Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.
Introduction Chronic kidney disease (CKD) has a prevalence of 9.1% globally, and frequently results in elevated serum phosphate, increasing cardiovascular morbidity and mortality risk in hemodialysis (HD) patients. DS-2330b, an oral NaPi-IIb inhibitor, reduced intestinal phosphate absorption in preclinical studies, but its effect in patients with CKD is unknown. This 2-part, randomized, placebo- and active-controlled, single- and repeated-dose, phase 1b study evaluated safety and efficacy of DS-2330b in patients with CKD on HD. Methods Part A, a 2-period, 2-way study, evaluated safety and pharmacokinetics of DS-2330b 250 mg in solution and tablet formulations. Part B assessed the safety of DS-2330b in solution (chosen based on results of part A) and its effect on serum phosphate. Patients were randomized to placebo 3 times daily (TID), DS-2330b 400 mg TID, DS-2330b 400 mg with sevelamer 1.6 g TID, and sevelamer 1.6 g with placebo TID for 14 days. Safety endpoints included adverse event (AE) monitoring. Results Six patients completed part A. Two patients experienced serious AEs considered unrelated to DS-2330b treatment. Thirty-two patients enrolled and completed part B. Serum phosphate mean change from baseline ± SD was −2.2±1.5 mg/dl versus −1.9 ± 1.1 mg/dl for DS-2330b monotherapy versus placebo. Patients receiving DS-2330b with sevelamer or sevelamer with placebo experienced the greatest serum phosphate decrease from baseline. Nine patients (28.1%) experienced ≥1 treatment-emergent AE (TEAE); 7 patients experienced drug-related TEAEs. The TEAE incidence was comparable between DS-2330b and control groups. Conclusions DS-2330b, alone or in combination with sevelamer, was safe and well tolerated but did not demonstrate clinically meaningful efficacy in HD patients.
Introduction: The addition of adjuvant chemotherapy to hormonal therapy is recommended for patients with lymph node-positive (LN+ve), estrogen receptor positive (ER+), HER2-ve early breast cancer, despite the fact that many women will remain disease-free even if they do not receive chemotherapy. Therefore, a number of patients with LN+ EBC may be unnecessarily exposed to the toxicities of chemotherapy with no treatment benefit. In the UK, the Oncotype DX® Recurrence Score (RS) is recommended by NICE for routine testing in patients with ER+ HER2-ve, lymph node negative early stage breast cancer. Approximately 32% of newly diagnosed breast cancer patients will have lymph node involvement but do not have distant metastasis at the time of diagnosis. Objectives: Primary objective is to characterize how the results on the Oncotype DX® assay impact the decision-making process of physicians in the UK for women with ER+ HER2-ve EBC with 1-3 lymph nodes involved who are potential candidates for chemotherapy, but for whom the benefits may be uncertain. Secondary objectives include; (1) Assess the impact of the Oncotype DX RS in clinical practice in patients with 1-3 lymph nodes positive EBC, (2)Analyse distribution of RS and (3)Observe the percentage of patients not receiving chemotherapy as a result of the Oncotype DX RS. Methods: Postoperative patients with lymph node positive disease: N=720. Micrometastasis = 70patients, 1 Lymph Node Positive = 400patients, 2 Lymph Node Positive = 200patients & 3 Lymph Node Positive = 50patients (exploratory analysis). Study start date October 2017 to projected study end date of December 2021. INTERIM Results: To date, 194 patients have entered the Oncotype DX Node POS Study since October 2017 from 13 recruiting institutions across the UK. The nodal status is as follows; micrometastasis = 21patients (10%), 1 lymph node positive = 103 patients (53%), 2 lymph node positive = 53 patients (27%) and 3 lymph node positive =17 patients (9%). The average age of patient was 57.5years (range 27-79). Of 194 patients, 189 have received a recurrence score in the 1-3 lymph node positive setting. Average RS was 13.8 (range 0-63). Micrometastasis category received an average RS of 15, 1 LN+ve category received an average RS of 15.5, 2 LN+ve category received an average RS of 15.8 and 3 LN+ve category received an average RS of 20.8. Of 189 patients the decision to administer chemotherapy changed in 140 patients (74%) once the Oncotype DX score had been received. Decision to administer chemotherapy remained the same in 49 patients (26%). This shows that Oncotype DX greatly alters the decision-making process in patients with 1-3 LN+ve, despite the trial not setting a chemotherapy cut-off score. Those patients who received a recurrence score of 18 or below = 129 (68%). Patients who received a recurrence score of above 18 = 60 (32%). The largest nodal category (1 LN+ve) witnessed the highest rate of patients receiving a RS of below 18 (70%), followed by 2 LN+ve (66%) and 3 LN+ve (43%). One patient with 2 lymph nodes positive received a RS of zero. Weak correlation was observed between histopathological factors and recurrence score. Conclusion: Interim results show the use of the Oncotype DX assay in patients with 1-3 lymph node-positive (LN+ve), ER+ HER2-ve, EBC significantly alters the decision-making process in guiding use of chemotherapy. Result show that 74% of patients were spared chemotherapy where there was deemed to be no additional benefit over hormonal therapy alone. This resulted in 140 patients being spared the unnecessary side effects and exposure to toxicities of chemotherapy. This also prevented overtreatment of patients from a healthcare economic cost perspective. Citation Format: Daniel Thomas, William Maxwell, Caroline Archer, Anne Rigg, Tamas Hickish, Jo Dent, Laura Pettit, Marianne Dillon, Christy Goldsmith, Mark Verrill, Ludger Barthelmes, Saira Khawaja, Yousef Sharaiha, Mark Davies, Fawaz Arikat, Sahail Khan, Asma Munir, Anita Huws, Simon DavidHenry Holt. Impact of the Oncotype DX breast cancer assay on treatment decisions in a UK population of patients with oestrogen receptor positive early breast cancer with 1-3 lymph nodes positive who are candidates for chemotherapy, but for whom the benefits are uncertain - Interim results [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 OT3-17-03.
Primary Osteosarcoma of the breast is an aggressive and relatively rare tumour whose prognosis is very poor.It is often a diagnostic dilemma to the pathologists and the surgeons are perplexed due to its aggressive behaviour as its pathology and prognostic factors are unclear. Due to its rarity we suggest pooling of tissue samples from various centres in biobanks for future studies (including molecular biological studies) so that its behaviour can be better understood.
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