Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer

Martin, Lesley-Ann; Davies, Giles; Weigel, Marion T.; Betambeau, Nadine; Hills, Margaret; Salter, Janine; Walsh, Geraldine; A’Hern, Roger; Dowsett, Mitch

doi:10.1007/s10549-010-1100-z

Cited by 38 publications

(24 citation statements)

References 40 publications

(31 reference statements)

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“…A low daily dose of the COX-inhibitor aspirin (25–50 mg per day) during the first postoperative year in patients with gastric and oesophageal cancer markedly improved 5-year survival rate, but only in patients with low-stage nondisseminated malignancies. 159 Three RCTs studied the short-term effects of COX2 inhibition (2–4 weeks before surgery) on tumour characteristics, in stage I–II primary breast cancer, 160 invasive transitional-cell carcinoma, 161 or prostate cancer. 162 The first two studies exhibited a modest increase in tumour-cell apoptosis, 160,161 whereas the third study also indicated a reduction in tumour-cell proliferation, microvessel density, angiogenesis and expression of the hypoxia inducible factor (HIF)-1α.…”

Section: Potential Perioperative Interventionsmentioning

confidence: 99%

“…159 Three RCTs studied the short-term effects of COX2 inhibition (2–4 weeks before surgery) on tumour characteristics, in stage I–II primary breast cancer, 160 invasive transitional-cell carcinoma, 161 or prostate cancer. 162 The first two studies exhibited a modest increase in tumour-cell apoptosis, 160,161 whereas the third study also indicated a reduction in tumour-cell proliferation, microvessel density, angiogenesis and expression of the hypoxia inducible factor (HIF)-1α. 162 A retrospective study showed improved survival rates after intraoperative administration of a nonselective COX inhibitor, ketorolac, in patients undergoing surgery for breast or lung cancer (but not kidney cancer).…”

Section: Potential Perioperative Interventionsmentioning

confidence: 99%

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Exploiting the critical perioperative period to improve long-term cancer outcomes

et al. 2015

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Evidence suggests that the perioperative period and the excision of the primary tumour can promote the development of metastases—the main cause of cancer-related mortality. This Review first presents the assertion that the perioperative timeframe is pivotal in determining long-term cancer outcomes, disproportionally to its short duration (days to weeks). We then analyse the various aspects of surgery, and their consequent paracrine and neuroendocrine responses, which could facilitate the metastatic process by directly affecting malignant tissues, and/or through indirect pathways, such as immunological perturbations. We address the influences of surgery-related anxiety and stress, nutritional status, anaesthetics and analgesics, hypothermia, blood transfusion, tissue damage, and levels of sex hormones, and point at some as probable deleterious factors. Through understanding these processes and reviewing empirical evidence, we provide suggestions for potential new perioperative approaches and interventions aimed at attenuating deleterious processes and ultimately improving treatment outcomes. Specifically, we highlight excess perioperative release of catecholamines and prostaglandins as key deleterious mediators of surgery, and we recommend blockade of these responses during the perioperative period, as well as other low-risk, low-cost interventions. The measures described in this Review could transform the perioperative timeframe from a prominent facilitator of metastatic progression, to a window of opportunity for arresting and/or eliminating residual disease, potentially improving long-term survival rates in patients with cancer.

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Section: Potential Perioperative Interventionsmentioning

confidence: 99%

Section: Potential Perioperative Interventionsmentioning

confidence: 99%

Exploiting the critical perioperative period to improve long-term cancer outcomes

et al. 2015

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“…These studies have demonstrated trends towards more clinical complete response, longer duration of clinical benefit, and greater progression-free survival with the addition of celecoxib [61–63]. A small study assessing the impact of a 14-day pre-surgical regimen of celecoxib in postmenopausal breast cancer patients also found a non-significantly greater decrease in Ki67 staining with celecoxib treatment that the authors thought warranted further investigation [64]. None of these trials analyzed the treatment benefit by BMI category, so it is impossible to determine from this data whether overweight/obese women in this patient population are more likely to benefit from COX-2 inhibition.…”

Section: Clinical Trials Of Cox-2 Inhibitorsmentioning

confidence: 99%

Targeting the COX-2 Pathway to Improve Therapeutic Response in the Obese Breast Cancer Patient Population

Bowers

deGraffenried

2015

Curr Pharmacol Rep

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Multiple studies have demonstrated that obesity is associated with a worse outcome for all breast cancer subtypes and that obese breast cancer patients do not respond as well as normal weight patients to aromatase inhibitor treatment and chemotherapy. While a number of mechanisms have been proposed to explain this link, recent studies have provided evidence that elevated local cyclooxygenase-2 (COX-2) expression and the resulting increase in prostaglandin E2 (PGE2) production may play an important role. COX-2 upregulation in breast tumors is associated with a poor prognosis, a connection generally attributed to PGE2’s direct effects on apoptosis and invasion as well as its stimulation of pre-adipocyte aromatase expression and subsequent estrogen production. Research in this area has provided a strong foundation for the hypothesis that COX-2 signaling is involved in the obesity-breast cancer link, and further study regarding the role of COX-2 in this link is warranted.

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“…Changes in the marker of cell proliferation as determined by Ki67 following 2 weeks of treatment have been shown to predict recurrence-free survival in groups of patients with breast cancer treated with different hormonal agents (6,7). Assessment of in vivo surrogate markers, such as Ki67, associated with comprehensive molecular profiling may elucidate the differential profile of treatment-sensitive versus treatment-nonresponsive tumors (8)(9)(10)(11). Ten to 14 days is the usual time interval between the diagnosis of breast cancer and primary surgery, offering a convenient window of opportunity for a short treatment with an experimental agent.…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039)

Leary

Evans

Johnston

et al. 2015

Clinical Cancer Research

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Purpose: Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors.Experimental Design: Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377). Biopsies pre-/posttreatment were analyzed for Ki67, apoptosis, HER2, EGFR, ER, PgR, pAKT, pERK, and stathmin by IHC. Further markers were measured by RT-PCR. Primary endpoint was change in Ki67. HER2þ was defined as 2þ/3þ by IHC and FISH þ . Results: One hundred twenty-one patients (lapatinib, 94; placebo, 27) were randomized; of these, 21% were HER2 þ , 78% were HER2 À nonamplified, 26% were EGFR þ . Paired samples containing tumor were obtained for 98% (118 of 121). Ki67 fell significantly with lapatinib (À31%; P < 0.001), but not with placebo (À3%). Whereas Ki67 reduction with lapatinib was greatest in HER2 þ breast cancer (À46%; P ¼ 0.003), there was a significant Ki67 decrease in HER2 À breast cancer (À27%; P ¼ 0.017) with 14% of HER2 À breast cancer demonstrating !50% Ki67 reduction with lapatinib. Among HER2 þ patients, the only biomarker predictive of Ki67 response was the EGFR/HER4 ligand epiregulin (EREG) (rho ¼ À0.7; P ¼ 0.002). Among HER2 À tumors, only HER3 mRNA levels were significantly associated with Ki67 response on multivariate analysis (P ¼ 0.01). In HER2 À breast cancer, HER2 and HER3 mRNA levels were highly correlated (rho ¼ 0.67, P < 0.001), with all Ki67 responders having elevated HER3 and HER2 expression. See related commentary by Campbell and Moasser, p. 2886 IntroductionLapatinib is a tyrosine kinase inhibitor (TKI) of both the epidermal growth factor receptor (EGFR, HER1) and human epidermal growth factor receptor-2 (HER2), which is an FDAapproved and commonly used drug in patients with HER2-positive (HER2 þ ) breast cancer (1-3). Targeting this drug to the most appropriate subset of breast cancer patients depends on a full understanding of the molecular determinants of response. Although HER2 overexpression [3þ by immunohistochemistry (IHC)] or amplification is an important predictor of response to lapatinib, it may not be the only requirement. EGFR (HER1) protein expression by IHC has not been shown to correlate with response to lapatinib (4), whereas the sensitizing EGFR gene mutations described in other tumor types (5) have not been reported in breast cancer. Either moderate levels of HER2 expression in the absence of gene amplification, the expression of other HER partners (i.e., EGFR, HER3), elevated levels of HER ligands, or activation of downstream effectors such as AKT and ERK could all be relevant to lapatinib responsiveness in breast cancer. As such, these additional biomarkers potentially could identify a subset of HER2 À nonamplified tumors that might respond to an EGFR/HER2 TKI. Changes in the marker of cell proliferation as determined by Ki67 following 2 weeks of treatment have been shown to predict recurrence-fre...

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Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer

Cited by 38 publications

References 40 publications

Exploiting the critical perioperative period to improve long-term cancer outcomes

Exploiting the critical perioperative period to improve long-term cancer outcomes

Targeting the COX-2 Pathway to Improve Therapeutic Response in the Obese Breast Cancer Patient Population

Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039)

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