The phosphatidylinositol‐3 kinase (PI3K)–AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic ...regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K–AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well‐characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT.
Purpose: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have
yielded ...variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer.
Experimental Design: Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a
median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between
mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast
cancer–specific survival were examined using Kaplan-Meier or competing risk methodology.
Results: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis,
hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA
mutated tumors have significant improvement in overall survival ( P = 0.03) and breast cancer–specific survival ( P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates
with node negativity ( P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis ( P = 0.004).
Conclusion: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will
significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase–targeted therapy. Future work
may define a population of older age breast cancer patients in whom therapy can be minimized. (Clin Cancer Res 2009;15(16):5049–59)
Various prognostic indicators have been investigated in neoadjuvant chemotherapy (NAC)-treated invasive breast cancer (BC). Our study examines if lymphovascular invasion (LVI) is an independent ...predictor of survival in women receiving NAC. We performed a retrospective analysis in 166 women with operable invasive BC who underwent adriamycin- and taxane-based NAC between 2000 and 2013. The presence of LVI was noted in breast excisions following NAC. Associations between progression-free and overall survival and LVI and other clinicopathologic variables were assessed. Median follow-up was 31 months (range 1.4–153 months) with a total of 56 events and 24 deaths from any cause. LVI was found in 74 of 166 patients (45 %). In univariate analysis, the presence of LVI was associated with worse progression-free survival (HR 3.37, 95 % CI 1.87–6.06, p < 0.01) and overall survival (HR 4.35, 95 % CI 1.61–11.79, p < 0.01). In multivariate models adjusting for breast cancer subtype, LVI was significantly associated with a decrease in progression-free survival (HR 3.76, 95 % CI 2.07–6.83, p < 0.01) and overall survival (HR 5.70, 95 % CI 2.08–15.64, p < 0.01). When stratified by subtype, those with hormone receptor or HER2-positive BCs with no LVI had the most favorable progression-free and overall survival. Those with both LVI and triple-negative BC had the worst progression-free and overall survival. LVI is an important prognostic marker and is associated with worse clinical outcome in breast cancer patients receiving NAC.
The treatment of hormone receptor-positive, HER2-negative breast cancer has become increasingly individualized, thanks to the development of genomic testing. Gene expression assays provide clinicians ...and patients with both prognostic and predictive information regarding breast cancer recurrence risk and potential benefit of chemotherapy. While the ability to tailor therapy based on clinicopathologic and genomic factors has enabled a growing number of women to forego chemotherapy, several questions remain regarding how best to apply genomic assay results across varying subgroups of women. Here, we review the role of genomic assays for patients with both lymph node-negative and lymph node-positive breast cancer, and how these assays may help us more precisely select patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancer with or without lymph node involvement who can safely omit chemotherapy in the future.
A diverse amount of therapies and agents, coupled with a deeper knowledge of breast cancer subtypes, may allow greater personalization of treatment for patients. Sacituzumab govitecan later received ...a full FDA approval based upon the randomized phase 3 ASCENT trial NCT02574455, which showed the same level of response and overall survival OS benefit vs standard of care chemotherapy.3 This approval was for patients with metastatic TNBC. At the 2022 San Antonio Breast Cancer Symposium SABCS, we presented data showing that HER2 expression was not related to outcome.7 HER2-low disease is of significant interest in the field now, especially for metastatic disease, given the approval of fam-trastuzumab deruxtecan-nxki Enhertu. Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician's choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC).
HER2-positive (HER2(+)) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi ...screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR(-)/HER2(+) tumors, eliciting tumor dependency in these cells. Mechanistically, HR(-)/HER2(+) cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6-Janus kinase 2 (JAK2)-STAT3-calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR(-)/HER2(+) breast cancers, opening novel targeted therapeutic opportunities.
mutation (
m) is a frequent cause of acquired resistance to aromatase inhibitor (AI) plus cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), which is a first-line therapy for ...hormone-receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Camizestrant is a next-generation oral selective estrogen receptor degrader (SERD) that in a phase II study significantly improved progression-free survival (PFS) over fulvestrant (also a SERD) in ER+/HER2- ABC. SERENA-6 (NCT04964934) is a randomized, double-blind, phase III study evaluating the efficacy and safety of switching from an AI to camizestrant, while maintaining the same CDK4/6i, upon detection of
m in circulating tumor DNA before clinical disease progression on first-line therapy for HR+/HER2- ABC. The aim is to treat
m clones and extend the duration of control of ER-driven tumor growth, delaying the need for chemotherapy. The primary end point is PFS; secondary end points include chemotherapy-free survival, time to second progression event (PFS2), overall survival, patient-reported outcomes and safety.
Purpose
Although metastatic breast cancer (MBC) is treatable, it is not curable and most patients remain on treatment indefinitely. While oncologists commonly prescribe the recommended starting dose ...(RSD) from the FDA-approved label, patient tolerance may differ from that seen in clinical trials. We report on a survey of medical oncologists’ perspectives about treatment-related toxicity and willingness to discuss flexible dosing with patients.
Methods
We disseminated a confidential survey via social media/email in Spring 2021. Eligible respondents needed to be US-based medical oncologists with experience treating patients with MBC.
Results
Of 131 responses, 119 were eligible. Physicians estimated that 47% of their patients reported distressing treatment-related side effects; of these, 15% visited the Emergency Room/hospital and 37% missed treatment. 74% (
n
= 87) of doctors reported improvement of patient symptoms after dose reduction. 87% (
n
= 104) indicated that they had ever, if appropriate, initiated treatment at lower doses. Most (85%,
n
= 101) respondents did not believe that the RSD is always more effective than a lower dose and 97% (
n
= 115) were willing to discuss individualized dosing with patients.
Conclusion
Treatment-related side effects are prevalent among patients with MBC, resulting in missed treatments and acute care visits. To help patients tolerate treatment, oncologists may decrease initial and/or subsequent doses. The majority of oncologists reject the premise that a higher dose is always superior and are willing to discuss individualized dosing with patients. Given potential improvements regarding quality of life and clinical care, dose modifications should be part of routine shared decision-making between patients and oncologists.
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