Ej Blok

Cytoplasmic Overexpression of HER2: a Key Factor in Colorectal Cancer

Trastuzumab, a humanized mouse monoclonal antibody directed against HER2 (Human Epidermal Growth Factor Receptor 2), is currently a keystone in the treatment of breast cancer. Meanwhile, trastuzumab has been validated for use in other types of cancer too. But the data on HER2 expression in colorectal cancer are ambiguous, with reported overexpression of HER2 varying between zero and 84%. In this review these studies are evaluated and compared. It shows that many factors influence the determination of HER2-expression, especially of the intracellular fraction of HER2. It is concluded that although membranous overexpression of HER2 is low in colorectal cancer with only 5% of all patients being positive, a significant proportion of the patients (30%) shows cytoplasmic HER2 overexpression. The clinical impact of enhanced intracellular HER2 is not known, because the nature and origin have not completely been revealed yet. Enlightening this process could be a stepping stone towards targeting of intracellular HER2 as a treatment option.

Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05)

Background The optimal duration of extended endocrine therapy beyond five years after initial aromatase inhibitor-based adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer is still unknown. Therefore, we conducted a clinical trial to compare two different extended endocrine therapy durations. Methods In the randomized phase III IDEAL trial, postmenopausal patients with hormone receptor-positive breast cancer were randomly allocated to either 2.5 or five years of letrozole after the initial five years of any endocrine therapy. The primary end point was disease free survival (DFS), and secondary end points were overall survival (OS), distant metastasis-free interval (DMFi), new primary breast cancer, and safety. Hazard ratios (HRs) were determined using Cox regression analysis. All analyses were by intention-to-treat principle. Results A total of 1824 patients were assigned to either 2.5 years (n = 909) or five years (n = 915) of letrozole, with a median follow-up of 6.6 years. A DFS event occurred in 152 patients in the five-year group, compared with 163 patients in the 2.5-year group (HR = 0.92, 95% confidence interval [CI] = 0.74 to 1.16). OS (HR = 1.04, 95% CI = 0.78 to 1.38) and DMFi (HR = 1.06, 95% CI = 0.78 to 1.45) were not different between both groups. A reduction in occurrence of second primary breast cancer was observed with five years of treatment (HR = 0.39, 95% CI = 0.19 to 0.81). Subgroup analysis did not identify patients who benefit from five-year extended therapy. Conclusion This study showed no superiority of five years over 2.5 years of extended adjuvant letrozole after an initial five years of adjuvant endocrine therapy.

Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial

BACKGROUND After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. METHODS The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4-8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5-3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. FINDINGS 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0-10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65-69) for the exemestane group and 67% (65-69) for the sequential group (hazard ratio 0·96, 0·88-1·05; p=0·39). INTERPRETATION The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. FUNDING Pfizer, Dutch Cancer Foundation.

Abstract S1-04: Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05)

Despite the success of adjuvant endocrine therapy in early breast cancer, approximately 50% of all recurrences still occur after the initial 5 years of follow-up. Earlier studies confirmed that endocrine therapy extension after 5 years of adjuvant tamoxifen with either tamoxifen or aromatase inhibitors up to 10 years leads to an improvement in survival. However, aromatase inhibitors are currently standard of care in the initial 5 years of adjuvant therapy, and the benefit of extended use beyond 5 years of AI based therapy is still debated. The randomized phase III IDEAL trial was designed to study the optimal duration of extended adjuvant endocrine therapy after the initial 5 years of any endocrine therapy. Between April 2007 and November 2011, 1824 postmenopausal, HR-positive early breast cancer patients were included by 74 hospitals in the Netherlands. Enrolled patients earlier received 5 years of any endocrine therapy (87.9% AI based),completed this treatment no longer than 2 years before randomization, and did not have any recurrence at the moment of inclusion. The included patients were randomly allocated to either 2.5 or 5 years of extended letrozole (daily 2.5mg). Primary outcome was disease free survival (DFS), secondary endpoints were overall survival (OS), distant disease free survival (DDFS), contralateral breast cancer and safety. Results & Discussion: Results will become available soon. Citation Format: Blok EJ, van de Velde CJH, Meershoek-Klein Kranenbarg EM, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers G-J, Nortier JWR, Rutgers EJT, Kroep JR. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05) [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 S1-04.

Systematic review of the clinical and economic value of gene expression profiles for invasive early breast cancer available in Europe

Gene expression profiles with prognostic capacities have shown good performance in multiple clinical trials. However, with multiple assays available and numerous types of validation studies performed, the added value for daily clinical practice is still unclear. In Europe, the MammaPrint, OncotypeDX, PAM50/Prosigna and Endopredict assays are commercially available. In this systematic review, we aim to assess these assays on four important criteria: Assay development and methodology, clinical validation, clinical utility and economic value. We performed a literature search covering PubMed, Embase, Web of Science and Cochrane, for studies related to one or more of the four selected assays. We identified 147 papers for inclusion in this review. MammaPrint and OncotypeDX both have evidence available, including level IA clinical trial results for both assays. Both assays provide prognostic information. Predictive value has only been shown for OncotypeDX. In the clinical utility studies, a higher reduction in chemotherapy was achieved by OncotypeDX, although the number of available studies differ considerably between tests. On average, economic evaluations estimate that genomic testing results in a moderate increase in total costs, but that these costs are acceptable in relation to the expected improved patient outcome. PAM50/prosigna and EndoPredict showed comparable prognostic capacities, but with less economical and clinical utility studies. Furthermore, for these assays no level IA trial data are available yet. In summary, all assays have shown excellent prognostic capacities. The differences in the quantity and quality of evidence are discussed. Future studies shall focus on the selection of appropriate subgroups for testing and long-term outcome of validation trials, in order to determine the place of these assays in daily clinical practice.

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer

PurposeFor postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy.MethodsIn the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses.ResultsIn node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47–0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38–0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13–1.06), although this additional analysis was underpowered for definite conclusions.ConclusionsThis study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

Abstract P2-09-08: Safety assessment of extended adjuvant endocrine therapy with letrozole; results of the randomized phase III IDEAL trial (BOOG 2006-05)

The implementation of adjuvant aromatase inhibitors (AI) has contributed significantly to an ongoing improvement in survival of early breast cancer patients, but the impact of extended AI on toxicity after use in the initial 5 years has not yet been studied. Earlier, it was established that even after 5 years of adjuvant tamoxifen, extended letrozole for 5 years was comparable to the earlier reported toxicities, without an effect on overall quality of life. The aim of the current study is to assess the reported toxicity in the IDEAL trial, investigating extended letrozole after 5 years of endocrine therapy. The Dutch phase III IDEAL trial was designed to study the optimal duration of extended adjuvant letrozole, by randomizing to either 2.5 or 5 years of letrozole after the completion of 5 years of any endocrine therapy. All patients were disease-free at the time of randomization. The primary outcome of this study, disease free survival after extended endocrine therapy, will be reported separately. Toxicity data were collected every 6 months in the first year, and annually thereafter until study completion. 1824 patients were included in the trial, of which 26 patients never started with therapy (n=1798). In total, 3434 adverse events were reported by 1283 patients, causing 360 (20%) patients to stop therapy due to these events. In total, 643 patients randomized to 5 years of therapy reported 1834 AEs (71.2%), whereas 640 patients on 2.5 years of therapy reported 1587 events (71.5%). In the 5 year AI group, 1456 (80%) of the AEs were reported within the initial 2.5 years causing 177 patients to stop therapy in this period, versus 29 patients who stopped due to toxicity after the therapy extension beyond 2.5 years. There was no significant difference in the proportion of grade 3/4 events between both groups (2.5yr: 9.8%, 5yr: 9.7%, X 2 p=0.52). Most reported AEs were arthralgia (n=248, 13.8% of all patients , 8.9% grade 3/4), hot flushes (n=215, 12%, 6.5% grade 3/4), osteoporosis (n=181, 10%, 2.2% grade 3/4), fatigue (n=156, 8.7%, 5.1% grade 3/4) and a decrease in joint function (n=114, 6.3%, 3.5% grade 3/4). In total, only one grade 5 AE was reported, which was unrelated to the treatment (bleeding and sepsis after cholecystectomy). Although the toxicity pattern is comparable to regular AI based adjuvant therapy, the percentage of specific adverse events like arthralgia and hot flushes is lower than expected. This observation is possibly a selection bias, since patients who encountered side effects during regular adjuvant therapy could have been less willing to participate in this trial. Remarkably, low numbers of AEs and therapy refusal due to toxicity were reported after therapy extension beyond 2.5 years. In conclusion, extended adjuvant endocrine therapy shows an acceptable toxicity pattern, and therapy extension beyond 2.5 years up to 5 years is well tolerated and safe. Citation Format: Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg EM, Duym-de Carpentier M, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers G-J, Nortier JWR, Rutgers EJT, van de Velde CJH. Safety assessment of extended adjuvant endocrine therapy with letrozole; results of the randomized phase III IDEAL trial (BOOG 2006-05) [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 P2-09-08.

Abstract PD2-07: 10-year follow-up and biomarker discovery for adjuvant endocrine therapy; results of the TEAM trial

Optimal endocrine therapy for postmenopausal, hormone-receptor positive (HR+) early breast cancer remains a point of discussion. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase III trial showed no significant differences for disease free survival (DFS) and overall survival (OS) at 5 years between exemestane monotherapy and sequential treatment (tamoxifen followed by exemestane). We now report disease related outcomes at 10 years of follow-up (FU), and an explorative analysis to assess the predictive value of clinicopathological and immune-related biomarkers. In the TEAM trial, postmenopausal women with HR+ positive early breast cancer were randomly assigned to exemestane alone or sequential therapy. For this analysis, TEAM patients from countries that completed 10 years of FU were included. The primary endpoint was DFS at ten years, analyzed by intention to treat. Secondary outcomes were OS and cumulative incidence of relapse. An explorative per protocol analysis for relapse free survival (RFS) was performed to identify predictive pathological and immunological biomarkers, including centrally determined ER (ER-poor 0-6 vs ER-rich 7-8) and PR (0-4 vs 5-8) Allred scores, and the immunological markers CD8, FoxP3, classical HLA class 1 and HLA-G which were described earlier (Engels et al, Breast Cancer Treat Res, 2015). In total, 6120 patients were eligible for the current analysis, 3075 patients with exemestane monotherapy and 3045 patients randomized to sequential treatment. Median follow up was 9.83 years. DFS was 66.8% in the exemestane group and 66.8% in the sequential group (hazard ratio (HR) 0.96, 95% CI 0.88-1.05, p=0.389). OS was 74% in the exemestane, and 73% in the sequential group, respectively (HR 0.98, 95% CI 0.89-1.09, p=0.737). The cumulative incidence of relapse was 20% and 22% in the exemestane and sequential groups, respectively (HR 0.88, 95% CI 0.79-0.99, p=0.031). In the explorative per protocol analysis (n=4041), Allred score were available for 2996 patients; immunological markers for 1754 patients. Patients with above median numbers of FoxP3-positive T-cells showed a benefit of exemestane monotherapy for RFS (HR 0.56, 95% CI 0.42-0.75, p After ten years of follow up, both exemestane monotherapy and sequential therapy remain appropriate options for postmenopausal HR+ early breast cancer patients. Interestingly, the number of regulatory T-cells was a predictive factor for the benefit of exemestane monotherapy, which implies a role of the local immune system in endocrine therapy. Furthermore, data suggested that patients with a higher differentiation grade or ER-rich tumor derive more benefit from exemestane monotherapy. Citation Format: Blok EJ, Derks MGM, Kuppen PJK, Meershoek-Klein Kranenbarg EM, Engels CC, Liefers G-J, Putter H, Seynaeve CM, Kroep JR, Nortier JWR, Rea DW, Hasenburg A, Markopoulos CJ, Paridaens R, Bartlett JMS, van de Velde CJH. 10-year follow-up and biomarker discovery for adjuvant endocrine therapy; results of the TEAM trial [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 PD2-07.

Abstract 5612: Cancer-immune interactions in luminal breast cancers:PI3KCAmutations, PI3K/AKT/mTOR activation and tumor-infiltrating lymphocytes

Introduction: Therapy resistance to adjuvant tamoxifen in estrogen receptor positive (ER+) breast cancer (BC) is related to activation of downstream proteins in the PI3K/AKT/mTOR pathway. However, clinical efficacy of mTOR inhibitors has so far been modest. Growing evidence shows that genomic make-up of cancer cells plays a crucial role in an anti-cancer immune response and this is reflected in the presence of tumor infiltrating immune cells. This begs the need for understanding the relationship between tumor-related immune activity, PIK3CA hot-spot mutations (PIK3CAm) and PI3K/AKT/mTOR pathway activation in ER+BC. Material and methods: The IKA trial recruited stage I to III postmenopausal BC patients (1982 till 1994), who were randomized to tamoxifen or no adjuvant therapy. Sequenom mass spectrometry-based genotyping was used for PIK3CAm assessment. Immune markers and phosphorylation status of proteins in the PI3K/AKT/mTOR pathway [p-AKT (Thr308 and 473), p-mTOR, p-ERK1/2, p-p-70S6K and p-4EBP1] were assessed by immunohistochemistry and scored by two pathologists. Expression of CD4, CD8 and FOXP3 was evaluated using automatic scoring by image-analysis software (SlidePath® or AxioVision®) and compared with manual scoring by two pathologists. Associations were assessed using multivariable logistic regression models, including as co-variables: age, tumor grade, lymph node status, tumor size, and progesterone receptor and HER2 status. Results: We included 563 ER+BC cases. PIK3CAm were found in 159 (32%) of the 486 tumors genotyped. On average, PI3K/AKT/mTOR downstream proteins and immune markers were scored in 409 tumors (range: 366 to 438). Stromal CD8 expression, but not CD4 or FOXP3, was significantly higher in PIK3CA mutated tumors (OR=1.11; 95%CI: 1.02-1.22). Stromal FOXP3 expression, but not CD4 or CD8, was significantly increased in tumors with activated proteins from the PI3K/AKT/mTOR pathway (except p-mTOR). The largest association was with p-4EBP1 (OR=1.34; 95%CI: 1.21-1.48) and smallest with p-70S6K (OR=1.15; 95%CI: 1.08-1.22). Conclusion: In our dataset of ER+BC, PIK3CAm are associated with higher level of CD8+ T cells. Tumors with activation of the PI3K/Akt/mTOR pathway tend to have more FOXP3+ T cells. Together, our results suggest that PIK3CA mutation/activation harbor an immune-related tumor microenvironment. Citation Format: Marcelo Sobral-Leite, Izhar Salomon, Mark Opdam, Karin Beelen, Ronald L. van Vlierberghe, Erik J. Blok, Hugo M. Horlings, Joyce Sanders, Koen Van de Vijver, Peter J. Kuppen, Sabine Linn, Marjanka K. Schmidt, Marleen Kok. Cancer-immune interactions in luminal breast cancers: PI3KCA mutations, PI3K/AKT/mTOR activation and tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5612. doi:10.1158/1538-7445.AM2017-5612

Abstract P6-01-05: Radiological evaluation of neo-adjuvant endocrine therapy in hormone-receptor positive early breast cancer

Recently, there is increased attention to neo-adjuvant endocrine therapy in breast cancer. Especially for selected tumour types and fragile elderly patients this might be a promising alternative to chemotherapy. Monitoring treatment effect during neo-adjuvant endocrine therapy is crucial to allow a timely switch to chemotherapy in case of a non-successful treatment. Most trials evaluating neo-adjuvant endocrine therapy use palpation as primary outcome and multiple radiological modalities as secondary outcomes. The aim of this study was to determine which evaluation corresponds best to pathological resection size after 6 months of neo-adjuvant endocrine therapy. This analysis was conducted in the TEAM-IIA trial in which 102 patients with early breast cancer (>2 cm and >50% ER expression) were treated with neo-adjuvant exemestane. In total, 83 patients were treated for 6 months and 19 for 3 months. Therapy response evaluation was performed using repeated palpation (mostly by the same clinician), mammography, ultrasound and MRI. Only measurements within 2 months before surgery were considered. After surgery, the size of the remaining tumour was reported and used as reference. In total, 93 resection size measurements were available. From the 93 patients for whom resection size was available, 69 patients were evaluated by palpation, 53 by ultrasound, 42 by mammography and 29 by MRI. Overall, palpation showed to be the most reliable predictor for resection size (correlation of 49%), followed by mammography (31%), ultrasound (14%) and MRI (1%). Mammography showed the smallest mean absolute error (MAE, 8.7 mm), followed by ultrasound (9.2 mm), palpation (11.4 mm) and MRI (12.3 mm). The low correlation of MRI with resection size was mostly due to a relative high number of radiological complete remissions (14%, n=4), of which only one was a true pathological complete response (pCR), while the other tumours were up to 80 mm at resection. Although of less influence on the correlation to resection size, false complete remissions were observed in all other modalities. Time to surgery was an important factor for all modalities. After correcting for non-predictive radiological complete responses and limiting the measurements to one month before surgery, all correlations increased significantly (mammography=72%, palpation=70%, ultrasound=58%, MRI=50%) with a concomitant decrease in mean absolute error. The low correlation of MRI with resection size was mostly due to non-visible measurements, interpreted as radiological complete remissions of which only one in four was a true pathological complete response (pCR) while the other tumours were 25, 65, and 80 mm at resection. This is the first study to report on the reliability of radiological evaluation during neo-adjuvant endocrine therapy. In this study, mammography was the most reliable radiological method, with stronger correlation and small mean absolute error. Non- visible observations in neo-adjuvant endocrine therapy did not always reflect pCR. Hence, in the neo-adjuvant endocrine therapy setting, radiological complete responses should be interpreted carefully, especially in MRI, and use of other modalities or improved image processing methods may be considered. Citation Format: Blok EJ, Charehbili A, Kroep JR, Seynaeve CM, van de Velde CJH, Kuppen PJK. Radiological evaluation of neo-adjuvant endocrine therapy in hormone-receptor positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-01-05.