Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in combination with fulvestrant in treatment refractory advanced breast cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1064-1064 ◽  
Author(s):  
Anna M. Varghese ◽  
Kathleen N. Moore ◽  
Erika Paige Hamilton ◽  
David Michael Hyman ◽  
Komal L. Jhaveri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Partial Response ◽  
Cancer Patients ◽  
Oral Mucositis ◽  
Phase 1 ◽  
Pik3ca Mutation ◽  
Mucosal Inflammation ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer ◽  
Biomarker Analysis

1064 Background: Thephosphatidylinositol 3-kinase (PI3K) /mammalian target of rapamycin (mTOR) pathway is frequently activated in breast cancer. LY3023414 (LY) is an oral ATP- competitive inhibitor that selectively and potently inhibits class I PI3K isoforms, mTOR, and DNA-PK. The recommended phase 2 dose (RP2D) of LY monotherapy was previously established to be 200 mg twice daily (BID). Here we present the safety and preliminary activity data of LY in combination with fulvestrant (F) for breast cancer patients (pts) as part of a multi-cohort Phase 1 study. Methods: Pts with advanced HR+, HER2- breast cancer refractory to standard treatment received 200 mg LY BID + 500 mg F (day 1 and 15, then once monthly). Eligible pts had measurable disease and baseline tumor tissue available. Primary objective was to determine a RP2D. Other objectives included assessment of pharmacokinetics (PK), antitumor activity, and biomarker analysis. Results: 9 pts received LY + F in the breast cancer expansion cohort. All pts had multiple lines of prior systemic therapy (range 3-12), including chemotherapy. Dose limiting toxicity was observed in one pt in the form of grade (Gr) 3 oral mucositis. Common possibly related adverse events included nausea (5 pts), vomiting (4 pts), oral mucositis (4 pts), decreased appetite (3 pts), fatigue (3 pts), mucosal inflammation (2 pts), and paresthesia (2 pts). No obvious impact of LY on F PK or of F on LY PK was observed. Median duration of treatment was 15 weeks (range 3-63). In the 6 pts evaluable for tumor response, there was 1 durable partial response according to RECIST (still on treatment for ≥11 months) and 4 further pts had a decrease in their target lesions for a disease control rate of 56%. The median progression-free survival for this cohort is 4.2 months (90% CI 1.8, NA). Of note, the partial response was observed in a pt harboring an activating PIK3CA mutation (H1047R). Further biomarker analysis is ongoing. Conclusions: The RP2D of LY in combination with F is 200mg BID and may cause tumor regression or stabilization in breast cancer pts. Clinical trial information: NCT01655225.

Impact of PIK3CA tumor mutation on the association of aspirin or NSAID use and time to breast cancer recurrence.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1521-1521 ◽  
Author(s):  
Anne Marie McCarthy ◽  
Wei He ◽  
Susan Regan ◽  
Andrew T. Chan ◽  
Beverly Moy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Pik3ca Mutation ◽  
Cancer Recurrence ◽  
Primary Diagnosis ◽  
Breast Cancer Recurrence ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer ◽  
N Use ◽  
Tumor Genotyping

1521 Background: Aspirin or NSAID (A/N) use post diagnosis is associated with lower risk of breast cancer recurrence and mortality in cohort studies. A potential mechanism is that A/Ns may suppress cell growth and induce apoptosis in tumors driven by phosphatidylinositol 3 kinase ( PIK3CA), the most common oncogene mutation in breast cancer. An interaction of A/Ns and PIK3CA mutation has been observed for colorectal cancer prognosis, but has not been studied in breast cancer. The objective was to assess time to breast cancer recurrence (TTR) with respect to A/N use and PIK3CAmutation. Methods: Patients with HR+/HER2- breast cancer treated at Massachusetts General Hospital in 2009-2014 who received tumor genotyping were included. PIK3CA mutations, including 8 common hotspot mutations, were assessed by a high-throughput tumor genotyping assay using DNA from formalin-fixed, paraffin-embedded tumor tissue. A/N use beginning 6 months post diagnosis through metastasis was extracted from electronic medical records using coded data and natural language processing. Patients with de novo metastatic disease or progressive disease within 6 months of primary diagnosis were excluded. TTR was estimated using Cox proportional hazards models. Results: Among breast cancer patients (N=212), 60 (28%) used A/Ns and 69 (33%) had PIK3CA mutation (see Table). After adjusting for age, stage, adjuvant endocrine therapy, radiation, and chemotherapy, A/N users had significantly longer TTR (HR=0.65 p=0.01). The association was similar for wild type (HR=0.58 p=0.01) and PIK3CA mutated tumors (HR=0.60 p=0.06), with no significant interaction of A/N use and PIK3CA (p=0.34). Conclusions: Among HR+ breast cancer patients, those who used A/Ns following primary diagnosis had longer TTR than non-users, regardless of tumor PIK3CA mutation status. The study provides a model for how tumor genomics could be integrated into secondary chemoprevention studies. [Table: see text]

scholarly journals Efficacy and safety of HER2 inhibitors in combination with or without pertuzumab for HER2-positive breast cancer: a systematic review and meta-analysis

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Shanshan Chen ◽  
Yu Liang ◽  
Zhangying Feng ◽  
Mingxia Wang
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Cancer Patients ◽  
Subgroup Analysis ◽  
Mucosal Inflammation ◽  
Secondary Outcome ◽  
Efficacy And Safety ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer ◽  
Significant Difference

Abstract Background Although the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose, efficacy and safety of this treatment differs from those of other pertuzumab-based dual anti-HER2 therapies remain controversial. This systematic review evaluates the efficacy and safety of H (trastuzumab or trastuzumab emtansine ± chemotherapy) + P (pertuzumab) compared with those of H in HER2+ breast cancer patients. Methods A comprehensive search was performed to identify eligible studies comparing the efficacy and safety of H + P versus H. The pathologic complete response (pCR), median progression-free survival (PFS) and overall survival (OS) were the primary outcomes, and safety was the secondary outcome. A subgroup analysis of pCR according to hormone receptor (HR) status was performed. All analyses were conducted using STATA 11.0. Results Twenty-six studies (9872 patients) were identified. In the neoadjuvant setting, H + P significantly improved the pCR [odds ratio (OR) = 1.33; 95% confidence interval (CI), 1.08–1.63; p = 0.006]. In the metastatic setting, H + P significantly improved PFS [hazard ratios (HRs) = 0.75; 95% CI, 0.68–0.84; p < 0.001]. There was a trend towards better OS but that it did not reach statistical significance (HRs = 0.81; 95% CI, 0.64–1.03; p = 0.082). A subgroup analysis revealed that the HER2+/HR- patients who received H + P showed the highest increase in the pCR. Rash, diarrhea, epistaxis, mucosal inflammation, and anemia were significantly more frequently observed with H + P than with H, whereas myalgia was less frequent (OR = 0.91; 95% CI, 0.82–1.01; p = 0.072), and no significant difference in cardiac toxicity was observed between these therapies (OR = 1.26; 95% CI, 0.81–1.95; P = 0.309). Conclusions Our study confirms that H + P is superior to H in the (neo)adjuvant treatment of HER2+ breast cancer, and increase the risk of acceptable and tolerable toxicity (rash, diarrhea, epistaxis, mucosal inflammation, and anemia). Trial registration A systematic review protocol was registered with PROSPERO (identification number: CRD42018110415).

scholarly journals Cost-effectiveness of paclitaxel, doxorubicin, cyclophosphamide and trastuzumab versus docetaxel, cisplatin and trastuzumab in new adjuvant therapy of breast cancer in china

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qiaoping Xu ◽  
Li Yuanyuan ◽  
Zhu Jiejing ◽  
Liu Jian ◽  
Li Qingyu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cost Effectiveness ◽  
Partial Response ◽  
Cancer Patients ◽  
Transition Probabilities ◽  
Complete Response ◽  
Sensitivity Analyses ◽  
Half Cycle ◽  
Breast Cancer Patients ◽  
Grade 3

Abstract Background Breast cancer is the most common cancer among women in China. Amplification of the Human epidermal growth factor receptor type 2 (HER2) gene is present and overexpressed in 18–20% of breast cancers and historically has been associated with inferior disease-related outcomes. There has been increasing interest in de-escalation of therapy for low-risk disease. This study analyzes the cost-effectiveness of Doxorubicin/ Cyclophosphamide/ Paclitaxel/ Trastuzumab (AC-TH) and Docetaxel/Carboplatin/Trastuzumab(TCH) from payer perspective over a 5 year time horizon. Methods A half-cycle corrected Markov model was built to simulate the process of breast cancer events and death occurred in both AC-TH and TCH armed patients. Cost data came from studies based on a Chinese hospital. One-way sensitivity analyses as well as second-order Monte Carlo and probabilistic sensitivity analyses were performed.The transition probabilities and utilities were extracted from published literature, and deterministic sensitivity analyses were conducted. Results We identified 41 breast cancer patients at Hangzhou First People’s Hospital, among whom 15 (60%) had a partial response for AC-TH treatment and 13 (81.25%) had a partial response for TCH treatment.No cardiac toxicity was observed. Hematologic grade 3 or 4 toxicities were observed in 1 of 28 patients.Nonhematologic grade 3 or 4 toxicities with a reverse pattern were observed in 6 of 29 patients. The mean QALY gain per patient compared with TCH was 0.25 with AC-TH, while the incremental costs were $US13,142. The incremental cost-effectiveness ratio (ICER) of AC-TH versus TCH was $US 52,565 per QALY gained. Conclusions This study concluded that TCH neoadjuvant chemotherapy was feasible and active in HER2-overexpressing breast cancer patients in terms of the pathological complete response, complete response, and partial response rates and manageable toxicities.

87P Epigenetics of the epigenetics: Impact of Let-7a expression restoration in CD8+ cells of HER2+ breast cancer patients

2021 ◽  
Vol 32 ◽  
pp. S58
Author(s):  
T. Monier ◽  
A. Samir ◽  
A.A. El Khodiry ◽  
R. Abdel Tawab ◽  
H.M. El Tayebi
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Cd8 Cells ◽  
Her2 Breast Cancer

scholarly journals Survival comparison of HER2 breast cancer patients according to HR status: analysis of a single Portuguese centre

The Breast ◽  
2021 ◽  
Vol 56 ◽  
pp. S62-S63
Author(s):  
G. Nogueira-Costa ◽  
J. Gramaça ◽  
I. Fernandes ◽  
C. Trabulo ◽  
J. Gonçalves ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer ◽  
Status Analysis

Clinical significance of crown-like structures to trastuzumab response in patients with primary invasive HER2+ breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12533-e12533
Author(s):  
Constantinos Savva ◽  
Charles N Birts ◽  
Stéphanie A Laversin ◽  
Alicia Lefas ◽  
Jamie Krishnan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adipose Tissue ◽  
Cancer Patients ◽  
Metastatic Disease ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Metabolic Reprogramming ◽  
Breast Cancer Patients ◽  
Adjuvant Trastuzumab ◽  
Her2 Breast Cancer

e12533 Background: Obesity is associated with breast cancer development and worse survival. Obesity can initiate, promote, and maintain systemic inflammation via metabolic reprogramming of macrophages that encircle adipocytes, termed crown-like structures (CLS). In breast cancer patients, CLS are present in 36-50% of patients and have been associated with anthropometric parameters. Here we focus on HER2+ breast cancer. The role of adiposity in HER2+ breast cancer is conflicting which may be attributed to the tumour heterogeneity. Adiposity has also been shown to affect the local immune environment of solid tumours. However, the prognostic significance of CLS in HER2+ breast cancer is still unknown. Methods: We investigated the prognostic significance of CLS in a cohort of 219 patients with primary HER2+ breast cancer who were diagnosed between 1982 to 2012 in Southampton General Hospital. This cohort includes 76 HER2+ trastuzumab naïve patients and 143 HER2+ patients treated with adjuvant trastuzumab. We stained FFPE tumour samples for the expression of CD68, CD16 and CD32B on CLS and correlated these to clinical outcomes. CLS were defined as CLS within distant adipose tissue, CLS within the adipose-tumour border (B-CLS) and intratumoural CLS. CLS were quantified manually in full face sections by two independent scorers and descriptive and Cox regression analysis was carried out. Results: A total of 201 tumours were suitable for CLS analyses. The median follow-up was 34.74 months (range, 0.43-299.08). In the trastuzumab naive cohort, B-CLS≤1 and B-CLS > 1 were present in 37 (52.11%) and 34 (47.89%), respectively. In the trastuzumab treated cohort, B-CLS≤1 were identified in 69 (53.08%) and B-CLS > 1 were found in 61 (46.92%) of the tumours. CLS were more commonly found in the adipose-tumour border (60.89%) rather than in the distant adipose tissue (36.14%) or intratumorally (14.36%). The presence of any CLS was significantly associated with BMI≥25 kg/m2 (p = 0.018). There was strong evidence of association between CD68+CD32B+ B-CLS and BMI≥25 kg/m2 (p = 0.007). Co-expression of CD16 and CD32B by B-CLS was more frequent in patients with BMI≥25 kg/m2 (p = 0.036). Survival analysis showed shorter time to metastatic disease in patients with CD68+ B-CLS > 1 (p = 0.011) in the trastuzumab treated cohort. Subgroup analysis revealed that in the BMI≥25 kg/m2 group, patients with CD68+ B-CLS > 1 had shorter time to metastatic disease compared to patients with B-CLS≤1 (p = 0.004). Multivariate cox regression showed that B-CLS > 1 is an independent prognostic factor for shorter time to metastatic disease in patients with primary HER2+ breast cancer that received adjuvant trastuzumab (HR 6.81, 95%CI (1.38-33.54), p = 0.018). Conclusions: B-CLS can be potentially used as a predictive biomarker to optimize the stratification and personalisation of treatment in HER2-overexpressed breast cancer patients.

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