Background: Patients diagnosed with primary breast cancer (BC) often have a couple weeks interval between diagnosis and definitive surgery. This time window provides the opportunity for assessing biological drug effects in a treatment naive population. The EPHOS-B trial was designed to measure the effect of pre-operative anti-HER2 therapy on proliferation and apoptosis in HER2+ BC patients. Patients & methods: EPHOS-B is a multicentre, 2-part randomized trial in patients with operable newly diagnosed HER2+ primary BC. In Part 1 patients were randomized (1:2:2) to no perioperative treatment (control), trastuzumab only or lapatinib only (11 days pre-operative therapy). Emerging evidence on the efficacy and safety of combination anti-HER2 therapy led to Part 2 in which patients were allocated to control, perioperative trastuzumab only or lapatinib and trastuzumab (1:1:2). The IDMC have agreed release of data from lapatinib Part 1 patients only. Tissue samples were taken at the time of diagnostic core biopsy and surgery, and analysed centrally for Ki67, apoptosis (activated caspase 3), PgR, HER3 and Bcl2 by immunohistochemistry (IHC). Local ER and PgR status were also recorded. Primary endpoint is change in Ki67 and/or apoptosis. Response is defined by a drop in Ki67 of ≥30% or a rise in apoptosis of ≥30% from baseline. Results: Between Nov-2010 and Jul-2013, 51 patients (pts) were allocated to perioperative lapatinib, with 49 (96.1%) receiving at least 1 dose. All pts were HER2+ (90% 3+ by IHC and 10% amplified by FISH, locally assessed) at entry. Median age was 51 years (IQR 48-60); 65% had tumours >2cm and 51% were grade 3 at surgery. According to local assessment, 61% were ER+ and 43% PgR+. Only 2 pts (4%) had a dose reduction and 1 pt (2%) discontinued lapatinib in the 3 days prior to surgery due to toxicity (rash, 3pts; nausea, 1pt). There were no delays in surgery. Paired samples were valid for analysis in 43/51 (84%); invalid pairs were mostly due to inadequate samples for scoring. Overall, 67% (95% CI: 52% to 81%) of pts demonstrated a ≥30% fall in Ki67 whilst a ≥30% rise in apoptosis was observed only in 30% of pts (95% CI: 17% to 46%). When assessed as continuous variables, Ki67 fell significantly from pre-treatment but there was no significant change in apoptosis detected (results in table). No correlation was observed between Ki67 change and change in apoptosis (p=0.5). Neither HER-3 expression nor BCL2 predicted response.  ER- HER2+, n=18ER+ PR- HER2+, n=7ER+PR+HER2+, n=17All, n=43*Ki67 % change from pre treatment-51% (-69% to -21%), p<0.001-53% (-78% to -11%), p=0.02-38% (-58% to -24%), p<0.001-45% (-57% to -32%), p<0.001Apoptosis % change from pre treatment-24% (-37% to +30%), p=0.27-13% (-48% to +125%), p=0.61-13% (-65% to +43%), p=0.19 Median % change (95% confidence interval), p-value: Wilcoxon signed-rank test. *1 pt missing ER status Conclusion: EPHOS-B demonstrates that ∼11 days' lapatinib has a marked anti-proliferative effect in HER2+ve breast cancers. The trial is ongoing and when complete will provide a definitive analysis of the relative biological effects of perioperative treatment with different anti-HER2 therapies (trastuzumab, lapatinib and their combination) in patients with HER2+ BC. Citation Format: Bundred N, Cameron D, Kalaitzaki E, Morley R, Cramer A, Webster-Smith M, Narayanan S, Brunt M, Horgan K, Hanby A, Ooi J, Hong A, Naik J, Evans A, Shaaban A, Bliss J. Effects of perioperative lapatinib in early HER2+ breast cancer - The UK EPHOS-B trial (CRUK/08/002). [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 PD5-06.

Background Perioperative therapy offers the opportunity to measure biological response to treatment in the primary tumor in early breast cancer (EBC), enhancing prospects for personalised medicine. Perioperative trials form an expanding component of the UK national breast cancer trials portfolio. Unlike traditional neoadjuvant studies, activity dovetails around timelines for standard treatment with no planned delay to primary surgery. Tissue samples collected prior to randomisation (baseline) & again at surgery address key biological endpoints & are essential for perioperative studies. Methods: As the UK's largest perioperative trial, POETIC (ER+ve postmenopausal EBC, +/− aromatase inhibitor therapy, biomarker & disease outcome) aims to recruit 4000 patients from 100+ centres. EPHOS-B (HER2+ve EBC, +/− lapatinib or trastuzumab) focuses on biomarker endpoints & aims to recruit 250 patients. Barriers to recruitment included 1) integration of research protocols into busy breast surgical clinics, extending a clinical trials culture across a multidisciplinary breast diagnostic team, & ensuring appropriate GCP training, 2) satisfying requirements for storing research tissue, 3) complying with government cancer wait times, 4) obtaining biomarker results within required timelines 5) ensuring completeness & quality of tissue samples. Additional challenges for EPHOS-B include managing requirements for scheduling of oncological therapy (e.g. trastuzumab) in pre-operative setting, delivery of such therapy outside the randomising hospital & rapid access to cardiac screening before randomisation. Results: The following strategies were developed to overcome barriers 1) increasing collaborative working at sites & adopting a pragmatic approach to type of tissue required. Centres choose to provide both FFPE tissue & tissue in RNA-later, or FFPE tissue only; 2) working with national regulators to agree interpretation of current legislation in designation of when tissue is “in transit” (enabling it to reside outside a tissue bank) & “research” tissue (where transfer to a tissue bank is required); 3) agreement with government that procedures integral to perioperative trials comply with cancer wait times; 4) promoting reorganisation of site processes for obtaining essential biomarker results; 5) pilot lab work to inform site guidance on tissue collection procedures to ensure quality of samples received. A tracking database allows completeness of tissue samples to be monitored. Work to improve timelines for HER2 testing in EPHOS-B is ongoing, & challenges of delivering anti-HER2 therapy in this setting have been addressed. Conclusions: Assessment of biological response to therapy in the primary tumor in EBC within national trials is feasible. Many barriers faced by POETIC have been overcome, & with recruitment now 100+ patients per month, newer centres benefit from earlier experience. Lessons learnt in POETIC apply to EPHOS-B, allowing investigators to focus on resolving more challenging issues specific to that trial. In many centres both trials have been important drivers in improving timeliness of molecular testing & therefore benefited the patient pathway in general as well as securing high quality trial data. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-03-04.

Neoadjuvant therapy is given before surgery to improve resectability, local control and/or survival. Post-operative radiation therapy for locally advanced rectal cancer has been long accepted, and since 1990 adding fluorouracil (5FU) chemotherapy became the NIH standard. However, trials then showed that pre-operative radiotherapy followed by surgery improved local control over surgery alone, but had a less consistent effect on overall survival. The German trial (Sauer, NEJM, 2004, 351:1731) showed a 5 year local relapse rate of 6% for pre-operative chemo-radiotherapy and 13% for post-operative chemo-radiotherapy for T3 or T4 or node-positive rectal cancer treated by TME. The EORTC 22921 trial (37% had TME) showed a similar reduction in local recurrence whether 5FU/leucovorin chemotherapy was given with pre-operative radiotherapy, after pre-operative radiotherapy plus surgery, or both (Bosset, NEJM, 2006, 355:1114. Trials show increased rates of complete pathological remission, increased acute toxicity, but no consistent effects on sphincter preservation rates or overall survival when chemotherapy is combined with pre-operative radiation.Many questions remain. The TROG/AGITG trial compares pre-operative radiotherapy as a short course (5 Gy X 5#) or long course with chemotherapy (50.4 Gy plus 5 FU infusion), with accrual just completed. Ongoing phase III trials explore capecitabine, adding other drugs to 5 FU, and post-operative adjuvant chemotherapy.Neo-adjuvant pre-operative radiation with concurrent chemotherapy, unless contra-indicated by comorbidity, has become widely accepted for T3 or T4 or node-positive rectal cancer based on MRI staging. Individual patient care is best planned by a multidisciplinary team.