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Objectives The Scottish Medicines Consortium (SMC) conducts early health technology assessment (HTA) of new medicines on behalf of NHSScotland. Assessment of end-of-life (EoL), orphan, and ultra-orphan medicines includes a process to gather evidence from patients and carers during Patient and Clinician Engagement (PACE) meetings. The output of PACE meetings is a consensus statement describing the medicine’s added value from the perspective of patients/carers and clinicians. The PACE statement is used by SMC committee members in decision making. This study compared how PACE participants and SMC committee members rate the importance of information in PACE statements for these medicines. Methods A survey was undertaken of patient group (PG) representatives and clinicians who participated in PACE meetings, and SMC committee members. Results PACE participants who responded (26 PG representatives and 14 clinicians) rated health benefits and ability to take part in normal life as important/very important. Convenience of administration and treatment choice received the lowest rating. Hope for the future received the most diverse response. PACE participants generally rated the importance of quality of life themes higher than committee members (n = 20) but the rank order was similar. Differences between the proportion of PACE participants and committee members who rated themes as important/very important were greatest for treatment choice and hope for the future. Conclusions In general, PACE themes and subthemes that were rated highly by PACE participants were also considered important by SMC committee members, indicating that information captured during PACE meetings is relevant when making decisions on EoL, orphan, and ultra-orphan medicines.

Aim To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial. Patients and methods 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac). Results At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74–1.00) for L+T versus T and 0.93 (95% CI, 0.81–1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70–1.06) for L+T versus T and 0.88 (95% CI, 0.71–1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64–1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69–1.00; 6-yr DFS% = 83% versus79%)] subgroups. Conclusion T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer. Trial Registration clinicaltrials.gov Identifier NCT00490139 .

Background: Preclinical models suggest that in some HER2 overexpressed breast cancer cases, the extracellular domain of HER2, containing the binding region for trastuzumab (T) is not present due to proteolytic cleavage. Previous measurement of HER2 ECD and ICD in HeCOG 10/05 suggested that breast cancer cases that have low levels of ECD show decreased benefit from adjuvant T therapy (Carvajal et al, 2015). These cases may be more likely to show benefit from lapatinib(L), a small molecular tyrosine kinase inhibitor. NeoALTTO, an international multi-institutional trial comparing pre-surgical treatment with L vs T vs both, showed that pCR rates were around 25-30% for L or T but increased to 50% for both. This cohort allows us to test the hypothesis that patients with low ECD may benefit more from L than T. Methods: ECD and ICD were measured 382 cases using quantitative immunofluorescence (QIF) with domain specific antibodies (SP3, Spring biosciences for ECD and CB11, Biocare for ICD). Slides were stained and scanned, then measured using the AQUA method of QIF. All fields of view were scored and FOVs were averaged to generate a QIF score for each case. Index TMAs were used to standardize all autostainer runs and to define the QIF score cut-point that is equivalent to the clinical cut-point for the index TMA cases. Each case was then assigned to one of three groups; 1) High ECD and ICD, 2) Low ECD but High ICD, and 3) low ICD. Results: In the lapatinib arm, both group 1 and 2 showed a pCR rate of 25% (p>0.99), but in the trastuzumab arm, Group 1 pCR rate was 34% compared to 19% for group 2 (p=0.38). In the combination arm, group 1 showed a pCR rate of 59% compared to 29% for group 2 (p=0.046). In a logistic regression model for pCR, after adjustment for treatment arm and HR status the ECD/ICD status shows a significant predictive value (p = 0.002). Although this study is not powered for event free survival (EFS), at 6 years of follow up we found that patients in group 2 on the lapatinib arm show 92% EFS compared to 69% EFS in group 1 (p=0.17). The opposite trend is seen in both trastuzumab arms where EFS for group 1 on T showed 70% vs 62% for group 2 (p=0.57) and 77% vs 71% on the T+L arm (p=0.74). In a Cox regression model for EFS after adjustment for treatment arm and HR status, the ECD/ICD status is not significant (p=0.88) Conclusions: Cases with low levels of ECD compared to ICD appear benefit less than those with high levels of both ECD and ICD as assessed by pCR from treatments containing T. In contrast, those same patients also appear to benefit more, as assessed by EFS, on the L arm. These observations are consistent with the hypothesis that this assay could stratify benefit from L vs T based on the status of the ECD. Further assessment using this assay on the ALTTO cases is currently underway and may help confirm this observation. Citation Format: Rimm DL, Carvajal-Hausdorf D, Harbeck N, Fumagalli D, Rodrik-Outmezguine V, delaPena L, deAzambuja E, Huober J, Baselga J, Piccart M, Holmes E, Pusztai L. Low levels of HER2 extracellular domain (ECD) compared to intracelluar domain (ICD) in NeoALTTO may segregate benefit from lapatinib and trastuzumab in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-07.

IntroductionThe Scottish Medicines Consortium (SMC) conducts early health technology assessment (HTA) of new medicines on behalf of NHSScotland. Evidence from patients and carers on end-of-life and orphan medicines is gathered during Patient and Clinician Engagement (PACE) meetings. The output is a consensus statement describing a medicine's added value from the perspective of patients/carers and clinicians, which is used by SMC committee members in decision-making. This study compared the importance of factors in the PACE statement to PACE participants and committee members.MethodsA survey of ninety-eight PACE participants (consisting of forty-two patient group (PG) representatives and fifty-six clinicians) investigated the importance of quality of life (QoL) themes (family/carer impact, health benefits, tolerability, psychological benefit, hope, normal life, treatment choice and convenience) identified from an earlier thematic analysis of PACE statements. The findings from PG representatives and clinicians were compared, and the overall results were further compared with those from a previous survey of committee members (n = 26).ResultsAmong PACE participants who responded (twenty-six PG representatives and fourteen clinicians), 100 percent rated ‘health benefits’ and ‘ability to take part in normal life’ as important / very important. ‘Convenience of administration’ and ‘treatment choice’ received the lowest rating with fifteen percent and nineteen percent respectively of PG representatives versus seven percent of clinicians rating each as very important. ‘Hope for the future’ received the most diverse response with fifty-eight percent of PG representatives and fourteen of clinicians rating this as very important.In general, PACE participants rated importance of QoL themes higher than committee members (n = 21) but the rank order was similar. Differences between the proportion of PACE participants and committee members who rated themes important/very important was greatest for ‘treatment choice’ (sixty-seven percent versus twenty percent respectively) and ‘hope for the future’ (eighty-two percent versus fifty-three percent).ConclusionsThe findings demonstrate some alignment between PACE participants’ and committee members’ responses, supporting the value of the PACE output in decision-making. Areas for further research are highlighted.

Background Design, conduct, and analysis of randomized clinical trials (RCTs) with time to event end points rely on a variety of assumptions regarding event rates (hazard rates), proportionality of treatment effects (proportional hazards), and differences in intensity and type of events over time and between subgroups. Design and methods In this article, we use the experience of the recently reported Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) RCT, which enrolled 8381 patients with human epidermal growth factor 2-positive early breast cancer between June 2007 and July 2011, to highlight how routinely applied statistical assumptions can impact RCT result reporting. Results and conclusions We conclude that (i) futility stopping rules are important to protect patient safety, but stopping early for efficacy can be misleading as short-term results may not imply long-term efficacy, (ii) biologically important differences between subgroups may drive clinically different treatment effects and should be taken into account, e.g. by pre-specifying primary subgroup analyses and restricting end points to events which are known to be affected by the targeted therapies, (iii) the usual focus on the Cox model may be misleading if we do not carefully consider non-proportionality of the hazards. The results of the accelerated failure time model illustrate that giving more weight to later events (as in the log rank test) can affect conclusions, (iv) the assumption that accruing additional events will always ensure gain in power needs to be challenged. Changes in hazard rates and hazard ratios over time should be considered, and (v) required family-wise control of type 1 error ≤ 5% in clinical trials with multiple experimental arms discourages investigations designed to answer more than one question. Trial Registration clinicaltrials.gov Identifier NCT00490139.

Indirect treatment comparisons are useful to estimate relative treatment effects when head-to-head studies are not conducted. Statisticians at the National Centre for Pharmacoeconomics Ireland (NCPE) and Scottish Medicines Consortium (SMC) assess the clinical and cost-effectiveness of new medicines as part of multidisciplinary teams. We describe some shared observations on areas where reporting of population-adjustment indirect comparison methods is causing uncertainty in our recommendations to decision-making committees when assessing reimbursement of medicines.

BACKGROUND: Lapatinib (L) plus trastuzumab (T) with weekly paclitaxel significantly increased the pathologic complete response (pCR) rate compared with the anti-human epidermal growth factor receptor 2 (HER2) agent alone plus paclitaxel. The event-free survival (EFS) and overall survival (OS) by the treatment arms L + T vs. T and L vs. T and the relationship between pCR and EFS/OS both in the whole study population and according to hormone receptor-negative and hormone receptor-positive cohorts after a median follow-up of 6.7 years were assessed. PATIENTS AND METHODS: Four hundred fifty-five patients with HER2-positive early breast cancer randomly received L 1500 mg/day (n = 154), T (common dose, n = 149) or L 1000 mg/day plus T (n = 152) for 6 weeks, followed by the assigned anti-HER2 treatment combined with paclitaxel weekly × 12. After surgery, patients received 3 cycles of fluorouracil, epirubicin and cyclophosphamide. The primary end-point was pCR (ypT0/is; for current analysis, it is ypT0/is ypN0), and the secondary end-points were EFS and OS. RESULTS: Six-year EFS rates were 67%, 67% and 74% with L, T and L + T, respectively (L vs T: hazard ratio [HR], 0.98 [95% confidence interval {CI}, 0.64-1.51; P = .93]; L + T vs T: HR, 0.81 [95% CI, 0.52-1.26; P = .35]). Six-Year OS rates were 82%, 79% and 85% for L, T and L + T, respectively (L vs T: HR, 0.85 [95% CI, 0.49-1.46; P = .56]; L + T vs T: HR, 0.72 [95% CI, 0.41-1.27; P = .26]). In landmark analyses, patients with a pCR had a significantly higher 6-year EFS (77% and 65%) and OS (89% and 77%) compared with those without a pCR for both overall and the hormone receptor-negative cohort. CONCLUSION: Achieving a pCR is important in HER2-positive disease and translates into better long-term outcome with regard to EFS and OS. ispartof: EUROPEAN JOURNAL OF CANCER vol:118 pages:169-177 ispartof: location:England status: published

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

The predictive value of PIK3CA mutations in HER2 positive (HER2+) breast cancer treated with neoadjuvant anti-HER2 and chemotherapy has been reported, but the power for subgroup analyses was lacking.We combined individual patient data from five clinical trials evaluating PIK3CA mutations and associations with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to a taxane-based chemotherapy. PIK3CA was genotyped in tumour biopsies taken before therapy.A total of 967 patients were included in this analysis; the median follow-up is 47 months. Overall, the pCR rate was significantly lower in the PIK3CA mutant compared with the wild-type group (16.2% versus 29.6%; P0.001). Within the hormone-receptor positive (HR+) subgroup, the PIK3CA mutant group had a pCR rate of only 7.6% compared with 24.2% in the wild-type group (P0.001). In contrast, in the HER2+/HR- group, there was no difference in pCR (27.2% versus 36.4%; P = 0.125) according to PIK3CA mutation status (interaction test P = 0.036). According to treatment arm, the pCR rate for mutant versus wild-type was 20.3% versus 27.1% for T (P = 0.343), 11.3% versus 16.9% for L (P = 0.369) and 16.7% versus 39.1% for T/L (P0.001). In the HR+ T/L group, the pCR rate was 5.5% versus 33.9% (interaction between HR and PIK3CA genotype P = 0.008). DFS and OS were not significantly different by mutation status, though the incidence rate of events was low. However, HR+/PIK3CA mutant patients seemed to have significantly worse DFS {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.00-2.45], P = 0.050; Pinteraction = 0.021}. T/L tended to improve DFS compared with T in the wild-type cohort, especially in the HR- group [HR 0.72, 95% CI (0.41-1.25), P = 0.242].Overall PIK3CA mutant/HER2+ tumours had significantly lower pCR rates compared with wild-type tumours, however mainly confined to the HR+/PIK3CA mutant population. No definite conclusions can be drawn regarding survival.

IntroductionThe Scottish Medicines Consortium (SMC) advises NHS Scotland on the clinical and cost-effectiveness of new medicines. Since 2014, evidence from patients and carers on end-of-life and orphan medicines has been gathered during Patient and Clinician Engagement (PACE) meetings. The output is a consensus statement which describes the added value of a new medicine from the perspective of the patient/carer and clinician. This study investigates the importance of factors identified through PACE to committee members and how these are used in their decision-making.MethodsSurvey methodology was used to gain an understanding of the factors from the PACE statement that are most likely to influence members (n = 26) in decision-making. The survey instrument was informed by a literature review and observation of PACE and SMC meetings. Likert scale questions were used to determine the relative importance of factors in the PACE statement, including information relating to eight prominent ‘quality of life’ themes (family/carer impact, health benefits, tolerability, psychological benefit, hope, normal life, treatment choice and convenience), that were identified by an earlier thematic analysis of these statements.ResultsAnalysis of survey responses will use mainly descriptive techniques to generate percentages and ranges. Correlation analysis will be considered to investigate relationships between members’ demographics, type of medicine (end-of-life, orphan) and the importance of different factors in the PACE statement. Preliminary results indicate that key quality of life themes highly valued by patients/carers are also important to committee members in their decision making. Challenges in assimilating qualitative patient-based evidence from PACE alongside quantitative clinical and economic data were highlighted.ConclusionsFindings from this survey will provide valuable insight into how PACE evidence is used by SMC decision makers alongside traditional clinical and economic evidence and will help shape future improvements to the PACE methodology.

Background: Two randomized trials recently demonstrated that regional nodal irradiation (RNI) could reduce the risk of recurrence in early breast cancer; however, these trials were conducted in the pretrastuzumab era. Whether these results are applicable to human epidermal growth factor receptor 2 (HER2)–positive breast cancer patients treated with anti-HER2-targeted therapy is unknown. Methods: This retrospective analysis was performed on patients with node-positive breast cancer who were enrolled in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization phase III adjuvant trial and subjected to BCS. The primary objective of the present study was to examine the effect of RNI on disease-free survival (DFS). A multivariable cox regression analysis adjusted for number of positive lymph nodes, tumor size, grade, age, hormone receptors status, presence of macrometastatis, treatment arm, and chemotherapy timing was carried out to investigate the relationship between RNI and DFS. Results: One thousand six hundred sixty-four HER2-positive breast cancer patients were included, of whom 878 (52.8%) had received RNI to the axillary, supraclavicular, and/or internal mammary lymph nodes. Patients in the RNI group had higher nodal burden and more frequently had tumors larger than 2 cm. At a median follow-up of 4.5 years, DFS was 84.3% in the RNI group and 88.3% in the non-RNI group. No differences in regional recurrence (0.9 % vs 0.6 %) or in overall survival (93.6% vs 95.3%) were observed between the two groups. After adjustment in multivariable analysis, there was no statistically significant association between RNI and DFS (hazard ratio = 0.96, 95% confidence interval = 0.71 to 1.29). Conclusions: Our analysis did not demonstrate a DFS benefit of RNI in HER2-positive, node-positive patients treated with adjuvant HER2-targeted therapy. The benefit of RNI in HER2-positive breast cancer needs further testing within randomized clinical trials.

Purpose Previous research has suggested that young age at diagnosis is an independent risk factor for breast cancer recurrence and death. No prior studies have adequately controlled for human epidermal growth factor receptor 2 (HER2) status or anti-HER2 treatment. We sought to evaluate whether age was a prognostic or predictive factor in the HERA trial. Patients and Methods We used 2-year median follow-up data and dichotomized age at 40 years to evaluate its prognostic effect on outcomes for women assigned to trastuzumab for 1 year or observation. Results Of the 1,703 women randomly assigned to 1 year of trastuzumab and 1,698 to observation, 722 (21%) were age ≤ 40 years at study entry. In separate Cox models, controlling for relevant prognostic and predictive factors, disease-free (DFS) and overall survival (OS) hazard ratios (HRs) were consistent for women age ≤ 40 versus > 40 years, regardless of treatment assignment (observation group: DFS HR age ≤ 40 v > 40 years, 1.18; 95% CI, 0.90 to 1.54; OS HR age ≤ 40 v > 40 years, 1.01; 95% CI, 0.60 to 1.69; trastuzumab group: DFS HR age ≤ 40 v > 40 years, 1.11; 95% CI, 0.81 to 1.51; OS HR age ≤ 40 v > 40 years, 1.18; 95% CI, 0.66 to 2.09). Interaction between age group and treatment effect was not statistically significant (DFS P = .89; OS P = .55). Conclusion In a retrospective analysis of a large randomized controlled trial of women with early-stage HER2-positive breast cancer, age was not strongly associated with risk of early recurrence or prediction of benefit from trastuzumab therapy. Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes.

Background: Retrospective studies of HER2−positive metastatic breast cancer (BC) showed an incidence of CNS metastases of 21% to 34%. We investigated the incidence and clinical aspects of CNS relapse (CNS-R) in patients (pts) enrolled in the HERA trial, a prospectively randomized adjuvant trial in node + or high-risk node - HER2−positive early BC pts. Methods: 3401 pts were randomized into the 1-year trastuzumab (1yT) or the observation (obs) arms of HERA (Piccart-Gebhart et al, 2005, Gianni et al, 2011). The cumulative incidences of first disease-free survival (DFS) events in the CNS vs other sites were estimated using competing risk analysis. The database of the main study had a clinical cut-off date of 9th June 2008. To obtain additional information regarding CNS-R (including occurrence of CNS-R after first DFS event), a specific CNS-directed questionnaire was sent to investigators of pts who were deceased as of July 2009. Information collected included the date of CNS-R, whether it was symptomatic, the type of CNS-R (brain metastases (BM) or meningeal carcinomatosis (MC)), methods of diagnosis, and treatments at the time of CNS-R. Results: 1yT significantly reduced the risk of other DFS events (p=0.000017, Gray's test), but not of CNS-R (p=0.55) as first event (see table). During the first year of follow up, CNS-R accounted for 15 (14.9%) of the 101 first DFS events in the 1yT arm and 15 (7.7%) of the 194 first DFS events in the obs arm. The analysis of baseline patient and tumor characteristics associated with CNS-R as first event confirmed known risk factors such as young age ( 413 of the 481 questionnaires (85.9%) were returned. 217 of the 413 deceased pts had a CNS-R diagnosed prior to death (52.5%), with more events occurring in the 1yT arm (see table). By contrast, the incidence of CNS-R as first DFS event was balanced across the arms. Based on the survey data, CNS-R was symptomatic in 189 pts (87.1%) with no differences between arms. BM were present in 211 pts (97.2%), absent in 5 (2.3%), and missing information in 1 (0.5%). MC was diagnosed in 25 pts (11.5%), absent in 187 (86.2%), missing information in 5 (2.3%). Frequencies for BM and MC were very similar in both arms. Conclusion: This retrospective analysis of a prospective large study shows more than 50% incidence of clinically diagnosed CNS-R in HER2−positive BC pts who have died. CNS-R was symptomatic in most pts. CNS-R at any time was less frequent in the 1yT arm (88 vs 129). There is no evidence that adjuvant trastuzumab increases the incidence of CNS-R. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-01.

Purpose We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) –positive breast cancer treated in randomized trials. Methods A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) –positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status. Results Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR-negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively. Conclusion Women with HER2-positive tumors ≤ 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and ≤ one positive lymph node may be candidates for trials assessing less aggressive treatment approaches.

Background Assessment of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) might be an important tool in identifying human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients unlikely to derive benefit from anti-HER2 therapies. However, studies to date have failed to demonstrate its predictive role in any treatment setting. Patients and methods Prospectively collected baseline core biopsies from 429 early-stage HER2-positive breast cancer patients treated with trastuzumab, lapatinib, or their combination in the Neo-ALTTO study were stained using two anti-PTEN monoclonal antibodies (CST and DAKO). The association of PTEN status and PI3K pathway activation (defined as either PTEN loss and/or PIK3CA mutation) with total pathological complete response (tpCR) at surgery, event-free survival (EFS), and overall survival (OS) was evaluated. Results PTEN loss was observed in 27% and 29% of patients (all arms, n = 361 and n = 363) for CST and DAKO, respectively. PTEN loss was more frequently observed in hormone receptor (HR)-negative (33% and 36% with CST and DAKO, respectively) compared with HR-positive tumours (20% and 22% with CST and DAKO, respectively). No significant differences in tpCR rates were observed according to PTEN status. PI3K pathway activation was found in 47% and 48% of patients (all arms, n = 302 and n = 301) for CST and DAKO, respectively. Similarly, tpCR rates were not significantly different for those with or without PI3K pathway activation. Neither PTEN status nor PI3K pathway activation were predictive of tpCR, EFS, or OS, independently of treatment arm or HR status. High inter-antibody and inter-observer agreements were found (>90%). Modification of scoring variables significantly affected the correlation between PTEN and HR status but not with tpCR. Conclusion These data show that PTEN status determination is not a useful biomarker to predict resistance to trastuzumab and lapatinib-based therapies. The lack of standardization of PTEN status determination may influence correlations between expression and relevant clinical end points. Clinical Trials This trial is registered with ClinicalTrials.gov: NCT00553358.

We appreciate the interest of Oguz et al in our meta-analysis of five large adjuvant trials to compare the efficacy of chemotherapy and trastuzumab versus chemotherapy alone in patients with small human epidermal growth factor 2 (HER2)–positive breast cancers of 2 cm or smaller. Their questions are important, because they relate to the potential to reduce the intensity of standard treatment of patients with small HER2-positive breast cancers. We agree that there are limited prospective data about the prognosis of T1abN0 HER2-positive tumors. Few of these patients were included in the randomized adjuvant trastuzumab trials because of concerns about potential cardiotoxicity with trastuzumab in patients perceived to be at low risk of recurrence. Therefore, we cannot provide additional prognostic information for patients with T1abN0 HER2-positive breast cancers. Such information must be obtained from retrospective series or prospective cohort studies. In addition, the selection of chemotherapy regimens for patients with small HER2-positive tumors is important, and we observed heterogeneous outcomes among the trials for the hormone receptor (HR)–negative cohort, which may be due in part to the difference in timing of chemotherapy. Thus, we hesitate to make any additional conclusions, because patients were not randomly assigned to chemotherapy regimens. Finally, we agree that additional analyses of retrospective series and prospective cohort studies will be important to identify additional patient subgroups that may warrant less (or more) intensive treatments. For example, in a previous meta-analysis of five of the adjuvant randomized trastuzumab trials, we identified a subgroup of patients with HR-positive, HER2-positive tumors of 2 cm or smaller, and one or no positive lymph nodes, who had excellent prognoses when treated with trastuzumab and chemotherapy with or without endocrine therapy; the 5-year disease-free survival was 91%, and the 5-year overall survival was 97%. These results, we hope, will provide a benchmark for the design of future trials to evaluate less aggressive treatment approaches.

512 Background: In the neoadjuvant NeoALTTO trial dual HER2 blockade with lapatinib (L) plus trastuzumab (T) combined with weekly paclitaxel significantly increased the pathologic complete response rate (pCR) compared with either anti-HER2 agent alone plus paclitaxel. At first analysis pts with pCR had a better event free survival (EFS) and overall survival (OS) after median follow-up of 3.84 yrs. Methods: 455 pts with operable HER2-positive breast cancer were randomized to receive either L (n=154) 1500mg/day, T 4mg/kg loading dose followed by 2mg/kg/wk (n=149) or L 1000mg/day plus T (n=152) for 6 weeks followed by the assigned anti-HER2 treatment combined with paclitaxel weekly x 12. Following surgery pts received 3 cycles fluorouracil, epirubicin and cyclophosphamide q 3 weeks. The assigned anti-HER2 treatment was continued for 34 weeks thereafter. Primary endpoint was pCR (ypT0/is), secondary endpoints were EFS and OS and the association between pCR and OS analyzed by landmark analysis 30 weeks after randomization. Median follow-up was 6.7 years. Results: 6-yrs EFS rate was 67%/ 67%/74% with L/T/TL, respectively (L vs T HR 0.98 [95% CI 0.64–1.51] p=0.93; TL vs T HR 0.81 [95% CI 0.52–1.26] p=0.35). In the hormone receptor negative group 6- yrs EFS rate was 61%/ 63%/74% for the 3 groups, respectively (L vs T HR 1.09 [95% CI 0.61–1.95] p=0.76; TL vs T HR 0.81 [95% CI 0.44–1.51] p=0.52). OS at 6 yrs was 82%/79%/85% for L, T and TL, respectively (L vs T: HR 0.85 [95% CI 0.49-1.46] p=0.56; TL vs T HR 0.72 [95% CI 0.41-1.27] p=0.26). In landmark analyses, pts with a pCR had significantly higher 6-yrs EFS (77% /65%) and OS (89% /77%) compared to those without pCR, both overall and for the hormone receptor negative cohort. Conclusions: The updated results of the NeoALTTO study confirm the sustained survival benefits for pts who achieve a pCR. EFS and OS after 6 yrs did not differ significantly between the 3 treatment groups. The combination of T and L showed numerically higher EFS compared to T, especially in the hormone-receptor negative group. Clinical trial information: NCT00553358. [Table: see text]

Molecular imaging receives increased attention for selecting patients who will benefit from targeted anticancer therapies. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) enrolled 455 women with invasive human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared rates of pathologic complete response (pCR) to neoadjuvant lapatinib, trastuzumab, and their combination. Each anti-HER2 therapy was given alone for 6 wk, followed by 12 wk of the same therapy plus weekly paclitaxel. The early metabolic effects of the anti-HER2 therapies on the primary tumors and their predictive values for pCR were assessed in a subset of patients. Methods: eighty-six patients underwent (18)F-FDG PET/CT at baseline and weeks 2 and 6 of anti-HER2 treatment. An imaging core laboratory provided central validation, and 2 independent reviewers, masked to assigned treatment arm and clinical outcomes, performed consensus (18)F-FDG PET/CT readings. Maximum standardized uptake value (SUVmax) reductions from baseline were used to measure metabolic response. Results: seventy-seven of the 86 enrolled patients presented an evaluable baseline (18)F-FDG PET/CT scan; of these, 68 and 66 were evaluable at weeks 2 and 6, respectively. Metabolic responses in the primary tumors were evident after 2 wk of targeted therapy and correlated highly with metabolic responses at week 6 (R(2) = 0.81). pCRs were associated with greater SUVmax reductions at both time points. Mean SUVmax reductions for pCR and non-pCR, respectively, were 54.3% versus 32.8% at week 2 (P = 0.02) and 61.5% versus 34.1% at week 6 (P = 0.02). (18)F-FDG PET/CT metabolic response rates at weeks 2 and 6 were 71.6% and 60%, respectively using European Organization for Research and Treatment of Cancer criteria; pCR rates were twice as high for (18)F-FDG PET/CT responders than nonresponders (week 2: 42% vs. 21%, P = 0.12; week 6: 44% vs. 19%, P = 0.05). Conclusion: early metabolic assessment using (18)F-FDG PET/CT can identify patients with an increased likelihood of pCR after neoadjuvant trastuzumab, lapatinib, or their combination when given with chemotherapy.

Summary Background Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. Methods We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5–4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. Results Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 [2%] of 1703 patients) and the observation group (32 [2%] of 1698; p=0·55 [Gray's test]). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 [57%] of 227) than in the group given trastuzumab for 1 year (88 [47%] of 186; p=0·06 [Gray's test]). Most CNS relapses were symptomatic (189 [87%] of 217). Conclusion Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. Funding None.

604Background: The optimal treatment of regional nodal areas following breast-conserving surgery (BCS) is a source of debate. Two randomized trials recently demonstrated that regional nodal irradiation (RNI) can reduce the risk of recurrence in early breast cancer; however,these trials were conducted in the pre-trastuzumab era.Whether these results are applicable to HER2-positive breast cancer patients treated with anti-HER2 targeted therapy, is unknown. Methods: This retrospective analysis was performed on patients with node-positive breast cancer, who were enrolled in the ALTTO phase III adjuvant trial and subjected to BCS. The primary objective of the present study was to examine the effect of RNI on disease-free survival (DFS). Secondary objectives included regional recurrences and overall survival (OS). A multivariate cox regression analysis adjusted for number of positive lymph nodes, tumor size, grade, age, hormone receptors status, presence of macrometastatis, treatment arm, and chemotherapy timin...

Background: We examined if alterations in nucleic acid variants, genes, pathways, and overall mutational load and clonal entropy are associated with pathologic complete response (pCR) and survival after neoadjuvant anti-HER2 therapies in the NeoALTTO trial. Methods: Whole exome sequencing was performed of 203 baseline biopsies with outcome information. The mean nucleotide coverage was 150x with >90% of target bases showing > 30x coverage in > 99% of samples. Somatic mutations were called by MuTect and indels by Strelka, using pooled reference normal DNA. Significantly mutated genes (FDR Results: Only 12 genes had mutation rates significantly above background and among these only PI3KCA was associated with lower pCR rate (OR=0.42, p=0.019). Genes with somatic mutations in more than 10 patients were also assessed, but none were associated with pCR or survival. Clonal entropy or adjusted mutation load also did not correlate with response. Mutations in 33 pathways showed significant association with response in the entire cohort. In the trastuzumab arm, 23 of the 33 pathways showed an association with response but none was independent of PIK3CA mutation. We constructed "PIK3CA-gene network" that included all unique genes (n=439) from theese 23 pathways. Of the 66 patients in the trastuzumab arm, 50 carried at least one mutation in one of the 439 genes and among these only 2 achieved pCR (4%) compared to 9 of 16 pCR (56%) among the wild type (OR=0.035; p < 0.001). The same genes/mutations had little impact on pCR in the lapatinib arm (pCR 20%). In the lapatinib arm, mutations in 3 pathways conferred higher probability of pCR. The "Regulation of RhoA activity" pathway, had the most significant association with pCR in the entire cohort (OR=3.77, p=0.0009) and in the lapatininb (pCR 67% vs 17%, OR=14.8, p=0.008) and lapatinib + trastuzumab (OR=3.0, p=0.06) arms, but not in the trastuzumab arm (OR=1.4, p=0.7). Event free and overall survival were also significantly higher in patients who had mutations in this pathway. Twenty seven of the 48 genes in this pathway had mutations affecting 33 patients but different genes were affected in different individuals. Conclusions: There are no high frequency recurrent single mutations associated with response to HER2-targeted therapies, other than PIK3CA. We identified several biological pathways, including RhoA activity, and a network of PIK3CA associated genes that are significantly associated with response when affected by mutations, however, different genes are mutated in different individuals. Citation Format: Pusztai L, Shi W, Jiang T, Nuciforo P, Holmes E, Harbeck N, Sotiriou C, Rimm D, Hatzis C, de la Peña L, Armour A, Piccart-Gebhart M, Baselga J. Whole exome sequencing of pre-treatment biopsies from the neoALTTO trial to identify DNA aberrations associated with response to HER2-targeted therapies. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-01.

Medical education has been characterized in terms of points of transition, which are accentuated by lack of relevant prior experience and can lead to extreme positive and negative emotions.Quantify the effect of maturity on medical students' transitions into the clinical environment and identify how experiences of transition might be improved.Eleven weeks after entering the clinical environment, 29 mature students (age over 21 at entry, median age 22) in a horizontally-integrated, predominantly undergraduate entry, problem-based curriculum offering little early clinical exposure and 58 matched non-mature students (median age 18 years) rated their experiences of transition and wrote free text comments about them.62% of mature students compared with 24% of controls described 'good transitions' (odds ratio [OR] for a good transition 6.1; p = 0.002) and mature students were more likely than controls to describe how they drew on their previous years in medical school (OR 2.7, p = 0.04) and their wider life experiences in making the transition (OR 3.9, p = 0.01). They were less likely to feel confused or daunted. Whether mature or not, prior workplace experience, having learned the theory of medicine by PBL, and being confident in their knowledge and skills helped students' transitions. Both mature and non-mature students valued the support of teachers and peers and would have valued clinical experience earlier.The fact that just a few extra years of life experience made such a large difference to students' experiences of transition illustrates how important social factors are in the personal development of medical students. In respondents' views, early clinical experience and early skills training could ease students' passage into the clerkship phase of their education.

511 Background: The predictive value of PIK3CA mutations in HER2+ BC has been shown conclusively. Data on subgroup analyses are lacking. Methods: We combined data from three studies evaluating PIK3...

Aim: The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial is a randomised phase III adjuvant breast cancer trial comparing 3 oral lapatinib (L)-containing regimens with trastuzumab (T), each given for 1 year. DFS results of L + T and T—> L compared to T, presented at ASCO 2014, showed a non-significant DFS benefit. Results of L vs T and key secondary analyses are presented for the first time. Methods: 8381 patients (pts) were randomised to receive either T (N = 2097), L (N = 2100), T —> L (N = 2091), or L + T (N = 2093) from 2007-2011. Primary comparison of L vs T evaluated non-inferiority at a margin of 1.11 and the futility boundary for this arm was crossed resulting in premature arm closure (Aug 2011). Pts in the L arm who were free of disease recurrence at that time were offered T as adjuvant treatment. Key secondary analyses including DFS by hormone receptor status and CNS endpoints are now presented. Results: In 4197 pts and at a median follow-up of 4.5 years, 366 (17%) DFS events in the L and 301 (14%) DFS events in the T arms were observed. 1090 (52%) pts in the L arm received at least one T dose. In post-hoc analysis, there was evidence that these pts benefitted from receiving T [hazard ratio (HR) = 0.67; 95% CI 0.49-0.91 from a time-dependent Cox model of DFS]. The non-inferiority HR was 1.34 (95% CI 1.15-1.56) in the ITT population; 1.45 for hormone receptor negative, 1.23 for hormone receptor positive. CNS as first site of metastases occurred in 2% of cases in all arms. AEs of any grade were more common with L than T: diarrhoea (64% vs 20%), rash or erythema (54% vs 20%) and hepatobiliary (25% vs 16%). Any cardiac events were infrequent in both arms, but more common in T compared to L (4.5% vs 1.9%; p Conclusions: Overall, L added to T did not statistically improve DFS. L did not appear to decrease the rate of CNS as first site of metastases. T confers a better outcome compared to L in pts with HER2-positive EBC and remains the standard of care. There is evidence of T benefit even when initiated later in the course of follow-up. Disclosure: E. De Azambuja: Disclosed an advisory role with GSK; honoraria from Roche; research funding from GSK; and travel grants from GSK/Roche; G. Viale: disclosed an advisory role with Roche and Dako; and honoraria from GSK, Roche, and Dako; R. Crescenzo: disclosed compensated employment with GlaxoSmithKline; and stock ownership with Glaxo SmithKline; K. Pritchard: disclosed an advisory role with Roche; honoraria from Roche; research funding from Roche; and expert testimony on behalf of Roche; C. Jackisch: disclosed honoraria from Roche and GSK; F. Boyle: disclosed honoraria from GlaxoSmithKline; and research funding from GlaxoSmithKline; R.D. Gelber: disclosed research funding from GSK and Roche; M. Piccart: disclosed consultancy with PharmaMar; honoraria from Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, Sanofi Aventis, Symphogen, Synthon, and Verastem; research grants from most companies. All other authors have declared no conflicts of interest.

508 Background: Adjuvant T plus chemotherapy improves disease-free survival (DFS) and overall survival (OS) vs. chemotherapy alone for pts with early stage HER2-positive breast cancer. We conducted a meta-analysis to estimate DFS and OS for pts with small tumors (≤2cm) in the T arms from 5 of the 6 randomized adjuvant trastuzumab trials. Pts with tumors ≤2cm, with 0 or 1 positive lymph nodes, and hormone receptor (HR) positive disease had a 5-year DFS of 91% and a 5-year OS of 97% (O’Sullivan, SABCS 2013; abstract:1327). We now plan to conduct an additional meta-analysis to assess the efficacy of T compared with no T for pts with small tumors (≤2cm). Methods: Six randomized controlled trials (RCT) were identified by a Medline search from 2004-2013. Trial groups from 5 phase III RCTs provided data (HERA, NCCTG N9831, NSABP B31, PACS 04, and FinHER).In total, 11,200 pts were randomized in these 5 trials;4,220 of whom had ≤2cm tumors, and known number of positive axillary lymph nodes and HR status(2,588 rand...

Background Trastuzumab (T) combined with chemotherapy improves survival of women with HER2-positive breast cancer. Dual therapy with T and other HER-2 targeted agents (lapatinib/pertuzumab) has demonstrated improved efficacy compared to T alone in advanced breast cancer, and is in clinical trials in early stage disease. We hypothesize that subgroups of patients with HER2-positive tumors and limited tumor burden (tumor size and no or few positive lymph nodes) have a favorable outcome and would not be candidates for dual therapy. This study will analyze the disease-free survival (DFS)and overall survival (OS) of patients with early stage breast cancer treated with chemotherapy and T in the seminal randomized studies (RCTs). Methods RCTs were identified by a Medline search from 2004-2013. Trial groups from five phase III RCTs agreed to provide data. TrialNumberEligibilityRegimenNSABP B312130T1-3; pN1, pN2a, or pN3a; M0ACx4 then Tx4 VSACx4 then THx4 then Hx40wkNCCTG N98313505T1-3; pN1-2; M0ACx4 then Tx12wk VS ACTx4 then Hx52wk VS ACx4 then Tx12wk then Hx40wkHERA5102T1-3; pN1-2; M0Any (neo)adjuvant regimen, then H q3wk x1yr VS H q3wk x 2yr VS observationFinHER232T1-4; N0-3; M0Vx3 or T*x3 then FECx3 VS Vx3 or T*x3 with Hx9wk then FECx3PACS043010(528 HER2+)T1-3; pN1-2; M0FE(100)Cx6 VSFE(100)Cx6 then Hx1yr VS T*E(75) x6 VS T*E(75) x6 then Hx1yrA, adriamycin; C, cyclophosphamide; T, paclitaxel; T*, docetaxel; H, trastuzumab; P, carboplatin; F, 5-fluorouracil; E, epirubicin; Treatment regimen also included 5 years of hormonal therapy for ER positive patients. The ER+/HER2+ and the ER-/HER2+ cohorts will be analyzed separately. Patients with tumors 3 cm or smaller (T1a, T1b, T1c and >2 cm- 3cm) and 0, 1, 2 and 3 positive lymph nodes will be included. Initially a log rank test will be used to determine if the survival results are different by study. If there is no difference across studies, Kaplan-Meier survival curves with confidence intervals will be estimated. If there is a difference between studies, individual Kaplan-Meier curves will be estimated and the mean of the curves will be estimated along with confidence intervals using the adjusted standard deviation. Estimates at 3, 5 and 8 years will be presented as well as estimates of the event rates within each subpopulation defined by tumor size, number of positive lymph nodes, and ER status. Survival endpoints of DFS, and OS as defined in the original studies will be analyzed. Results and Conclusion Data from the five trials will be analyzed and an abstract provided prior to the meeting. Subgroups of patients with a very favorable outcome when treated with adjuvant chemotherapy and T will be identified. Our survival estimates might serve as benchmarks for future trials evaluating therapy reduction. Our results will complement those of the Dana Farber single arm multicenter trial in patients with “low risk” HER2-positive disease (APT trial; NCT00542451), being submitted to SABCS 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-03.

Immunoassays have been developed for human collagenase, stromelysin, tissue inhibitor of metalloproteinases (TIMP) and TIMP complexed with both of the active enzymes. Selection of antibodies of defined specificity enabled measurement of both the pro and active forms of the metalloproteinase. Free TIMP was quantified by the selection of a monoclonal antibody which did not recognise TIMP when complexed with metalloproteinases. Detection of enzyme-inhibitor complexes was achieved by capturing the TIMP component of the complex and revealing the metalloenzyme using specific antibodies.