We have observed a decrease in Ki67 and ER and a rise in PgR after 14 days of treatment with tamoxifen that was related to subsequent response. This is the first study in which an early decrease in a proliferation marker has been shown to relate to subsequent clinical response.

This study was undertaken to evaluate our ability to detect multiple molecular markers of prognosis and response to treatment in fine needle aspirates (FNA) from patients with primary breast carcinomas. 147 patients with operable primary breast carcinomas who had been recruited to a randomized trial of primary medical therapy (PMT) versus adjuvant chemoendocrine therapy were analysed. FNAs were taken prior to therapy and from this multiple slides were produced using cytospin cytocentrifugation and stored at -80 degrees C for subsequent immunocytochemical analysis (ICA). ICA was performed for oestrogen receptor (ER), progesterone receptor (PgR), p53, Ki67, and Bcl-2. Part of the aspirate was snap frozen and used for flow cytometric analysis of ploidy and S-phase fraction (SPF). In a subgroup of 50 patients who had surgery prior to systemic therapy, as well as FNAs, sections were also taken from paraffin-embedded blocks and stained by ICA for ER, PgR and p53 for validation. In these patients ER was additionally measured by enzyme immunoassay (EIA) from frozen tissue taken at surgery. ER, PgR, p53, Bcl-2, and Ki67 were successfully detected by ICA while ploidy and SPF were successfully measured by flow cytometry from FNA material. The percentage positive values obtained were reasonable and as follows: 74% for ER, 70% for PgR, 36% for p53, 80% for Bcl-2,68% of tumours were aneuploid and 32% diploid. Significant relationships between these measurements were observed in accordance with expectations. The concordance for ER, PgR, and p53 from FNA when compared to ICA of matching histological sections was 91.5%, 75.5%, and 75% respectively. For ER the concordance between measurement by ICA of cytological and histological samples and by EIA of frozen tissue was 82.5% and 84% respectively. These results indicate that multiple molecular markers can be adequately tested on cytological preparations from primary breast tumours. These markers can be used to determine prognosis and predict response to PMT.

Background IMPORT HIGH is a randomised, multi-centre phase III trial testing dose escalated simultaneous integrated boost (SIB) against sequential boost each delivered by intensity modulated radiotherapy (IMRT) for early stage breast cancer with higher risk of local relapse. The primary endpoint was initially breast induration at 3 years, requiring 840 patients; accrual was extended (target 2568) with the new primary endpoint of local relapse. We report adverse effects (AE) at 3 years. Methods Women age ≥18 after breast conservation surgery for pT1-3 pN0-pN3a M0 invasive carcinoma were eligible. Randomisation was 1:1:1 between 40Gy/15F to whole breast (WB) + 16Gy/8F sequential photon boost to tumour bed (40+16Gy), 36Gy/15F to WB, 40Gy to partial breast + 48Gy (48Gy) or + 53Gy (53Gy) in 15F SIB to tumour bed. AEs were assessed annually by clinicians in all patients and in a planned sub-set (840) of patients by photographs at 3 years and by patients at 6 months, 1 and 3 years. AE scores were dichotomised as none/mild vs marked for photographs and none/mild vs moderate/marked for patients and clinicians. Fisher's exact tests compared groups; principal comparison (protocol-specified) between 53Gy and 48Gy (p<0.01 defined as statistical significance). Results 2617 women consented between 03/2009 and 09/2015 from 39 UK radiotherapy centres. Median follow-up was 49.1 (IQR 36.8-63.2) months. Median age was 49 (IQR 44-56); 9%, 38% & 53% were tumour grade 1, 2 & 3 respectively; 30% were node positive. 66% received chemotherapy and 73% endocrine therapy. 3-year AE data were available for 2017 clinician assessments, 641 photographs and 842 patient assessments. Proportions of patients with marked AEs were low overall. Rates of moderate/marked AEs at 3 years were broadly similar between the randomised groups; with a suggestion of a slightly increased risk for breast induration in 53Gy compared with control (borderline significance). AE at 3 years 40+16Gy n(%)48Gy n(%)53Gy n(%)ClinicianBreast induration;N656668654None451 (69)483 (72)445 (68)Mild167 (25)141 (21)146 (22)Moderate32 (5)42 (6)56 (9)Marked6 (1)2 (1)7 (1)P-value 0.57010.0102  0.0443Breast shrinkage;N655669654None442 (68)472 (71)448 (69)Mild167 (26)161 (24)166 (25)Moderate40 (6)33 (5)35 (5)Marked6 (1)3 (1)5 (1)P-value 0.25410.5772  0.6373Breast distortion;N656669654None451 (69)464 (69)442 (68)Mild169 (26)170 (25)170 (26)Moderate33 (5)32 (5)38 (6)Marked3 (1)3 (1)4 (1)P-value 0.90310.4862  0.4113PatientChange in breast appearance;N287264285None38 (13)50 (19)58 (20)Mild164 (57)151 (57)142 (50)Moderate57 (20)45 (17)54 (19)Marked28 (10)18 (7)31 (11)P-value 0.14910.9992  0.1243PhotographChange in breast appearance;N218210213None183 (84)185 (88)177 (83)Mild25 (11)23 (11)32 (15)Marked10 (5)2 (1)4 (2)P-value 0.03610.1732  0.6853148Gy v 40+16Gy; 253Gy v 40+16Gy; 353Gy v 48Gy Conclusions These results represent the largest and most mature reported AE outcomes of breast SIB within a clinical trial. At 3 years, rates of moderate/marked AEs were similar between SIB IMRT and WB + sequential boost IMRT delivered over 3 and 4.5 weeks respectively. Citation Format: Coles CE, Griffin CL, Kirby AM, Haviland JS, Titley JC, Benstead K, Brunt AM, Chan C, Ciurlionis L, Din OS, Donovan EM, Eaton DJ, Harnett AN, Hopwood P, Jefford ML, Jenkins PJ, Lee CE, McCormack M, Sherwin L, Syndikus I, Tsang Y, Twyman NI, Ventikaraman R, Wickers S, Wilcox MH, Bliss JM, Yarnold JR. Dose escalated simultaneous integrated boost radiotherapy for women treated by breast conservation surgery for early breast cancer: 3-year adverse effects in the IMPORT HIGH trial (CRUK/06/003) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-05.