Peter Dubsky

Purpose In PIK3CA mutant breast cancer, downstream hyperactivation of the PI3K/AKT/mTOR pathway may be associated with increased glycolysis of cancer cells. The purpose of this study was to investigate the functional association of PIK3CA mutational status and tumor glycolysis in invasive ER+/HER2− early breast cancer. Procedures This institutional review board-approved retrospective study included a dataset of 67 ER+/HER2− early breast cancer patients. All patients underwent 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography/X-ray computed tomography ([¹⁸F]FDG PET/CT) and clinico-pathologic assessments as part of a prospective study. For this retrospective analysis, pyrosequencing was used to detect PIK3CA mutations of exons 4, 7, 9, and 20. Tumor glucose metabolism was assessed semi-quantitatively with [¹⁸F]FDG PET/CT using maximum standardized uptake values (SUV_max). SUV_max values were corrected for the partial volume effect, and metabolic tumor volume was calculated using the volume of interest automated lesion growing function 2D tumor size, i.e., maximum tumor diameter was assessed on concurrent pre-treatment contrast-enhanced magnetic resonance imaging. Results PIK3CA mutations were present in 45 % of all tumors. Mutations were associated with a small tumor diameter (p < 0.01) and with low nuclear grade (p = 0.04). Glycolytic activity was positively associated with nuclear grade (p = 0.01), proliferation (p = 0.002), regional lymph node metastasis (p = 0.015), and metabolic tumor volume (p = 0.001) but not with tumor size/T-stage. In invasive ductal carcinomas, median SUV_max was increased in PIK3CA-mutated compared to wild-type tumors; however, this increase did not reach statistical significance (p = 0.05). Multivariate analysis of invasive ductal carcinomas revealed [¹⁸F]FDG uptake to be independently associated with PIK3CA status (p = 0.002) and nuclear tumor grade (p = 0.046). Size, volume, and regional nodal status had no influence on glycolytic activity. PIK3CA mutational status did not influence glycolytic metabolism in lobular carcinomas. Glycolytic activity and PIK3CA mutational status had no significant influence on recurrence-free survival or disease-specific survival. Conclusions In ER+/HER2− invasive ductal carcinomas of the breast, glucose uptake is independently associated with PIK3CA mutations. Initial data suggest that [¹⁸F]FDG uptake reflects complex genomic alterations and may have the potential to be used as candidate biomarker for monitoring therapeutic response and resistance mechanisms in emerging therapies that target the PI3K/AKT/mTOR pathway.

The St Gallen Writing Committee on behalf of the St Gallen Panel thanks the authors for their letter [1]. The St Gallen Consensus process is built upon the collective recommendations from a multidisciplinary, international panel of breast cancer experts, including radiation/clinical oncologists. The goal is to recommend standard approaches to breast cancer management based on the integration of data from clinical trials and other types of evidence including subset analyses, and outcomes from biologically determined subtypes of breast cancer with experiences drawn from contemporary practice including innovations in surgery, radiotherapy, and systemic treatment. We note that the recent AJCC staging revisions also now integrate traditional stage distribution with biologically determined breast cancer subtypes for most appropriately gauging clinical risk. The St Gallen Panel provides consensus [2] on many controversial areas but does not adhere to a process prerequisite for broad guidelines.

E12050 Background: Mutations in the PIK3CA gene encoding are most common in ER+/HER2- breast cancers. PIK3CA mutational status, is a molecular trait with a relevant biologic downstream effect that can be quantitatively assessed using [¹⁸F]FDG PET/CT and thus might be used to translate imaging into indications such as prognostic and predictive assessments in ER+/HER2- breast cancers. In this study we test the relationship of PIK3CA mutational status and other tumor characteristics with aerobic glycolysis in primary ER+/HER2- breast cancers. Methods: In this IRB approved prospective study tissue samples of 70 early primary ER+/Her2- breast cancers without distant metastasis were assessed for PIK3CA mutational status. Pyrosequencing was used to detect PIK3CA mutations of exons 4, 7, 9 and 20. Glucose-uptake of breast tumors was assessed quantitatively with [¹⁸F]FDG PET/CT using standardized uptake values (SUVmax). Results: PIK3CA mutations were detected in 32 patients (46%), a wild-type status in 38 patients. Mean SUVmax values were 5.54 (CI 4.21 – 6.87) and 4.64 (CI 3.71 – 5.58) (p = 0.257). A significant correlation of G1 tumors and PIK3CA mutations was found in IDC patients (p < 0.05). In 22 patients (31%) axillary lymph node metastases were found, which were associated with increased SUVmax levels (p < 0.01). SUVmax correlated positively with Ki67 (r = 0.53; p < 0.01) and tumor size (r = 0.25; p < 0.05). Stratified by PIK3CA status correlation of SUVmax and tumor size increased in the mutation subgroup (r = 0.53; p < 0.01). In subgroup analysis tumors with a PIK3CA-mutation and ≥ 2cm show a mean SUVmax of 8.08 vs 4.49 in wild-type tumors or tumors < 2cm (p < 0.001). SUVmax < 6.00 can depict a wild-type status in tumors ≥ 2cm (PPV 87%). Conclusions: Patients with early ER+/HER2- BC and PIK3CA mutations demonstrated higher [¹⁸F]FDG avidity compared to patients with wild-type tumors. Due to the small sample size significant differences could not be identified. Tumors ≥ 2cm with a SUVmax > 6 are frequently associated with a PIK3CA-mutational genotype. Thus, these patients may benefit from additional [¹⁸F]FDG PET/CT for guidance of prognostic and predictive assessments.

TPS613 Background: Taselisib is an orally bioavailable, potent, selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the alpha isoform showing enhanced activity against PIK3CA mutant cancer cell lines. Clinical data have demonstrated confirmed partial responses in patients with PIK3CA mutant breast cancer (BC) treated with single-agent taselisib. Enhanced antitumor activity has been noted when taselisib is combined with either letrozole or fulvestrant in preclinical and Phase Ib clinical studies. Methods: LORELEI is a Phase II, two-arm, randomized, double-blind, multicenter, study of neoadjuvant letrozole and taselisib versus letrozole and placebo in postmenopausal women with newly diagnosed ER+/HER2-, untreated, Stage I-III operable BC. Other eligibility criteria include tumor size ³ 2 cm by magnetic resonance imaging (MRI), ECOG PS 0-1, and evaluable tumor tissue for PIK3CAgenotyping. Patients treated with anti-diabetic drugs are not eligible. Patients are randomized (1:1) to receive continuous letrozole (2.5 mg) with either taselisib (4 mg on a 5 days on/ 2 days off schedule) or placebo for 16 weeks, followed by surgery. Stratification is based on tumor size and nodal status. The co-primary endpoints are overall objective response rate (ORR) by centrally assessed breast MRI via modified RECIST criteria and pathologic complete response (pCR) rate in breast and axilla at time of surgery in all randomized patients and PIK3CA mutant patients. Secondary endpoints include ORR by centrally-assessed MRI and pCR rate in PIK3CAwild-type patients. The sample size was calculated to detect an absolute percentage increase of 24% in ORR with 80% power at 16% 2-sided alpha and an absolute percentage increase of 18% in pCR rate with 80% power at 4% 2-sided alpha. An interim safety analysis has been conducted by an IDMC with the recommendation of continue the trial without modifications. As of 7 Jan 2016, 198 of the 330 patients have been enrolled, and global enrollment is ongoing. Clinical trial information: NCT02273973.

Validated multigene signatures (MGS) provide additional prognostic information when evaluating clinical features of ER(+), HER2(-) early breast cancer. We have studied the quantitative and qualitative impact of MGS on multidisciplinary team (MDT) recommendations. We prospectively recruited 75 ER(+), HER2(-) breast cancer patients. Inclusion was based on biopsy assessment of grade, hormone receptor status, HER2, clinical tumour and nodal status. A fresh tissue sample was sent for MammaPrint (MP), TargetPrint analysis at surgery. Clinical risk was decided by the MDT in the absence of MP results and repeated following the collection of MP results. Decision changes were recorded and a health technology assessment was undertaken to compare cost effectiveness. The majority of patients were assigned low to intermediate clinical risk by the MDT. According to MP, 76% were low risk. A very high correlation between local IHC and the TargetPrint assessment was shown. In over a third of patients, discordance between clinical and molecular risk was observed. Decision changes were recorded in half of these cases (18.6%) and resulted in two out of three patients not requiring chemotherapy. The use of MP was also found to be more cost effective. The multigene signature MP revealed clinical and molecular risk discordance in a third of patients. The impact of this on MDT recommendations was most profound in cases where few clinical risk factors were observed and enabled some women to forgo chemotherapy. The use of MGS is unlikely to have an impact in either clinically low-risk women or in patients with more than one relative indication for chemotherapy.

Background: ER+/HER2− breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. Methods: A total of 1702 postmenopausal ER+/HER2− breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan–Meier method and Cox regression analysis were used in an early (0–5 years) and late time interval (>5 years post diagnosis). Results: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. Conclusion: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

148 Background: Triple-negative breast cancer (TNBC) patients (pts) without pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) have an unfavourable prognosis. ABCSG trials 14 and 24 defined 6 cycles of epirubicin/docetaxel (+/- capecitabine) as active NAC regimen; pts without pCR commonly received another 4-8 cycles of adjuvant CMF. Different studies suggested that breast tumours harbouring BRCA-1 germline mutations were resistant to taxane-based therapy while sensitivity to DNA-damaging agents was retained. BRCA-1 mutations are rare in sporadic BC; BRCA-1 promotor methylation (PM), however, is frequently observed. We hypothesized that pts with TNBC harbouring BRCA1 PM would benefit from adjuvant CMF salvage therapy. Methods: For this analysis, we included all pts with TNBC refractory to taxane-based NAC who received adjuvant CMF. DNA was extracted from formalin-fixed paraffin-embedded tissue samples, purified and bisulfite-converted. The TaqMan assay was used in order to perform a quantitative methylation-specific PCR. Actin-b was used as reference gene to normalise the amount of provided DNA; bisulfite-converted, artificially methylated DNA was used as positive control. Results: Twenty-four pts, median age 47 years, were available for this analysis. In 9/24 pts (37.5%), BRCA-1 PM was detected. At a median follow-up of 27.5 months, 1/9 pts (11.1%) with BRCA-1 PM had a disease-free survival (DFS) event, as compared to 10/15 (66.6%) in the non-methylated group (p = 0.013; Fisher’s exact test). Kaplan Meier estimation of DFS in the non-methylated group was 24 months (95% CI 14.06-33.94) and was not reached in the methylated group (n.s.). Conclusions: In TNBC refractory to taxane-based NAC, adjuvant CMF is of limited efficacy. In tumours harbouring BRCA-1 PM, however, a significant decrease of DFS events was observed. Therefore, tumours harbouring defects in genetic repair mechanism might be exceptionally sensitive to drugs causing DNA-damage. Further clinical investigation of this concept is warranted.