Monitoring tumour burden and therapeutic response through analyses of circulating cell-free tumour DNA (ctDNA) and extracellular RNA (exRNA) in multiple myeloma (MM) patients were performed in a Phase Ib trial of 24 relapsed/refractory patients receiving oral azacitidine in combination with lenalidomide and dexamethasone. Mutational characterisation of paired BM and PL samples at study entry identified that patients with a higher number of mutations or a higher mutational fractional abundance in PL had significantly shorter overall survival (OS) (p = 0.005 and p = 0.018, respectively). A decrease in ctDNA levels at day 5 of cycle 1 of treatment (C1D5) correlated with superior progression-free survival (PFS) (p = 0.017). Evaluation of exRNA transcripts of candidate biomarkers indicated that high CRBN levels coupled with low levels of SPARC at baseline were associated with shorter OS (p = 0.000003). IKZF1 fold-change <0.05 at C1D5 was associated with shorter PFS (p = 0.0051) and OS (p = 0.0001). Furthermore, patients with high baseline CRBN coupled with low fold-change at C1D5 were at the highest risk of progression (p = 0.0001). In conclusion, this exploratory analysis has provided the first demonstration in MM of ctDNA for predicting disease outcome and of the utility of exRNA as a biomarker of therapeutic response.

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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 &gt;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&lt;0.001-53% (-78% to -11%), p=0.02-38% (-58% to -24%), p&lt;0.001-45% (-57% to -32%), p&lt;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.

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