Dataset Information

A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

ABSTRACT:

Purpose

Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors-a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk.

Patients and methods

We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints.

Results

Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35-49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3-4 adverse events related to low-dose tamoxifen.

Conclusions

In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

SUBMITTER: Bhatia S

PROVIDER: S-EPMC7887034 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

Bhatia Smita S Palomares Melanie R MR Hageman Lindsey L Chen Yanjun Y Landier Wendy W Smith Kandice K Umphrey Heidi H Reich Caroline A CA Zamora Kathryn W KW Armenian Saro H SH Bevers Therese B TB Blaes Anne A Henderson Tara T Hodgson David D Hudson Melissa M MM Korde Larissa A LA Melin Susan A SA Merajver Sofia D SD Overholser Linda L Pruthi Sandhya S Wong F Lennie FL Garber Judy E JE

Clinical cancer research : an official journal of the American Association for Cancer Research 20201203 4

<h4>Purpose</h4>Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors-a population with breast cancer risk comparable with <i>BRCA</i> mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk.<h4>Patients and methods</h4>We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 ...[more]

PMID: 33272980

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Project description:Tamoxifen is a drug that has been in worldwide use for the treatment of estrogen receptor (ER)-positive breast cancer for over 30 years; it has been used in both the metastatic and adjuvant settings. Tamoxifen's approval for breast cancer risk reduction dates back to 1998, after results from the Breast Cancer Prevention Trial, co-sponsored by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, showed a 49% reduction in the incidence of invasive, ER-positive breast cancer in high-risk women. Despite these positive findings, however, the public's attitude toward breast cancer chemoprevention remains ambivalent, and the toxicities associated with tamoxifen, particularly endometrial cancer and thromboembolic events, have hampered the drug's uptake by high-risk women who should benefit from its preventive effects. Among the strategies to overcome such obstacles to preventive tamoxifen, two novel and potentially safer modes of delivery of this agent are discussed in this paper. Low-dose tamoxifen, expected to confer fewer adverse events, is being investigated in both clinical biomarker-based trials and observational studies. A series of systemic biomarkers (including lipid and insulin-like growth factor levels) and tissue biomarkers (including Ki-67) are known to be favorably affected by conventional tamoxifen dosing and have been shown to be modulated in a direction consistent with a putative anti-cancer effect. These findings suggest possible beneficial clinical preventive effects by low-dose tamoxifen regimens and they are supported by observational studies. An alternative approach is topical administration of active tamoxifen metabolites directly onto the breast, the site where the cancer is to be prevented. Avoidance of systemic administration is expected to reduce the distribution of drug to tissues susceptible to tamoxifen-induced toxicity. Clinical trials of topical tamoxifen with biological endpoints are still ongoing whereas pharmacokinetic studies have already shown that appropriate formulations of drug successfully penetrate the skin to reach breast tissue, where a preventive effect is sought.

Project description:BackgroundBreast Cancer (BC) prevention strategies range from lifestyle changes such as increasing physical activity and reducing body weight to preventive drugs like tamoxifen, known to reduce BC incidence in high-risk women. Sex Hormone Binding Globulin (SHBG) is related to BC risk due to its ability to bind circulating estradiol at high affinity and to regulate estradiol action. A study protocol is presented based on the assessment of the effect of different interventions such as tamoxifen at 10 mg every other day (LDT), intermittent caloric restriction (ICR) two days per week, lifestyle intervention (LI, step counter use) and their combination on the modulation of SHBG and several other biomarkers associated to BC.MethodsA randomized phase II biomarker study will be conducted in 4 Italian centers. Unaffected women aged between 18 and 70 years, carriers of a germline pathogenetic variant (BRCA1, BRCA2, PALB2, or other moderate penetrance genes), or with a >5% BC risk at 10 years (according to the Tyrer-Cuzick or the Breast Cancer Surveillance Consortium Risk models) or with a previous diagnosis of intraepithelial neoplasia will be eligible. A total of 200 participants will be randomized to one of the four arms: LDT; LDT + ICR; LI; LI + ICR. Interventions will span six months, with baseline and follow-up clinic visits and interim phone calls.DiscussionThe aim of the study is to verify whether LDT increases circulating SHBG more than LI with or without ICR after 6 months. Secondary objectives include assessing HOMA-index, inflammatory markers, adiponectin/leptin ratio, quality of life (QoL), safety, toxicity, mammographic density, and changes in microbiome composition across groups. The study's innovation lies in its inclusion of diverse BC risk categories and combination of pharmaceutical and behavioral interventions, potentially enhancing intervention efficacy while balancing tamoxifen's side effects on QoL, especially menopausal symptoms.Trial registrationEuCT number:2023-503994-39-00; Clinical trials.gov NCT06033092.

Project description:BackgroundTumor progression following endocrine therapy is considered to indicate resistance to endocrine drugs due to a variety of mechanisms. An insufficient dose of endocrine drugs is one of the causes for treatment failure in some patients with high hormone-receptor (HR)-expressing advanced breast cancer. This study aimed to explore the efficacy of high-dose tamoxifen (TAM) treatment in patients with advanced breast cancer with highly expressed HR.Materials & methodsThis was a single-arm, phase II pilot study that enrolled patients with advanced breast cancer with high HR expression (estrogen receptor ⩾60% and/or progesterone receptor ⩾60%) following routine endocrine therapy. All enrolled patients received a high-dose of TAM (100 mg/day) until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Exploratory endpoints included the predictive value of 16α-18F-17β-fluoroestradiol quantitative positron emission tomography/computed tomography (18F-FES PET/CT) for treatment efficacy.ResultsA total of 30 patients were enrolled between September 2017 and February 2019. The median PFS was 6 months [95% confidence interval (CI) 4.9-7.1] and the median OS was 15.6 months (95% CI 8.3-22.9). Five patients experienced a partial response (PR) and none experienced a complete response (CR), with an ORR of 16.7% and CBR of 33.3%. No severe adverse events were observed. Lesions with 18F-FES maximum standardized uptake value (SUVmax) ⩾4 had a significantly longer PFS [median 9.2 months, (95% CI 6.9-11.6)] compared with lesions with a 18F-FES SUVmax <4 [median 4.8 months, (95% CI 3.9-5.6); p = 0.022].ConclusionA high-dose of TAM is effective and safe for patients with advanced breast cancer with high HR expression. 18F-FES SUVmax values may predict the local clinical benefits of high-dose TAM .Trial registration[ClinicalTrials.gov identifier: NCT0304565].

Project description:Controversy persists about whether certain antidepressants reduce tamoxifen's effectiveness on lowering breast cancer recurrence. We investigated whether taking tamoxifen and antidepressants (in particular, paroxetine) concomitantly is associated with an increased risk of recurrence or contralateral breast cancer. We examined 16 887 breast cancer survivors (TNM stages 0-II) diagnosed between 1996 and 2007 and treated with tamoxifen in two California health plans. Women were followed-up through December 31, 2009, for subsequent breast cancer. The main exposure was the percent of days of overlap when both tamoxifen and an antidepressant (paroxetine, fluoxetine, other selective serotonin reuptake inhibitors, tricyclics, and other classes) were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models with time-varying medication variables. Of the 16 887 women, half (n = 8099) used antidepressants and 2946 women developed subsequent breast cancer during the 14-year study period. We did not find a statistically significant increased risk of subsequent breast cancer in women who concurrently used paroxetine and tamoxifen. For 25%, 50%, and 75% increases in percent overlap days between paroxetine and tamoxifen, hazard ratios were 1.06 (95% CI = 0.98 to 1.14, P = .09), 1.13 (95% CI = 0.98 to 1.30, P = .09), and 1.20 (95% CI = 0.97 to 1.49, P = .09), respectively, in the first year of tamoxifen treatment but were not statistically significant. Hazard ratios decreased to 0.94 (95% CI = 0.81 to 1.10, P = .46), 0.89 (95% CI = 0.66 to 1.20, P = .46), and 0.85 (95% CI = 0.54 to 1.32, P = .46) by the fifth year (all non-statistically significantly). Absolute subsequent breast cancer rates were similar among women who used paroxetine concomitantly with tamoxifen vs tamoxifen-only users. For the other antidepressants, we again found no such associations. Using the comprehensive electronic health records of insured patients, we did not observe an increased risk of subsequent breast cancer in women who concurrently used tamoxifen and antidepressants, including paroxetine.

Dataset Information

A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

Purpose

Patients and methods

Results

Conclusions

Publications

A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

Similar Datasets

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