BACKGROUNDAdjuvant tamoxifen is recommended for all women with estrogen receptor‐positive breast carcinoma without regard for age. We investigated age‐dependent variations in adjuvant tamoxifen prescription patterns in a cohort of women 80 years of age and older.METHODSWe studied 92 women diagnosed at four U.S. sites with primary, early‐stage breast carcinoma. Each woman consented to a medical record review and participated in two telephone interviews. We compared the proportion of tamoxifen prescriptions received by women 85–92 years of age with those received by women 80–84 years of age. Relative risks (RR) and 95% confidence intervals (95% CI) were generated using generalized estimating equations. Confounding by demographic, disease, and treatment characteristics was assessed.RESULTSBefore adjustment, patients 85–92 years of age were 28% less likely to receive a tamoxifen prescription compared with patients 80–84 years of age (RR = 0.72, 95% CI 0.57–0.91). In this sample, patients not prescribed tamoxifen had substantially more comorbidity. After adjusting the crude finding for comorbidity, the RR was 0.74 (95% CI 0.58–0.93). In addition, the oldest patients and those not prescribed tamoxifen were significantly less likely to be married or have living children. After adjusting the crude finding for these two factors, the RR was 0.75 (95% CI 0.59–0.95). There was no confounding by the other demographic, disease, or treatment covariates assessed.CONCLUSIONGiven the increasing longevity of the oldest old, undertreatment with adjuvant tamoxifen may put older breast carcinoma patients at an increased risk of disease recurrence and breast carcinoma mortality. Cancer 2002;95:2465–72. © 2002 American Cancer Society.DOI 10.1002/cncr.10985
Background: Breast tumor initiating cells (TIC) use Notch receptors/ligands with other pathways for self renewal, resulting in tumor proliferation and progression. We showed that Notch inhibition with gamma secretase inhibitors (GSI) potentiates the effects of tamoxifen (tam) in xenografts (Rizzo et al. Cancer Res 2008). It is unknown whether GSIs plus endocrine therapy result in modulation of Notch and other proliferation markers in human breast cancer. Our objective was to add short exposure of the GSI MK-0752 to ongoing tam or letrozole (letr) during the presurgical window to determine 1) feasibility, 2) safety/tolerance, and 3) impact on biomarkers. We report the initial cohort of this pilot study (ClinTrials. gov NCT00756717). Methods: Patients (pts) with early stage ERα + breast cancer were treated with 25 days of tam or letr. On day 15 MK-0752 was added to endocrine therapy (350 mg orally 3 days on, 4 days off, 3 days on), with definitive surgery day 25. Formalin fixed, paraffin embedded biopsies were obtained at baseline, day 14 and final surgery, with histologic confirmation of tumor content >50% and RNA extraction by standard methods. Q-PCR was done for Notch1, Notch3, Notch4, Deltex, Jagged1, c-myc, HEY1, HEY2, HES1, PS2, C-Myc, Cyclin A2, NOXA (pro-apoptotic protein), Ki67, Dicer-1, RPL13 (internal control). Ct averages for 3 replicates were used and mRNA levels were calculated by the 2ΔΔCt method. Baseline gene expression levels were used as comparators for days 14 and 25 levels in each pt. The first cohort of 10 pts was analyzed to determine if enough signals were present to justify expanding the cohort at this dose to 20 pts and possibly test a second cohort on an alternate MK-0752 dose/schedule. Results: The initial cohort of 10 pts completed all therapy (4 tam, 6 letr), all biopsies and definitive surgery on schedule. One other pt withdrew prior to starting MK-0752 due to hypertension. Toxicity was minimal: grade 1 periorbital edema/cough, nausea, and axillary paresthesias in 1 pt each; grade 1 facial rash, 2 pts; and grade 2 fatigue, 1 pt. There was no diarrhea or surgical complications. Significant changes occurred in molecular marker levels after MK-0752 plus tam/letr (day 25) vs. end of tam/letr alone (day 14) as follows: Ki67 mRNA decreased in 9/10 pts; Notch4 decreased, 10/10; NOXA increased, 6/10; and Notch1 decreased, 6/10. Other markers showed inter-individual variations and will be presented, along with results of the global gene expression profiling (in progress). Conclusions: The addition of a short exposure of the GSI MK-0752 to ongoing endocrine therapy was feasible, safe, and well tolerated in pts with ERα + early breast cancer prior to definitive surgery. It results in anti-proliferative and pro-apoptotic effects at the molecular level. Notch4, which plays a key role in breast TIC, was the most consistent molecular marker of response in this setting. This suggests a potential anti-TIC effect of this combination and a role in overcoming endocrine resistance. Accrual to the expanded cohort is underway. If findings are confirmed, the second study with alternate MK-0752 dose/schedule may commence. Funding: Swim Across America, Inc. (clinical trial costs); Merck (drug supply, profiling) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-12.
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