Background Circadian rhythms regulate cellular physiology and could in fl uence the ef fi cacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271). Methods 1278 patients with high-risk hormonal receptor positive (HR+)/ HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00 - 11:59 (morning), 12:00 - 17:59 (afternoon), 18:00 - 23:59 (evening), or 24:00 - 05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespeci fi ed secondary endpoint of the trial and the results of this observational study are reported here. Findings ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53 - 1.12]). The association between ET intake timing and DFS according to the strati fi cation factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22 - 0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68 - 1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16 - 0.91]). Interpretation Tamoxifen intake in the evening/nighttime could be recommended in patients with high -risk HR+/ HER2- BC while awaiting for results from further ET timing studies. Funding UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research -UK, Myriad Genetics, and Novartis. Copyright (c) 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

DESTINY-Breast04 (NCT03734029) assessed T-DXd vs TPC in pts with HER2-low mBC (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−). At primary data cutoff (DCO; January 11, 2022), median overall survival (mOS) for the full analysis set (FAS = hormone receptor-positive [HR+] and hormone receptor-negative [HR−]) was 23.4 months (mo) for T-DXd vs 16.8 mo for TPC (hazard ratio, 0.64; P = 0.001), with 18.4 mo median follow-up (F/U). Here, we report results from a pre-planned further F/U (DCO, March 1, 2023). Pts were randomly assigned 2:1 to T-DXd or TPC. At the updated DCO, analyses of OS (HR+ and FAS), progression-free survival (PFS) by investigator (HR+ and FAS), and safety were conducted. At DCO, median F/U was 32 mo. Median treatment duration was 8.2 mo (range, 0.2-39.1 mo) for T-DXd and 3.5 mo (range, 0.3-19.7 mo) for TPC. Efficacy results are shown in the table. Grade ≥3 treatment-emergent adverse events (TEAEs) were lower in T-DXd vs TPC (54.4% vs 67.4%). The most common TEAEs were gastrointestinal or hematological in nature; all-grade nausea (T-DXd: 76.0%; TPC: 30.2%) and vomiting (T-DXd: 40.7%; TPC: 13.4%) were most common for T-DXd and decreased neutrophil count (T-DXd: 22.1%; TPC: 36.0%) was most common for TPC. Exposure-adjusted incidence rates for any-grade TEAEs were 1.2 and 2.6 for the T-DXd vs TPC arm, respectively. No new adjudicated drug-related interstitial lung disease/pneumonitis events were reported with longer F/U (primary DCO: 45 pts [12.1%] for T-DXd; 1 pt [0.6%] for TPC). Results from the 32-mo median F/U for DESTINY-Breast04 confirms the sustained clinically meaningful improvement for T-DXd vs TPC previously demonstrated in HER2-low mBC, regardless of HR status. Similar to the primary analysis, the overall safety profile was generally manageable with longer duration of treatment exposure.Table: 376OSummary of efficacy resultsHR+FAST-DXd n = 331TPC n = 163T-DXdN = 373TPCN = 184mOS, mo (95% CI)23.9 (21.7-25.2)17.6 (15.1-20.2)22.9 (21.2-24.5)16.8 (14.1-19.5)mOS Hazard ratio (95% CI)0.69 (0.55-0.87)0.69 (0.55-0.86)OS rate at 24 mo, %a (95% CI)49.0 (43.3, 54.5)35.1 (27.3, 43.0)47.3 (41.9, 52.4)32.0 (24.8, 39.3)OS rate at 36 mo, %a (95% CI)26.5 (20.7-32.7)16.9 (10.2-25.0)26.2 (20.8-31.9)16.3 (10.3-23.6)mPFS by investigator, mo (95% CI)9.6 (8.4-10.0)4.2 (3.4-4.9)8.8 (8.3-9.8)4.2 (3.0-4.5)mPFS Hazard ratio (95% CI)0.37 (0.30-0.46)0.36 (0.29-0.45)m, median. Estimated and CI for OS rate at the specified time point are from Kaplan-Meier analysis. Open table in a new tab

DESTINY-Breast04 (NCT03734029) demonstrated significantly improved overall and progression-free survival (PFS) with T-DXd vs TPC in pts with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-negative) mBC, with manageable safety. Here, we report additional safety data. Pts with centrally confirmed HER2-low mBC, treated with 1-2 prior lines of chemotherapy, were randomly assigned 2:1 to receive T-DXd or TPC. An analysis of selected treatment-emergent adverse events (TEAEs) and age (<65 vs ≥65 years [y]) was done; endpoints included time to first onset (TTO), duration of first event (DUR), and resolution. At data cutoff (January 11, 2022), median (m) treatment duration was 8.2 months (mo; range [r], 0.2-33.3) for T-DXd vs 3.5 mo (r, 0.3-17.6) for TPC. Exposure-adjusted incidence rates (EAIRs; per pt-y) for any-grade TEAEs were lower for T-DXd vs TPC (1.30 vs 2.66). mTTO and mDUR of any-grade interstitial lung disease (ILD) in pts treated with T-DXd were 129 days (d; r, 26-710 d) and 47 d (r, 13-365 d). 13 pts had adjudicated drug-related grade 1 ILD; of those pts, 6 were rechallenged with T-DXd after resolution (details to be presented). Incidence of any-grade drug-related neutropenia (NP) and febrile NP was lower for T-DXd vs TPC; subsequent granulocyte colony-stimulating factor use was 6.7% vs 19.8%. Nausea/vomiting (N/V) events in T-DXd vs TPC were 79.5% vs 35.5%. T-DXd-treated pts received more antiemetic prophylaxis (AP; 50.9%) vs TPC-treated pts (37.2%); 92.3% of T-DXd and 68.8% of TPC N/V events in AP-treated pts resolved. Incidence of any-grade drug-related TEAE was consistent between pts aged <65 y and ≥65 y. For T-DXd, incidence of grade ≥3 TEAEs and TEAEs associated with drug discontinuations (DD) was higher in pts aged ≥65 y compared to those aged <65 y; the most common TEAE associated with DD was ILD/pneumonitis. However, mPFS favored T-DXd over TPC in all patients, regardless of age. EAIR, TTO, and DUR data for selected TEAEs will be presented. T-DXd demonstrated a manageable safety profile to support its use as the new standard of care in pts with HER2-low mBC.

In the phase III DESTINY-Breast04 trial (NCT03734029), T-DXd significantly improved progression-free survival (PFS) and overall survival (OS) vs TPC in pts with HER2-low mBC regardless of hormone receptor expression. Breast cancers with low ER expression (IHC 1-10%) represent a subset of pts that may mimic the clinical behavior of triple-negative breast cancer. Here, we report analyses of pts with ER IHC 0% and 1-10%. Pts with HER2-low (HER2 IHC 1+ or IHC 2+/ISH−) mBC who had been previously treated with 1 or 2 lines of chemotherapy were randomly assigned (2:1) to either T-DXd or TPC (physician's choice of chemotherapy). Exploratory analyses of efficacy and safety, using the primary analysis data cutoff (Jan 11, 2022), were conducted for pts with ER IHC 0-10%. 110 pts were included (ER IHC 0% n = 58; ER IHC 1-10% n = 52). Efficacy results are shown in the table. Pts with ER IHC 1-10% treated with T-DXd had longer PFS (median PFS, 8.4 months with T-DXd vs 2.6 months with TPC; hazard ratio, 0.24 [95% CI, 0.12-0.48]) and OS (hazard ratio, 0.35 [95% CI, 0.16-0.75]) vs TPC. In ER IHC 0-10% pts, the most common any-grade treatment-emergent adverse events (TEAEs; ≥20% of pts in either arm) were nausea, vomiting, fatigue, decreased appetite, alopecia, constipation, anemia, diarrhea, transaminases increased, white blood cell count decreased, and neutrophil count decreased. 40 (53.3%) and 24 (75.0%) pts in the T-DXd and TPC groups, respectively, experienced grade ≥3 TEAEs. Table: 192MOEfficacy in ER IHC 0% and ER 1-10% subgroupsT-DXdTPCER IHC 0%1n = 40n = 18PFS, median (95% CI), months8.5 (4.3-11.7)2.9 (1.4-5.1)OS, median (95% CI), months18.2 (13.6-NE)8.3 (5.6-20.6)cORR, % (95% CI)50 (33.8-66.2)16.7 (3.6-41.4)ER IHC 1-10%n = 35n = 17PFS, median (95% CI), months8.4 (5.6-12.2)2.6 (1.2-4.6)OS, median (95% CI), months20.0 (13.5-NE)10.2 (7.8-14.5)cORR, % (95% CI)57.1 (39.4-73.7)5.9 (0.1-28.7)CI, confidence interval; cORR, confirmed objective response rate; NE, not evaluable.1Reported as hormone receptor-negative cohort in Modi S et al. N Engl J Med. 2022;387:9-20. Open table in a new tab CI, confidence interval; cORR, confirmed objective response rate; NE, not evaluable. 1Reported as hormone receptor-negative cohort in Modi S et al. N Engl J Med. 2022;387:9-20. Efficacy, including survival, of T-DXd over TPC in pts with HER2-low ER 1-10% mBC was consistent with the outcomes observed in pts with HER2-low ER 0% mBC. T-DXd safety in the ER IHC 0-10% subgroup was manageable and consistent with the primary analysis.

Background AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. Methods Participants ( N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and “others” who were not randomised. Results Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (−13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/− 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. Conclusions By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. Trial registration Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have greatly improved survival in subjects with HER2-positive breast cancer (BC). However, there are many more subjects with BC with HER2-low expression (immunohistochemistry [IHC] 1+ or 2+/in situ hybridization negative), for whom no HER2-targeted therapies are approved. [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a humanized HER2 antibody, peptide-based cleavable linker, and topoisomerase I inhibitor payload. It has a drug-to-antibody ratio of 7 to 8, and the membrane permeability of the cleaved payload induces a cytotoxic bystander effect. In an ongoing, phase 1 study, T-DXd demonstrated an objective response rate (ORR) of 44.2% (19/43) with a manageable safety profile in heavily pretreated, advanced HER2-low BC (Modi et al, SABCS 2018). Results from the pivotal, phase 2 study of subjects with HER2-positive BC previously treated with [ado-] trastuzumab emtansine (DESTINY-Breast01) confirmed the activity observed in the phase 1 trial and will be presented at the meeting (Krop, et al). Here, we describe the phase 3 trial evaluating T-DXd in subjects with HER2-low BC. Study Description: DESTINY-Breast04 is a randomized, phase 3, 2-arm, open-label, multicenter trial comparing the efficacy and safety of T-DXd with investigator’s choice of treatment in HER2-low (IHC1+ or IHC2+/ISH−), unresectable and/or metastatic BC. The trial started in December 2018 and is recruiting subjects from 223 sites in North America, Europe, and Asia. Approximately 540 subjects (480 hormone receptor [HR]+ and 60 HR-) will be randomized (2:1) to T-DXd (5.4 mg/kg intravenously every 3 weeks) or investigator’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Randomization will be stratified by HER2 IHC status, number of prior treatments, and prior CDK4/6 inhibitor therapy/HR status. HER2 IHC will be assessed and confirmed by central testing based on archival samples. The primary efficacy endpoint is progression-free survival (PFS) per RECIST v1.1, determined by blinded independent central review. Secondary efficacy endpoints include investigator-assessed PFS, overall survival, ORR, and duration of response. Safety endpoints include treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest (including interstitial lung disease/pneumonitis, cardiotoxicity, and infusion-related reactions). For further information about this trial, visit ClinicalTrials.gov (NCT03734029). Citation Format: Shanu Modi, Shoichiro Ohtani, Caleb Lee, Yibin Wang, Kapil Saxena, David A. Cameron. A phase 3, multicenter, randomized, open-label trial of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs investigator’s choice in HER2-low breast cancer (DESTINY-Breast04) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-07-02.

Patients with pancreatic cancer experience significant benefit from treatment but are often not offered aggressive, life-prolonging therapies based on the historically poor prognosis of metastatic disease. The goal of this study was to improve the competency of oncologists in making optimal treatment choices for patients with metastatic pancreatic cancer. An online, interactive, text-based continuing medical education (CME)-certified activity was developed by Medscape Oncology. This activity included 2 patient cases, which served as the foundation for interactive questions. The educational design included a “test, then teach” approach to elicit cognitive dissonance, with evidence-based feedback provided, following each learner response. A repeated pairs pre-/post-assessment study design with 3 case-based questions and 1 confidence question was used. A chi-square test assessed differences from pre- to post-assessment. P values .26 is extensive). The activity was launched online 3/28/19 and data were collected through 5/9/19. Participation in education resulted in statistically significant improvements and an extensive educational effect for oncologists (n=167; p < 0.0001, V =.416). Oncologists on average responded correctly to pre-assessment questions 48% of the time, increasing to 87% post-assessment. 17% of oncologists had a measurable increase in confidence in their ability to select appropriate treatment regimens for patients with locally advanced or metastatic pancreatic cancer, based on disease- and patient-specific characteristics. Significant improvements in competency were observed in: selection of appropriate treatment regimens for patients with locally advanced or metastatic pancreatic cancer, based on disease- and patient-specific characteristics (e.g., performance status) (31% vs. 78%; p < 0.0001, V = .475 and 39% vs. 87%; p < 0.0001; V = .502) and coordinating care across the multidisciplinary team (73% vs. 95%; p < 0.0001; V = .292). This online, interactive, case-based, CME-certified educational activity resulted in significant gains in oncologist competency in selecting optimal therapy for patients with pancreatic cancer and coordinating care across the multidisciplinary teams. These results demonstrate the effectiveness of on-demand education in improving the translation of clinical knowledge into practice scenarios while improving clinician confidence.

Context. The 16 Myr old star 1SWASP J140747.93-394542.6 (V1400 Cen) underwent a series of complex eclipses in May 2007, interpreted as the transit of a giant Hill sphere filling debris ring system around a secondary companion, J1407b. No other eclipses have since been detected, although other measurements have constrained but not uniquely determined the orbital period of J1407b. Finding another eclipse towards J1407 will help determine the orbital period of the system, the geometry of the proposed ring system and enable planning of further observations to characterize the material within these putative rings. Aims. We carry out a search for other eclipses in photometric data of J1407 with the aim of constraining the orbital period of J1407b. Methods. We present photometry from archival photographic plates from the Harvard DASCH survey, and Bamberg and Sonneberg Observatories, in order to place additional constraints on the orbital period of J1407b by searching for other dimming and eclipse events. Using a visual inspection of all 387 plates and a period-folding algorithm we performed a search for other eclipses in these data sets. Results. We find no other deep eclipses in the data spanning from 1890 to 1990, nor in recent time-series photometry from 2012-2018. Conclusions. We rule out a large fraction of putative orbital periods for J1407b from 5 to 20 years. These limits are still marginally consistent with a large Hill sphere filling ring system surrounding a brown dwarf companion in a bound elliptical orbit about J1407. Issues with the stability of any rings combined with the lack of detection of another eclipse, suggests that J1407b may not be bound to J1407.

Abstract This abstract was withdrawn by the authors.

Background: ONT-380 is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities (severe skin rash and diarrhea). In preclinical studies, ONT-380 demonstrated synergistic activity with T, and was active in HER2+ models of brain metastases (mets). In a Phase 1b study, ONT-380 was combined with C and T in pts with HER2+ MBC previously treated with trastuzumab emtansine (T-DM1) and T. Objective responses were seen, including in pts with brain mets. The combination was well tolerated, with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID, equivalent to the single agent MTD). Based on these data, ONT-380 is now being evaluated in a Phase 2 study in combination with C and T (HER2CLIMB). Trial Design: The primary study objective is to assess the effect of ONT-380 vs. placebo given with C + T on progression-free survival (PFS) based on independent central review. Additional objectives include ORR, duration of response, clinical benefit rate, and safety. The study population includes adult pts with progressive HER2+ locally advanced or MBC who have had prior treatment with a taxane, T, pertuzumab and T-DM1 but not C or lapatinib. Pts with brain mets,including untreated or progressive mets, may be enrolled. 180 pts will be enrolled in North America and Europe. Pts are receiving C (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) and T (8 mg/kg IV loading dose; 6 mg/kg IV once every 21 days), and are being randomized in a 2:1 ratio to ONT-380 300 mg PO BID or placebo. Pts with isolated CNS progression may continue on study treatment after undergoing local CNS therapy. An independent Data Monitoring Committee is monitoring pt safety. Citation Format: Hamilton E, Borges V, Murthy R, Anders C, Cameron D, Carey L, Muller V, Curigliano G, Gelmon K, Hortobagy G, Krop I, Loibl S, Pivort X, Pegram M, Slamon D, Hurvitz S, Tsai M, Winer E. A phase 2 randomized, double-blinded, controlled study of ONT-380 vs. placebo in combination with capecitabine (C) and trastuzumab (T) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (MBC) (HER2CLIMB) [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 OT1-02-09.

Introduction: Evidence has recently emerged to suggest that mutations in the PIK3CA gene in colorectal cancer might identify patients that receive greater benefit from aspirin in the adjuvant setting. Add-Aspirin is a planned and funded, double blind, placebo-controlled, randomised trial assessing the potential benefits of aspirin after primary curative therapy for non-metastatic cancer (colorectal, gastro-oesophageal, breast and prostate cancer). Participants (n = 9920 which includes 2600 with colorectal cancer) will receive aspirin 100mg daily, aspirin 300mg daily or matching placebo for at least 5 years. Each tumour specific cohort is individually powered and has a separate co-primary outcome measure. Methods: We assessed current data on the association between PIK3CA mutation status and benefit from aspirin after a colorectal diagnosis, as well as other genetic mutations associated with benefit from aspirin to assess how this should be addressed within the setting of a planned randomised adjuvant trial. Results: Long-term follow-up of randomised trials designed to assess vascular benefits of aspirin, show that taking daily low-dose aspirin for 5 years reduces the incidence of cancer, particularly those that arise from the gastrointestinal tract (1). Observational data suggest aspirin is associated with a lower risk of developing BRAF-wild type colorectal tumours (2). Recent data on the association between PIK3CA mutation status, aspirin use and survival outcomes involve small numbers of patients with mutations, and include stage I-IV patients where the biological effects may be different and are not consistent (see table1). Conclusion: The potential benefits of aspirin include effects on both the development of primary tumours, as well as the development and spread of metastases which may involve different signaling pathways. To date the data suggest that patients with both mutated and wild type PIK3CA colorectal tumours may benefit from aspirin after a diagnosis of colorectal cancer. Add-Aspirin incorporates an active run-in period which can be utilised to ascertain PIK3CA mutation status in the colorectal cohort prior to randomisation and used as a stratification factor, providing a framework to investigate this important clinical question efficiently and reliably. Subgroup analyses by PIK3CA status are planned and accumulating data will be reviewed by an Independent Data Monitoring Committee ensuring the full potential benefits of aspirin are realised. References: 1. Rothwell, P.M., et al., Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet, 2011. 377(9759): p.31-41. 2. Nishihara, R., et al., Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA, 2013. 309(24): p.2563-71. 3. Liao, X., et al., Aspirin Use, Tumor PIK3CA Mutation, and Colorectal-Cancer Survival. NEJM, 2012. 367(17): p.1596-1606. 4. Domingo, E., et al., Evaluation of PIK3CA Mutation As a Predictor of Benefit From Nonsteroidal Anti-Inflammatory Drug Therapy in Colorectal Cancer. J Clin Oncol, 2013. 31(34): p.4297-305. 5. Kothari, N., et al., Regular aspirin (ASA) use and survival in patients with PIK3CA-mutated metastatic colorectal cancer (CRC). J Clin Oncol, 2014. 32 (suppl3; abstr386). 6. Reimers, M.S., et al., Low dose aspirin use after diagnosis, HLA class I tumour expression and colon cancer survival. JAMA Internal Medicine (in press), 2014.

At least three papers have now used comparisons of secular trends in age specific mortality in breast cancer to make inferences about the effectiveness of mammographic screening.1 2 3 4 However, Autier et al were circumspect in their interpretation, acknowledging that the “larger reduction in mortality in women <50 years old may reflect better targeting of effective treatments and response to …

Purpose:Biomarkers from two randomized phase III trials were analyzed to optimize selectionof patients for lapatinib therapy. Experimental Design: In available breast cancer tissue from EGF30001 (paclitaxelF lapatinib in HER-2-negative/unknownmetastatic breast cancer, n = 579) and EGF100151 (capecitabineF lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory. Results:The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P < 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among ‘‘HER-2-negative’’ breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory. Conclusions:Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib. Lapatinib (Tykerb/Tyverb) is an orally available, smallmolecule inhibitor of tyrosine kinase activity of both epidermal growth factor receptor (EGFR) type 1 (ErbB1 or HER-1) and type 2 (HER-2 or ErbB2). Lapatinib has been approved in combination with capecitabine for the treatment of women with HER-2-positive metastatic breast cancer that has progressed after treatment with an anthracycline, a taxane, and