks, 95% CI 27-39). No cardiac toxicity or discontinuation of trastuzumab was reported. After a median follow-up of 30 months only 2 pts relapsed, both with pCR. Conclusions: This study confirms the high activity of trastuzumab combined with chemotherapy based on anthracyclines and taxanes as primary treatment for HER2 positive BC. DLNP is an active and safe option to minimize cardiotoxicity. [Table: see text]

Abstract 4699: Responsecharacteristics and overall survival of 781 patients with triple-negativebreast cancer - a meta-analysis on 7 German neoadjuvant studies.

Abstract Background: A specific chemotherapy for patients with early triple-negative breast cancer (TNBC, <10% expression of oestrogen- and progesterone receptor (ER, PR) as well as normal HER2 expression) has not been proven so far. Patients and methods: We analysed baseline and treatment characteristics of 4592 patients who received anthracycline/taxane+/-trastuzumab-containing therapy within one of 7 German prospective neoadjuvant studies during the years 1999 to 2008 and had information on hormone- and HER2-receptor status available for their prognostic and predictive impact on pathologic complete remission (pCR; ypT0 ypN0) and overall survival (OS). Results: 781 patients had TNBC and 3188 patients had non-TNBC. Compared to non-TNBC patients, TNBC patients had a significantly higher pCR rate (29.7% versus 9.9%, p<.0001); but showed a significantly lower OS-rate (5 yr OS for TNBC 75%, for non-TNBC 88%; p<.0001). In case a pCR was achieved, TNBC patients showed a trend towards better OS compared to non-TNBC patients (5 yr OS for TNBC 97%, for non-TNBC 93%; p=.192). OS of TNBC and non-TNBC patients did not differ regarding duration of therapy (≤12 versus >12 weeks), type of regimen (combination versus sequential), dosing (conventional versus dose dense), dose of anthracyclines or taxanes (high versus low) or substance (docetaxel versus paclitaxel) in baseline factor adjusted multivariate analyses; despite univariate analyses suggested a better outcome for TNBC patients if treated by combination chemotherapy (p=.018) or higher anthracycline dose (p=.079). However, early partial or complete clinical response to the first 2-4 cycles of neoadjuvant therapy (74.0% in TNBC versus 65.7% in non-TNBC) correlated strongly with OS for TNBC patients (p=.004), but only marginally for non-TNBC patients (p=.055). Conclusion: Patients with TNBC achieving a pCR after neoadjuvant therapy have a highly favourable prognosis at least as good as patients with non-TNBC and pCR. Different therapeutic approaches don't show an impact on OS in TNBC. However, pCR and interestingly, early clinical response to neoadjuvant treatment, correlates with favourable OS in patients with TNBC. Citation Format: Gunter von Minckwitz, Claudia Mamouhdian-Dekordi, Sibylle Loibl, Jens-Uwe Blohmer, Serban Dan Costa, Carsten Denkert, Holger Eidtmann, Bernd Gerber, Claus Hanusch, Joern Hilfrich, Jens Huober, Andreas Schneeweiss, Stefan Paepke, Keyur Mehta, Michael Untch, Christian Jackisch. Responsecharacteristics and overall survival of 781 patients with triple-negativebreast cancer - a meta-analysis on 7 German neoadjuvant studies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4699. doi:10.1158/1538-7445.AM2013-4699

Abstract 1220: PIK3CA mutations in primary HER2-positive and triple negative breast cancer.

Abstract Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer. PIK3CA mutations are the most frequent ones in breast cancer. Mutations were most frequently found in exons 9 and 20. Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2+ve breast cancer. We therefore investigate PIK3CA mutations in HER2+ve and triple negative (TN) primary breast cancer (BC) and correlate the mutations with pathological complete response (pCR) after neoadjuvant therapy. Methods: We prospectively evaluated PIK3CA mutations in the 600 participants of the neoadjuvant Geparsixto study (NCT01426880). The study investigates the effect of adding carboplatin to a liposomal doxorubicin/taxane combination for the treatment of patients with HER2+ve and TN primary BC. HER2+ve patients received concomitantly trastuzumab and lapatinib, the TN patients bevacizumab. HER2, hormone receptors (HR), and Ki67 were centrally confirmed. PIK3CA genotyped in tumor material from formalin fixed, paraffin embedded core biopsies before therapy using classical Sanger sequencing of exon 9 and 20. Results: From September 2011 to November 2012, 600 patients with centrally confirmed HER2+ve or TN primary BC have been included in the Geparsixto study. Median age was 46 years (range 21-78); most tumors were cT2 (66%); cN0 (60%); ductal invasive (92%), grade 3 (65%); within the HER2+ve group 62% were HR positive. So far, in 344 randomized patients PIK3CA mutations have been evaluated, 155 with HER2+ve and 189 with TN disease. Overall at least one mutation could be detected in 17.9%; in 19.4% of the HER2+ve and 6.3% of the TN BC. An exon 9 mutation could be detected in 7.8% of the HER2+ve and 3.2 of the TNBC cases and an exon 20 mutation in 12.6% of the HER2+ve and 4.2 of the TN cases. A mutation in both exons was detectable in one case only. PIK3CA mutations were more frequent in the HER2+ve/HR+ve group 22.9% vs 13.6% in the HER2+ve/HR-ve group. Conclusion: PIK3CA mutations are more frequent in HER2+ve than in TN BC which is in line with previous reports. Results on all 600 patients and correlation with pCR in the two subgroups will be presented at the meeting. The project has been funded within the EU-FP7 project RESPONSIFY No 278659. Citation Format: Sibylle Loibl, Carsten Denkert, Sherene Loi, Fabrice Andre, Annika Lehmann, Andreas Schneeweiss, Jens Uwe Blohmer, Christian Jackisch, Stephan Gade, Peter Fasching, Christian Schem, Christos Sotiriou, Michael Untch, Gunter von Minckwitz. PIK3CA mutations in primary HER2-positive and triple negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1220. doi:10.1158/1538-7445.AM2013-1220

Transdermal Oestradiol in the Management of Castration-resistant and Corticosteroid-resistant Prostate Cancer — a Dose Escalation Study

s / Clinical Oncology 25 (2013) e67ee74 e72 [1]. Prophylactic use of granulopoiesis-stimulating factors, such as granulocyte-colony-stimulating factor (G-CSF), is being increasingly used to prevent chemotherapy-induced neutropaenia [2e4]. To compare the rate of febrile neutropaenia before and after implementation of G-CSF prophylaxis in patients receiving chemotherapy for testicular cancer. To determine the impact of these events on unscheduled care. Materials andmethods: Over an 18month period, we prospectively audited the incidence of febrile neutropaenia before (n 1⁄4 12) and after (n 1⁄4 8) implementation of prophylactic pegylated G-CSF (6mg SC 24 h post-chemotherapy) in patients receiving comparable chemotherapy regimens. Identification of febrile neutropaenic episodes and resultant impact on treatment recorded. There were no significant differences in chemotherapy regimens or other supportive care apart from the use of G-CSF. Results: The rate of neutropaenic sepsis was significantly different between the pre-GCSF and post-GCSF group (42% versus 0%, P 1⁄4 0.05). In the pre-GCSF group, 4 patients developing febrile neutropaenia went on to have G-CSF with subsequent cycles. Those developing febrile neutropaenia in the preGCSF group had a cumulative 31 days of unscheduled inpatient stay. This included one patient admitted to intensive care. There were no unscheduled inpatient stays in the post-GCSF group. Conclusion: Use of prophylactic G-CSF following chemotherapy for testicular cancer significantly reduces the incidence of febrile neutropaenia and subsequent inpatient stays.

Abstract P1-14-01: Adding capecitabine and trastuzumab to neoadjuvant breast cancer chemotherapy - first survival analysis of the GBG/AGO intergroup-study GeparQuattro.

Abstract Background: Previous results of the GeparQuattro study demonstrated that adding capecitabine either simultaneously or sequentially to EC-Docetaxel (D) neoadjuvant chemotherapy could not increase pathological complete response rates (pCR) (von Minckwitz G, JCO 2010). However, patients with HER2-positive disease treated simultaneously with trastuzumab showed a significant higher pCR rate than patients with HER2-negative disease treated with chemotherapy alone (Untch M, JCO 2010). We here report survival after a median follow up of 58 months including 279 relapses and 191 deaths. Patients and methods: Patients with either large operable (cT3) and locally advanced (cT4) tumors, or hormone-receptor (HR)-negative receptor status, or HR-positive tumors but clinically node-positive disease were recruited to receive 4 cycles of EC (90mg/m2/600mg/m2) and randomized to either 4 cycles of D (100mg/m2) or 4 cycles of DX (75mg/m2/1800mg/m2) or 4 cycles of D (75mg/m2) followed by 4 cycles of X (1800mg/m2) (D→X). Patients with HER-2 positive tumors received 1 year of trastuzumab, the first part concurrent to all chemotherapy cycles. All patients with HR+ tumors received endocrine therapy according to current standard. The intent-to-treat survival analysis included 1421 patients for the chemotherapy question and 1495 patients for the trastuzumab question. Analyses were adjusted by age, stage, size, nodal status, histologic type, grade, hormone-receptor (HR) and HER2-status at baseline (if applicable). Results: No difference in DFS and OS was seen for patients receiving D, DX or D-X overall (hazard ratio 0.978, p = 0.984 and hazard ratio 0.986, p = 0.684, respectively) as well as by phenotype defined according to St. Gallen (all P>0.354). Patients with HER2-positive disease treated additionally with trastuzumab showed significantly better OS (p = 0.015) compared to patients with HER2-negative disease treated with chemotherapy alone. DFS was significantly better for trastuzumab-treated patients with HR-negative tumors (p = 0.046), but not with HR-positive tumors (p = 0.790). OS after first relapse was significantly better in trastuzumab-retreated patients with HER2-positive tumors (p = 0.032) compared to relapsed patients with HER2-negative tumors. Patients with an early response after 4 cycles, with a clinical response at surgery and with a pCR showed a significantly better DFS and OS compared to patients without pCR (p = 0.022, P < 0.0001, P < 0.0001). This benefit was most prominent in patients with triple-negative tumors. Conclusions: Survival analysis of the GeparQuattro study confirmed the results of the primary endpoint analysis on pCR. Capecitabine could not improve outcome when added to anthracycline-taxane-based chemotherapy. As suggested by a recent integrated multi-level meta-analysis (von Minckwitz, BCRT 2011) effect of capecitabine could not be properly assessed in this study as planned docetaxel doses in arms DX and D®X were lower than in arm D. Survival of HER-2 positive patients surmounts that of HER2-negative patients if trastuzumab is used in the neoadjuvant as well as in the metastatic setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-01.

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

Abstract 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 < 0.0001). However, this difference was confined to the TNBC subgroup (45% vs. 31%; OR 1.85; 95%CI [1.33–2.56]; p < 0.001). Only in the triple negative cohort age had independent predictive factors for achieving a. pCR. Compared to patients >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 < 0.0001; age HR: 1.06 [95%CI 0.74–1.51]; p = 0.77); within the Luminal A group age but not pCR had independent prognostic information for DFS (age: HR 2.5 [95% CI 1.6–3.9] p < 0.001; pCR: HR 0.72 [95%CI 0.37–1.41] p = 0.34). In the Luminal A group the worst DFS was seen in the group <=35years/no-pCR and the best DFS in the <=35 years with pCR (log rank p = 0.27; HR 0.05 wide CI due to small sample size; p = 0.5). 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 P3-05-02: Pathological assessment of discordant cases for molecular (BluePrint and MammaPrint) versus clinical subtypes for breast cancer among 621 patients from the EORTC 10041/BIG 3–04 (MINDACT) trial

Abstract Background: Biology has become the main driver of breast cancer therapy. Intrinsic biological subtypes by gene expression profiling have been identified. Pathology can be used to define surrogates of these subtypes but these are not always concordant, which may lead to different treatment plans. We investigated the concordance between BluePrint and MammaPrint (microarray-based) breast cancer subtypes and pathological surrogates (based on ER, PR, HER2 & Ki67). Methods: Using available data (centrally assessed pathology and genomics) from the MINDACT pilot phase [Rutgers et al. EJC 2011] 621 tumors were analyzed. Patients were classified according to 4-category based pathology (ER, PR, HER2 and Ki67); additionally, classification was performed adhering to the recent St. Gallen recommendations [Goldhirsch et al. 2011], which recognizes an additional category (Luminal B HER2+). Based on BluePrint and MammaPrint 4 subtypes are formed: Luminal A (Luminal-type/MammaPrint Low Risk); Luminal B (Luminal-type/MammaPrint High Risk); HER2-type; and Basal-type. This study is an analysis of discordant patient groups (i.e. clinical HER2+/BluePrint Luminal-type; clinical Hormone Receptor (HR)-positive/BluePrint Basal-type) providing comparison of centrally assessed tumor heterogeneity as well as comparison of quantified ER, PR and HER2 results. Results: Ki67 is often used as biomarker to distinguish Luminal A from Luminal B subgroups. The concordance between MammaPrint and centrally assessed Ki67 in Luminal-type patients is 71%, with a κ score of 0.35 (95% CI 0.26–0.45) indicating that Ki67 and MammaPrint cannot reliably substitute for each other. There is a relatively large group of clinical HER2+ cases that are BluePrint Luminal-type (29 out of 76; 38%) indicating that tumor expression of the Luminal profile is dominant compared with expression of the HER2 profile. These patients have high IHC ER results and fall into the group that St Gallen separately defines as Luminal B HER2-type. These patients may have lower response to trastuzumab [von Minckwitz et al. JCO 2012]. 12 out of 76 BluePrint Basal-type patients are clinical HR+. These patients have low centrally assessed IHC ER and PR expression (≥1% and <10%). Conclusions: Marked differences are observed between BluePrint and MammaPrint (microarray based) breast cancer subtypes and centrally re-assessed pathological surrogates (based on ER, PR, HER2 & Ki67). The greatest discordance is seen in the sub-stratification of Luminal patients, and in the HR+/HER2+ patients. The observed subtype discrepancies may have an important impact on treatment decision making. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-02.

Abstract P3-06-11: Response and long-term outcomes after neo-adjuvant chemotherapy: Pooled dataset of patients stratified by molecular subtyping using MammaPrint and BluePrint

Abstract Background: Classification into molecular subtypes may increasingly be important for the selection of therapy for patients with early-stage breast cancer. Previous analyses had shown that breast cancer subtypes have distinct clinical outcome [Sorlie et al. PNAS 2001; Esserman et al. BCRT 2011]. In our study, we analyzed the response to neo-adjuvant chemotherapy and long-term outcomes using the 70-gene profile (MammaPrint) together with an 80-gene molecular subtyping profile (BluePrint). Methods: This analysis was performed on data from 421 patients: 141 patients from the I-SPY I trial; 230 patients from the biomarker discovery program at MD Anderson (131 and 99 respectively; Hess et al. JCO 2006; Iwamoto et al. BCRT 2011]; and 50 patients from the City of Hope [Somlo et al. ASCO 2010]. All patients were treated in the neo-adjuvant setting with chemotherapy. MammaPrint and BluePrint outcomes were determined from either 44K Agilent arrays run at Agendia or available through the I-SPY I data portal, or from Affymetrix U133A arrays. The combination of MammaPrint and BluePrint resulted in four distinct molecular groups: Luminal A (MammaPrint Low Risk/Luminal-type), Luminal B (MammaPrint High Risk/ Luminal-type), Basal-type and HER2-type. Results: The overall pCR of this patient cohort was 22% but differed substantially among the defined BluePrint molecular subgroups. pCR was observed in 3% of the Luminal A and 12% of Luminal B, in 38% of the HER2-type and in 42% of the Basal-type samples. 42% of patients with clinical HER2-positive phenotype are classified as Luminal-type by BluePrint: eight patients as Luminal A and 34 patients as Luminal B. 5-year distant metastases-free survival (DMFS) of patients with HER2-type by BluePrint who achieve pCR is 87%, compared with 78% for clinical HER2+ patients with pCR. These data are in line with a recent retrospective analysis of a large cohort of patients, which showed that pCR rate is not a suitable surrogate for clinical HER2+/Hormone Receptor-positive patients and is not associated with outcome [von Minckwitz et al. JCO 2012]. BluePrint classifies more patients as Basal-type (n = 120) with higher pCR rate (42%), compared with clinical subtyping (triple negative, n=93) with a pCR rate of 31%. Despite including eight clinical HER2+ and 11 triple-negative patients, those with BluePrint Luminal A subtype (n = 88) have excellent 5-year DMFS of 94% and appear to have no benefit from chemotherapy (low pCR rate). Conclusions: Molecular subtyping using BluePrint with MammaPrint can help to improve outcomes of patients in the neo-adjuvant setting over clinical subtyping. We observed differences in pCR and DMFS following neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint; for example, patients with Luminal A breast cancer (assessed with MammaPrint and BluePrint) have a good baseline prognosis with excellent survival and may not benefit from chemotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-11.

Abstract P3-06-05: Expression of SPARC in human breast cancer and its predictive value in the GeparTrio neoadjuvant trial.

Abstract Background: Secreted protein acidic and rich in cysteine (SPARC) is an albumin-binding protein and associated with poor prognosis in multiple cancers. The aim of this analysis was to determine the frequency of SPARC expression among different molecular breast cancer subtypes and to evaluate its predictive value for therapy response after neoadjuvant anthracycline/taxane based chemotherapy (CTX) in participants of the GeparTrio trial. Methods: We evaluated tumoral SPARC expression by immunohistochemistry on tissue microarrays (TMAs) constructed from formalin-fixed paraffin-embedded (FFPE) pre-treatment core biopsies from 667 patients (pts) of the GeparTrio trial. The details of the GeparTrio study design are described elsewhere (von Minckwitz, JNCI 2008). Cutoffs for SPARC expression were determined using the web-based software Cutoff Finder (http://molpath.charite.de/cutoff/). Results: SPARC protein expression was measurable by IHC on the TMAs and 176 (26.4 %) of 667 tumors were SPARC positive. SPARC expression was increased in pts with triple-negative breast cancer (TNBC) compared to hormone receptor or HER2 positive subtypes (p = 0.039). SPARC positivity was associated with an increased pCR rate in the overall population (p < 0.001). SPARC negative tumors had a pCR rate of 15%, which increased to 27% in SPARC positive tumors. Similarly, in TNBC the pCR rate increased from 26% in SPARC negative tumors to 47% in SPARC positive tumors (p = 0.032). In multivariate logistic regression analysis adjusted for standard clinicopathological factors, SPARC was independently predictive in the overall population (p = 0.010) as well as the subgroups of pts with TNBC (p = 0.036). Conclusions: SPARC is expressed in all biological breast cancer subtypes with TNBC revealing the highest expression rate. Our data suggest that SPARC expression may provide predictive information for response to neoadjuvant CTX. As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of nab-Paclitaxel, prospective analysis of SPARC expression is planned in the GeparSepto trial. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-05.

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

Abstract 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 < 0.0005). For DFS and OS, the groups were significantly linked to prognosis in univariate and multivariate analysis. A detailed subgroup analysis was performed showing that Ki67 was significantly predictive for pCR in all molecular subgroups. However, in subgroup survival analysis, Ki67 was prognostic in luminal, but not in triple-negative tumors. 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.

Abstract OT3-4-02: MINT I: Multi-Institutional Neo-adjuvant Therapy, MammaPrint Project I

Abstract Background: Women with locally advanced breast cancer (LABC) are often treated with neo-adjuvant chemotherapy to reduce the size of the tumor prior to surgery, to enable breast conserving surgery and to observe the clinical effect of therapy in real time. Studies have shown that the 25–27% of individuals who have a pathologic complete response (pCR) to neoadjuvant therapy have a survival advantage of 80% in 5 years, which is double the expected survival of the remaining patients without pCR. If patients who are likely to show a pCR could be identified prior to initiation of therapy, it would enable more informed treatment decisions – patients likely to respond would be served well by current neoadjuvant chemotherapy protocols, while those unlikely to respond may be better suited to innovative new strategies for drug discovery [von Minckwitz et al. JCO 2006]. Genomics assays, which are widely used to provide prognostic and predictive information in early breast cancer, have the potential to provide information on the likelihood of a patient with LABC responding to neo-adjuvant therapy [Glück et al. ASCO 2012]. Trial design: MINT I is a prospective study designed to test the ability of molecular profiling, as well as traditional pathologic and clinical prognostic factors, to predict responsiveness to neo-adjuvant chemotherapy in patients with LABC. MammaPrint risk profile, BluePrint molecular subtyping profile, TargetPrint estrogen receptor (ER), progesterone receptor (PR) and HER2 single gene readout, and the 56-gene TheraPrint Research Gene Panel will be analyzed on a fresh tumor specimen using the whole genome array. Patients will receive neo-adjuvant chemotherapy pre-specified in the protocol. Response will be measured centrally. pCR is defined as the absence of invasive carcinoma in both the breast and axilla at microscopic examination of the resection specimen, regardless of the presence of carcinoma in situ. Eligibility: The study will include women ≥18 years with histologically-proven invasive breast cancer T2 (≥3.5cm)-T4, N0M0 or T2-T4N1M0, adequate bone marrow reserves and normal renal and hepatic function who signed an IRB approved informed consent. Objectives: The objectives of the study are to: 1. Determine the predictive power of MammaPrint and BluePrint for sensitivity to neo-adjuvant chemotherapy as measured by pCR.2. Compare TargetPrint ER, PR and HER2 with local and centralized IHC and/or CISH/FISH assessment.3. Identify correlations between TheraPrint and response to neo-adjuvant chemotherapy.4. Identify and/or validate predictive gene expression profiles of clinical response or resistance to neo-adjuvant chemotherapy.5. Compare BluePrint with IHC-based subtype classification. Statistical methods: Standard statistical tests such as the Pearson Chi-square test will be used to characterize and evaluate the relationship between chemoresponsiveness and gene expression patterns. Accrual: A total of 226 eligible patients will be enrolled from multiple institutions. To date (June 06, 2012), 31 patients have been enrolled. Clinical trial registry number: NCT01501487. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-4-02.

Recognition and Handling of Discordant Negative Human Epidermal Growth Factor Receptor 2 Classification by Oncotype DX in Patients With Breast Cancer

REFERENCES 1. Blumenfeld Z: Gonadotropin-releasing hormone agonist for preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 30:3310, 2012 2. Tomao F, Benedetti Panici P, Tomao S: Gonadotropin-releasing hormone agonists for the preservation of ovarian function during chemotherapy. J Clin Oncol 30:3310, 2012 3. Munster PN, Moore AP, Ismail-Khan R, et al: Randomized trial using gonadotropinreleasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 30:533-538, 2012 4. Badawy A, Elnashar A, El-Ashry M, et al: Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: Prospective randomized study. Fertil Steril 91:694-697, 2009 5. Del Mastro L, Boni L, Michelotti A, et al: Effect of the gonadotropinreleasing hormone analogue triptorelin on the occurrence of chemotherapyinduced early menopause in premenopausal women with breast cancer: A randomized trial. JAMA 306:269-276, 2011 6. Gerber B, von Minckwitz G, Stehle H, et al: Effect of luteinizing hormone– releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: The GBG 37 ZORO study. J Clin Oncol 29:2334-2341, 2011 7. Leonard RC, Adamson D, Anderson R, et al: The OPTION trial of adjuvant ovarian protection by goserelin in adjuvant chemotherapy for early breast cancer. J Clin Oncol 28:89s, 2010 (abstr 590) 8. Sukumvanich P, Case LD, Van Zee K, et al: Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: A prospective study. Cancer 116:3102-3111, 2010 9. Fornier MN, Modi S, Panageas KS, et al: Incidence of chemotherapyinduced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer 104:1575-1579, 2005

Correlation between in vitro chemotherapy sensitivity and PARP-1 expression in patients with breast cancer.

10627 Background: Based on its potential use as a therapeutic target through PARP inhibitors expression of Poly-A-Ribose-Polymerase-1 (PARP-1) has come into scientific focus. Furthermore, it could be demonstrated that cytoplasmic PARP-1 expression varies depending on molecular breast cancer subtypes and that it correlates with an increased response to neoadjuvant taxane-anthrazykline containing chemotherapy (von Minckwitz et al., J Clin Oncol 2011). In-vitro-chemotherapy sensitivity and resistance assays (CSRAs) are a means to directly measure chemotherapy sensitivity in a given tumor uninfluenced by host factors. Methods: We conducted a systematic immunohistochemical tissue-microarray (TMA)-based analysis of 550 samples of invasive breast cancers to evaluate the expression of a set of molecular markers including estrogen receptor (ER), progesterone receptor (PR) and HER2 as well as PARP-1. Triple negative breast cancers (TNBC) were identified through lack of (over-)expression of ER, PR and HER2. All carcinomas were analyzed in an in vitro CSRA protocol for epirubicin/docetaxel (ED) and epirubicin/cyclophosphamide (EC). In-vitro-chemotherapy sensitivity was analyzed using an adenosine triphosphate (ATP) bioluminescence assay. Results: Moderate/high expression of PARP-1 was found in 48 and 33% of cases with TNBC and non-TNBC, respectively (p=0.015). No correlation between TNBC phenotype and cytoplasmic expression was observed. However, increased expression of both cytoplasmic and nuclear PARP-1 was correlated with an increased in-vitro sensitivity against ED (p=0.012 and 0.025, respectively) but not EC (p=0.27 and 0.62, respectively). Conclusions: Our results support previous observations demonstrating a significant correlation between expression of PARP-1 and an increased sensitivity against taxane-anthracycline chemotherapy independent of tumor phenotype.

Defining the Benefits of Neoadjuvant Chemotherapy for Breast Cancer

Preoperative or neoadjuvant chemotherapy is an option in patients with early-stage breast cancer. Neoadjuvant treatment has been compared with standard, postoperative adjuvant chemotherapy with the dual goals of improving survival and facilitating local therapies. Unfortunately, neoadjuvant chemotherapy does not seem to improve overall survival, as demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 trial, among others. Neoadjuvant chemotherapy may convert a previously unresectable, locally advanced breast cancer to an operable tumor, and in primarily operable tumors, downstaging results in a small increase (7% to 12%) in breast conservation rates. However, many patients experience insufficient response or are not candidates for breast preservation, irrespective of response, because of either skin or chest wall involvement or multicentric or multifocal disease. Furthermore, an estimated 10% of American women choose mastectomy as a personal preference despite their surgeons’ recommendation of breast-conserving therapy. Aside from the potential clinical benefits that are achieved by downstaging, neoadjuvant therapy allows direct and early observation of the response to treatment, which in theory could lead to modifications of the treatment plan in the event of poor response. However, clinical and radiographic monitoring during neoadjuvant chemotherapy to predict pathologic complete response (pCR) is notoriously inaccurate. Furthermore, although it is clear that those patients with a poor initial response have a worse prognosis, modification of chemotherapy after observed poor response has not resulted in clinically meaningful improvements in outcome. On the basis of the limited clinical advantages of neoadjuvant chemotherapy, postoperative adjuvant systemic therapy is considered the standard of care. The preoperative setting could provide an opportunity to study the impact of systemic therapies on breast cancer biology. As a research tool, neoadjuvant chemotherapy is useful because of the availability of tumor response as an end point and the availability of tissue for biopsy and biomarker development. To facilitate neoadjuvant trials, empirical definitions of pCR have been developed with the goal of using pCR as a surrogate for long-term outcomes. Numerous studies have demonstrated that the burden of pathologically detected residual disease after neoadjuvant chemotherapy is associated with long-term prognosis. However, there has been little if any agreement regarding the precise definition of pCR. In the article that accompanies this editorial, von Minckwitz et al address this controversy in a review of their experience with more than 6,000 patients treated in a series of seven prospectively conducted clinical trials of neoadjuvant anthracycline and taxane–based chemotherapy (some including trastuzumab). They compared multiple existing definitions of pCR to determine how robustly each definition serves as a surrogate for patient survival outcomes. Not surprisingly, they found that the pCR definition that allowed the least residual cancer in the breast and nodes was most highly correlated with the best survival. Although some authors have reported that small amounts of residual invasive or in situ cancer do not seem to be prognostic, the data from this highly powered, pooled analysis of prospectively performed neoadjuvant trials suggest otherwise: any finding of residual cancer—in situ, invasive, or in axillary lymph nodes—was associated with a worse prognosis compared with absolutely no evidence of residual disease. This result, by itself, would probably not have warranted publication in such a high-impact journal as Journal of Clinical Oncology. However, the authors have provided clarity with respect to the results of neoadjuvant chemotherapy by further evaluating the prognostic implications of pCR, using their best definition, within the separate intrinsic breast cancer biologic subtypes. In their large data set, von Minckwitz et al clearly demonstrate that pCR to anthracycline and taxane–based chemotherapy (or lack thereof) had no substantial prognostic value in patients with luminal A (estrogen receptor [ER] positive and/or progesterone receptor [PgR] positive, human epidermal growth factor receptor 2 [HER2] negative, grade 1 or 2) tumors. In fact, the pCR rate is so low in this group (6.7%) that residual disease after treatment with cytotoxic chemotherapy should be expected. Perhaps more surprisingly, pCR in luminal B/HER2-positive tumors (ER positive and/or PgR positive, HER2 positive, all grades) was relatively uncommon (11% to 22%), even with the use of trastuzumab, and achievement of pCR in this subgroup was also not prognostic for survival. In contrast, patients whose subtype is typically associated with a worse prognosis (triple negative, or ER negative and HER2 positive) were much more likely to have pCR (28% to 32%), and those who achieved pCR had a much better outcome. Although the reasons for these findings are not entirely clear from these data, a possible explanation is that lack of pCR to chemotherapy in less proliferative JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 15 MAY 2

Pathologic complete response after neoadjuvant therapy of breast cancer: pitfalls and shortcomings

Response assessment by imaging methods has always been considered not precise enough and not sufficiently correlated with outcome of patients. In opposite, response assessment by pathological examination was considered to be objective and strongly correlated with a high chance for a cure. Pathologic complete response (pCR) was therefore recommended as the gold standard for response evaluation after neoadjuvant treatment [1]. However, with recent treatment advances, detection of pCR became more frequent and knowledge increased about the potential pitfalls and shortcomings of this surrogate endpoint marker. Whereas older definitions of pCR referred only to the absence of residual invasive or even gross invasive disease in the breast [2], newer definitions requested also tumorfree axillary nodes or even no residual in situ disease in the breast. This was based on observations in the last decade that patients with no tumor residuals in the breast but involved nodes showed a significant relapse risk [3], and just recently that even patients with in situ breast tumor residuals only showed a higher relapse risk than patients without any residuals in the breast and nodes [4]. Especially the last observation was contradictory to the beliefs that in situ disease is not responsive to systemic treatment at all, and that residual in situ disease cannot be the source of subsequent distant metastasis. However, these beliefs have to be revisited due to evidence reported in this issue of the journal that neoadjuvant chemotherapy given together with trastuzumab can eliminate adjacent ductal carcinoma in situ in about 50 % of cases [5]. As residual in situ disease might simply indicate a higher chance of non-detected residual invasive disease which might explain the higher relapse risk of these patients observed in larger cohorts [4]. Nevertheless, harmonization of pCR definitions within clinical trials or at least elaborate reporting of the components of residual disease is warranted. Aiming to identify a cohort of patients with a minimum risk for relapse, the most conservative definition should be used. The increasing understanding of the biology of distinct intrinsic breast cancer subtypes raises the question if the chance to achieve a pCR after specific treatments is comparable as well as if pCR correlates similarly with survival in all subtypes. With regard to chemotherapy, hormonereceptor (HR) status has so far been shown to be a reproducible predictor for pCR with higher pCR rates in HRnegative tumors than in HR-positive tumors [6]. It was suspected that pCR rates might be higher in HR-positive tumors if endocrine treatment is added. Indeed, a small trial presented in this issue of the journal found a significantly higher pCR rate when letrozole was given in combination with chemotherapy compared to chemotherapy alone [7]. However, this is in contrast to larger trials reported earlier by our group and as well the ECTO group again in this issue of the journal where neither tamoxifen [8] nor exemestane [9] in combination with chemotherapy achieved sufficient pCR rates. However, we have learned that pCR nicely correlates with survival in HR-negative (triple-negative or HER2-positive) tumors, but much less or not at all in HR-positive tumors [4]. So the observed lower pCR rate in HR-positive tumors does not predict an unfavorable prognosis of these patients. Other surrogate endpoint markers for HR-positive tumors are therefore warranted. A multitude of markers has been proposed to better predict outcome of neoadjuvant chemotherapy, reports on another 4 of these markers are published in this issue of the journal [10–13]. Therefore, some general prerequisites G. von Minckwitz (&) German Breast Group, c/o GBG Forschungs GmbH, Martin-Behaim-Strase 12, 63263 Neu-Isenburg, Germany e-mail: gunter.vonminckwitz@germanbreastgroup.de

11 Everolimus (Rad001) as Treatment in Breast Cancer Patients with Bone Metastases Only – First Results of the Multi-centre, Placebo-controlled, Randomized Discontinuation Phase II RADAR Study

not received. 10 Invited Modulation of Resistance to Hormonal Agents Abstract not received.not received. 11 Proffered paper oral Everolimus (Rad001) as Treatment in Breast Cancer Patients with Bone Metastases Only − First Results of the Multi-centre, Placebo-controlled, Randomized Discontinuation Phase II RADAR Study N. Harbeck, N. Maass, C. Mundhenke, C. Lerchenmuller, J. Barinoff, J. Ettl, B. Aktas, V. Nekljudova, G. von Minckwitz, S. Loibl. Unifrauenklinik Koln, Brustzentrum, Koln, Germany; Universitatsfrauenklinik Aachen, Gynakologie und Geburtshilfe, Aachen, Germany; Universitatsklinikum Kiel, Gynakologie und Geburtshilfe, Kiel, Germany; Gemeinschaftspraxis, Onkologie, Munster, Germany; Dr.-Horst-Schmidt-Kliniken, Gynekologie und Onkologie, Wiesbaden, Germany; Klinikum rechts der Isar, Frauenklinik, Munchen, Germany; Universitatsklinikum Essen, Klinik fur Frauenheilkunde und Geburtshilfe, Essen, Germany; German Breasts Group, Statistic Department, Neu-Isenburg, Germany; German Breasts Group, Medicine and Research, Neu-Isenburg, Germany Background: RAD001 is an orally bioavailable rapamycin ester analogue, which acts by selectively inhibiting mTOR (mammalian target of rapamycin). mTor is a key player in down stream signaling of different pathways In vitro, RAD001 stops formation and activity of osteoclasts. Therefore, treating advanced breast cancer with progressive bone metastases with RAD001 seems to be reasonable. Patients and Methods: We evaluated RAD001 in a placebo-controlled, phase II, randomized discontinuation study in breast cancer patients (pts) with bone metastases only. Pts were eligible if they had HER2-negative, hormone-receptor (HR)-positive or -negative disease, with a maximum of 2 previous lines of endocrine therapy (ET) and 1 previous line of chemotherapy (CT). All pts received zoledronate and pts with HR-positive disease could receive (ET). All pts started with RAD001 during a run-in phase of 8 weeks. Pts with stable disease were randomized to RAD001 or placebo; pts with response continued with RAD001 and pts with progression went off study. Primary outcome was time to progression (TTP) in pts being stable on 8 weeks of RAD001. Main secondary objectives were response rate after 8 weeks, TTP in pts with a response after 8 weeks of RAD001, overall clinical benefit, safety and toxicity of RAD001. It was assumed that placebo would obtain a median TTP of 8 weeks which would then be increased by to 16 weeks (hazard rate of 2), thus requiring 76 randomized pts. It was expected that 70% of all pts would have stable disease after the run-in phase. Overall, 110 pts were planned for enrollment. Due to slow recruitment and a dysbalance between pts randomized and discontinued, study recruitment stopped in December 2012. Results: From 11/06 until 12/10, 89 pts were enrolled. Median age was 59.5 years. All were HER2-negative, 93% had HR-positive disease. 15% had prior chemotherapy; 58% had prior ET for metastases. 1/3 received concomitant ET. Three pts did not start therapy, 41 discontinued during run-in phase, 32 due to progression. Six continued as responder, of whom three are still on treatment. 39 pts. with SD after the run in phase were randomized to RAD001 or placebo. Twenty-seven stopped due to progression; 9 discontinued due to AE, 4 are still on treatment. Conclusion: This is the first trial recruiting pts with bone metastases only for treatment with RAD001. Overall 7/89 showed a sustained response on RAD001 + zoledronate ± ET. Final analysis will be presented at the meeting. 12 Proffered paper oral Everolimus Added to Exemestane Reduced Bone Markers in Postmenopausal Women with Advanced Breast Cancer (ABC): the BOLERO-2 Trial M. Gnant, G.N. Hortobagyi, H. Rugo, H.A. Burris, S. Noguchi, K.I. Pritchard, J. Baselga, T. Sahmoud, H. Bauly, M. Piccart. Medical University of Vienna, Department of Surgery, Vienna, Austria; University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, USA; University of California San Francisco, Helen Diller Family Comprehensive Cancer, San Francisco, USA; Sarah Cannon Research Institute, Drug Development Program, Nashville, USA; Osaka University, Department of Breast and Endocrine Surgery, Osaka, Japan; Sunnybrook Odette Cancer Center and the University of Toronto, Department of Medicine, Toronto, Canada; Massachusetts General Hospital Cancer Center, Division of Hematology/Oncology, Boston, USA; Novartis Pharmaceuticals Corporation, Global Oncology Department, Florham Park, USA; Novartis Pharma AG, Biostatistics, Basel, Switzerland; Jules Bordet Institute, Department of Medicine,

What Can Be Learned From Trials Running Short of Patients or Events?

chemotherapy for locally recurrent or metastatic breast cancer: Safety and efficacy in an open-label study in 2,251 patients. Ann Oncol 22:595-602, 2011 18. Miles D, Chan A, Romieu G, et al: Randomized, double-blind, placebocontrolled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer: AVADO. J Clin Oncol 26:43s, 2008 (suppl 15; abstr 1011) 19. Brufsky A, Rivera RR, Hurvitz SA, et al: Progression-free survival (PFS) in patient subgroups in RIBBON-2, a phase III trial of chemotherapy (chemo) plus or minus bevacizumab (BV) for second-line treatment of HER2-negative, locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 28:119s, 2010 (suppl 15; abstr 1021) 20. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005 21. Bear HD, Tang G, Rastogi P, et al: Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310-320, 2012 22. von Minckwitz G, Eidtmann H, Rezai M, et al: Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366:299-309, 2012 23. Gianni L, Romieu G, Lichinistser M, et al: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) docetaxel (DOC) as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC). Cancer Res 71:S4-S8, 2011 (suppl 24) 24. An SJ, Huang YS, Chen ZH, et al: Posttreatment plasma VEGF levels may be associated with the overall survival of patients with advanced non-small cell lung cancer treated with bevacizumab plus chemotherapy. Med Oncol [epub ahead of print on April 3, 2011] 25. Peppercorn J, Shapira I, Collyar D, et al: Ethics of mandatory research biopsy for correlative end points within clinical trials in oncology. J Clin Oncol 28:2635-2640, 2010