PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype

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]

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Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer

Annals of Oncology ◽

10.1093/annonc/mdz007 ◽

2019 ◽

Vol 30 (3) ◽

pp. 418-423 ◽

Cited By ~ 16

Author(s):

M.V. Dieci ◽

P. Conte ◽

G. Bisagni ◽

A.A. Brandes ◽

A. Frassoldati ◽

...

Keyword(s):

Breast Cancer ◽

Disease Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Distant Disease ◽

Free Survival ◽

Adjuvant Trial ◽

Her2 Breast Cancer ◽

Infiltrating Lymphocytes ◽

Disease Free

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Abstract PR05: The effect of chemotherapy on HER2+ breast cancer heterogeneity measured by STAR-FISH: Detection of PIK3CA mutation and HER2 amplification at single-cell level in situ

10.1158/1557-3125.advbc15-pr05 ◽

2016 ◽

Author(s):

Michalina Janiszewska ◽

Lin Liu ◽

Vanessa Almendro ◽

Yanan Kuang ◽

Cloud Paweletz ◽

...

Keyword(s):

Breast Cancer ◽

Single Cell ◽

Pik3ca Mutation ◽

Single Cell Level ◽

Her2 Amplification ◽

Cell Level ◽

Cancer Heterogeneity ◽

Her2 Breast Cancer ◽

Fish Detection

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

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1064 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1064-1064 ◽

Cited By ~ 1

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.

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