HR-positive Disease Research Articles

Age and Survival Estimates in Patients Who Have Node-Negative T1ab Breast Cancer by Breast Cancer Subtype

Aim This article evaluates the risk of recurrence for patients who have small node-negative breast cancer by age and tumor subtype. Methods One thousand twelve patients with a T1a,bN0 breast cancer diagnosed between 1990 and 2002 who did not receive chemotherapy or trastuzumab were included. Patients and tumor characteristics were compared using the χ 2 or Wilcoxon's rank sum tests. Survival outcomes were estimated with the Kaplan-Meier method and compared using the log-rank statistic. Cox proportional hazards models were used to determine association of breast cancer subtypes and age at diagnosis with other covariates. Results Median age was 51.5 years. There were 771 hormone receptor (HR)-positive, 98 HER2-positive, and 143 triple-negative breast cancers (TNBC). Six hundred ninety-three patients were > 50 years, and 33 patients were ≤ 35 years. For 5-year survival estimates, there were 118 deaths and overall survival was 94.6% (95% confidence interval [CI] = 93.2%, 96.1%). After adjusting for breast cancer subtype and other tumor characteristics, patients ≤ 35 had 2.51 (95% CI = 1.21-5.22) times greater risk of worse recurrence-free survival (RFS), and 2.60 (95% CI = 1.05-6.46) times greater risk of worse distant RFS (DRFS) compared to patients > 50 years old. Compared to patients with HR-positive disease, patients with HER2-positive breast cancer had 4.98 (95% CI = 2.91-8.53) times the risk of worse RFS and 4.70 (95% CI = 2.51-8.79) times greater risk of worse DRFS, and patients with TNBC had 2.71 (95% CI = 1.59-4.59) times greater risk of worse RFS and 2.08 (95% CI = 1.04-4.17) times greater risk of worse DRFS. Conclusions In this cohort, patients with T1a,bN0 breast cancer, young age and breast cancer subtype were significantly associated with RFS and DRFS.

Risk of a Second Breast Cancer Associated with Hormone-Receptor and HER2/neu Status of the First Breast Cancer

Hormone-receptor (HR) and HER2/neu-receptor (HER2) status of breast tumors are important indicators for targeted therapies. We examine the association of receptor status and risk for a second breast cancer. We analyzed data on 106,331 women in the California Cancer Registry whose first cancer is locoregional invasive breast disease, diagnosed from 1999 through 2005, yielding 1,613 second primary breast cancers. Standardized incidence ratios (SIR) with 95% confidence intervals (CIs) were used to evaluate risk of second tumors, accounting for age at first diagnosis, duration at risk, and race/ethnicity. Among non-Hispanic whites, HR-positive first tumors signal a reduction in risk for second breast cancers (SIR = 0.83, 95% CI: 0.77-0.89) whereas HR-negative status signals elevated risk (SIR = 1.48, 95% CI: 1.29-1.70). Asian/Pacific Islanders, African Americans, and Hispanics are at elevated risk of second breast cancers regardless of HR status of the first tumor. Hispanics with HR-negative first tumors are at greater risk than those with HR-positive disease (HR(-): SIR = 3.76, 95% CI: 2.97-4.71; HR(+): SIR = 1.86, 95% CI: 1.56-2.20). HER2 status does not differentiate risk for second tumors in any group examined. HR status of a first breast cancer is a marker for risk of a second breast cancer. HER2 status does not seem to be a marker of risk for a second breast cancer. Risk differences across race/ethnic groups by HR status suggest heterogeneity of breast cancers across race/ethnicity. These data suggest that HR status may be helpful in shaping strategies to reduce risk of a second breast cancer, while HER2 status seems uninformative for this purpose.

Lipophilic Statin Use and Risk of Breast Cancer Subtypes

Statins are widely used and of high interest as potential chemopreventive agents for cancer. Preclinical studies suggest that lipophilic statins have anticancer properties targeting hormone receptor (HR)-negative breast cancer. Few epidemiologic studies have investigated the relationship between lipophilic statin use and risk for breast cancer, stratified by HR status. We conducted a large case-control study within Kaiser Permanente of Northern California (KPNC) to determine whether chronic use of lipophilic statins is associated with decreased risk of HR-negative breast cancer or other breast cancer subtypes. We identified 22,488 breast cancer cases diagnosed from 1997 to 2007, and 224,860 controls matched to cases based upon birth year and duration of KPNC pharmacy coverage. Use of lipophilic statins was ascertained using the comprehensive electronic pharmacy records of KPNC. We found no association between lipophilic statin use (≥2 y versus never) and overall breast cancer risk (odds ratio(adj), 1.02; 95% CI, 0.97-1.08) in conditional logistic regression models adjusted for oral contraceptive and hormone therapy use. Women who used lipophilic statins did not have a decreased risk of HR-negative breast cancer (odds ratio(adj), 0.98; 95% CI, 0.84-1.14) nor altered risk of HR-positive disease (odds ratio(adj), 1.03; 95% CI, 0.97-1.10). Furthermore, lipophilic statin use was not associated with risk of any of the intrinsic subtypes, luminal A, luminal B, human epidermal growth factor receptor 2 positive/estrogen receptor negative, or triple negative. Our results do not support an association of lipophilic statin use with the risk for breast cancer in general or with risks of HR-negative or other breast cancer subtypes specifically. These findings do not confirm previous reports of a possible preventive association.

Abstract 1838: Lipophilic statin use and risk of breast cancer subtypes

Abstract Background: Preclinical studies suggest that lipophilic statins have anti-cancer properties and that hormone receptor (HR)-negative breast cancer is the most responsive subtype. Kumar et al. (2008) reported that patients with HR-negative cancers were less likely to have used lipophilic statins than patients with HR-positive disease. However, this study within Kaiser Permanente Northern California (KPNC) included only cases diagnosed in 2003 and, because of its case-only design, was unable to make risk inferences. We conducted a large case-control study spanning 11 years within KPNC to investigate whether lipophilic statin use is associated with: (1) decreased risk of HR-negative breast cancer, (2) increased risk of HR-positive breast cancer or (3) both. Furthermore, we investigated whether lipophilic statin use is associated with the risk of the intrinsic breast cancer subtypes and attempted to replicate Kumar et al.'s results. Methods: We identified 22,486 cases with invasive breast cancer of known HR-status diagnosed at KPNC from 1997 to 2007. Controls were individually matched to cases at a ratio of 10:1, based on year of birth and KPNC pharmacy coverage. Use of the lipophilic statins, oral contraceptives (OC) and menopausal hormones (HT) was ascertained via KPNC's electronic pharmacy records. Case-control odds ratios (OR) were adjusted for age, pharmacy coverage, OC and HT use; case-only ORs were additionally adjusted for race. We performed an external adjustment for the unmeasured confounders obesity and alcohol use. Results: We found no association between lipophilic statin use (≥ 2 years vs. never) and overall breast cancer risk (OR=1.02; 95% CI=0.97-1.08; p=0.42). Lipophilic statin users did not have a decreased risk of HR-negative breast cancer (OR=0.98; 95% CI=0.84 −1.14; p=0.74), or an increased risk of HR-positive disease (OR=1.03; 95% CI=0.97-1.10; p=0.31). Lipophilic statin use was not associated with risk of any of the intrinsic breast cancer subtypes, luminal A, luminal B, HER2+/ER- and triple negative. In case-only analysis including all 11 years, HR-negative cases had slightly lower odds of being lipophilic statins users (OR=0.91; 95% CI=0.78-1.05; p=0.18), however, this result was not statistically significant. We were able to replicate Kumar et al.'s findings for 2003, which was the only year in the 11-year study period with a statistically significantly lower proportion of HR-negative cases among statin users, and thus, likely a stochastic outlier. Conclusions: Our results do not support an association between lipophilic statin use and breast cancer risk in general or the risk of ER, PR and HER2-defined subtypes specifically. Any effect, if it exists at all, is likely much smaller than previous studies suggested. These findings should be considered in the interpretation of several ongoing breast cancer chemoprevention trials of lipophilic statins as well as in the planning of future interventional studies using statins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1838.

Genotypic characterization of phenotypically defined triple-negative breast cancer

500 Background: Triple negative breast cancer (TNBC) is associated with a higher risk of recurrence and earlier recurrences than other breast cancer phenotypes. We evaluated the genotypic features of TNBC compared with hormone receptor (HR)-positive disease, and also evaluated genotypic features associated with recurrence. Methods: RNA extracted from tumor samples obtained from 764 patients with stage I-III breast cancer was analyzed by RT-PCR for 371 genes. All patients received adjuvant chemotherapy (plus hormonal therapy in HR-positive disease) in trial E2197; HR and HER2 expression were evaluated by immunohistochemistry (IHC) in a central lab (J Clin Oncol 26:2473–2481). An unsupervised clustering analysis was performed in all samples (N=764). Cox proportional hazard models were used to identify differences in gene expression in TNBC versus HR-positive disease, and with recurrence in phenotypically defined (by IHC) TNBC (N=246) and HR-positive (N=465) disease. Results: Unsupervised analysis revealed two major clusters that differed with regard to HR expression by IHC. Supervised analysis comparing the TNBC vs. HR-positive phenotypes revealed 269 genes (73%) with significantly different expression (p<0.0001). The top 10% of genes exhibiting higher expression the TN group included genes associated with nucleosome assembly (CENPA), kinase activity (TTK), cell division (KIFC2), proliferation (BUB1), intracellular signaling (DEPDC1), DNA repair (CHK1), anti-apoptosis (GSTP1), and transcriptional regulation (MYBL2). There was increased expression of genes for which inhibitors are currently being evaluated, including AURKB and CHK1 in TNBC, and IGF1R and RhoC in HR-positive disease. Although GRB7 expression was significantly lower in the TN group, increased expression of GRB7 was the only gene in the TNBC group (but not the HR-positive group) associated with increased recurrence (p=0.04), and did not correlate with nodal status, tumor size, or grade. Conclusions: We genotypically characterized breast cancers that have also undergone rigorous phenotypic characterization.. There were significant differences in gene expression between the TN and HR-positive groups, including genes for which targeted agents are currently being evaluated in the clinic. [Table: see text]

Trastuzumab (H) treatment in patients (pts) with metastatic breast cancer (MBC): An observational retrospective study in four hospitals from Bogotá, Colombia (ONCOLGroup study)

e12016 Background: Breast cancer is the second most common cancer diagnosed in Colombian women, and approximately 26% of MBC are HER-2-positive in our population. The purpose of this study was to assess the characteristics and outcome of pts with HER-2-positive MBC treated with H-based therapy in Bogotá. Methods: This retrospective study included 119 pts treated between 2000 and 2007. Overall response rates (ORR), clinical benefit (CB), time to progression (TTP), and overall survival (OS) were estimated. Most common grade 2/3 toxicities are reported as well as variables that influenced survival. Results: Median age was 62 years (range, 37 to 75). Eighty-seven (73%) pts had recurrent disease and the rest had de novo MBC. Performance status was ≥70% in 114 pts, 66% had ≤2 metastatic sites, and 58% had hormone receptor positive disease. Previous adjuvant therapy before H included antracyclines in 68% and taxanes in 39% of the pts. H was part of the first-line therapy for MBC in 86.5% of the pts, leading to a 54% ORR in 103 evaluable pts. CB was 81% and median TTP was 6.1 months. (range, 1.2 to 26 mo). The most common toxicities in this setting included neutropenia ≥G3 (9%) and neuropathy ≥G3 (7%). H was given as part of second line therapy to 54 (45%) pts, but only 41 had evaluable disease. A 56% ORR was found in this subgroup, 85% CB and 4.7-month median of TTP. Grade ≥G3 hand-foot syndrome was the main toxicity (14%). Median OS after the diagnosis of MBC was 23 months (range, 1.6–93 mo), being longer for pts with HR-positive disease (p = 0.036), in pts with loco-regional relapse (p = 0.029), and in those older than 50 (p = 0.0025). Only two variables independently predicted OS: age (HR: 0.4, 95% CI: 0.35–0.93, p = 0.046) and HR status (HR: 0.7, 95% CI: 0.60–0.86, p = 0.040). Two pts (1.7%) had H-induced heart failure. Conclusions: H in combination with chemotherapeutic agents has been proved to be an effective and safe treatment for HER-2-positive MBC. The results from our series agreed with those reported in the medical literature and guarantee the regular use of H in Colombia. No significant financial relationships to disclose.

Superiority of sequential docetaxel over standard FE100C in patients with intermediate risk breast cancer: survival results of the randomized intergroup phase III trial EC-Doc.

Abstract Abstract #78 Background: Taxane based adjuvant chemotherapy (CHT) is standard of care in node-positive breast cancer. Several pre-planned subgroup analyses detected the maximum benefit from taxanes in patients with 1-3 positive lymph nodes (LN).
 According to the St. Gallen consensus CHT in endocrine responsive tumors is optional in these patients. Recently the ABCSG reported excellent survival data after endocrine therapy +/- bisphosphonates without CHT in low to intermediate risk breast cancer (Gnant et al., ASCO 2008). The EC-Doc trial compares a modern sequential taxane-based regimen with standard FE100C in patients with 1-3 positive LN.
 Methods: Patients from 18 to 65 years with primary breast cancer and 1 to 3 positive LN were eligible if they had operable breast cancer with histologically confirmed free margins. M0 status was assessed by conventional staging. 2011 patients were randomized to a phase III trial comparing 4 cycles E90C600 q3w followed by 4 cycles of Docetaxel100 q3w (n=1008) (Arm A) versus 6 cycles of F500E100C500 q3w (n=828) or C600M40F600 d1, 8 q4w (n=175) (Arm B). The primary endpoint is EFS. Secondary endpoints are OS, toxicity and quality of life.
 Results: Baseline characteristics were well balanced between both study arms. Arm A/B: mean age 51.5/51.5 years, median tumor size 2.0/2.0, HR positive 77.7% / 78.3%, G3 34.1% / 34.4%. Toxicity data from the EC-Doc trial were recently presented (Nitz et al. , ASCO 2008). After a median follow up of 41 months both estimated 5-year EFS (91% vs. 86%, p=0.005) and OS (95% vs. 90%, p=0.004) were significantly better in the EC-Doc arm.
 For the comparison of EC-Doc vs. FE100C the respective values were: HR 0.58, p=0.004, estimated 5 year EFS 91% / 85% and 5 year estimated OS 95% / 91% (p =0.03). For the hormone receptor positive subpopulation the HR was 0.51 in favour of EC-Doc (p= 0.007).
 Conclusions: Our study indicates a superiority of sequential taxane-based EC-Doc CHT in terms of EFS and OS over standard FE100C in an intermediate risk group. The addition of modern third generation taxane based CHT to conventional endocrine treatment is associated with excellent EFS and OS in patients with 1-3 positive LN.
 As shown even for the subgroup of patients with HR positive disease the benefit from third generation taxane based CHT is substantial so that an endocrine only adjuvant strategy may result in undertreatment. With respect to the excellent survival rates prospective randomized trials testing the existing genetic tests are mandatory.
 Updated survival and efficacy analysis in distinct molecular subtypes (Her-2/neu, triple-negative) will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 78.

Randomized, Controlled Trial of Cyclophosphamide, Methotrexate, and Fluorouracil Versus Cyclophosphamide, Doxorubicin, and Fluorouracil With and Without Tamoxifen for High-Risk, Node-Negative Breast Cancer: Treatment Results of Intergroup Protocol INT-0102

We evaluated the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-negative breast cancer patients with and without tamoxifen (TAM), overall and by hormone receptor (HR) status. Node-negative patients identified by tumor size (> 2 cm), negative HR, or high S-phase fraction (n = 2,690) were randomly assigned to CMF, CAF, CMF + TAM (CMFT), or CAF + TAM (CAFT). Cox regression evaluated overall survival (OS) and disease-free survival (DFS) for CAF versus CMF and TAM versus no TAM separately. Two-sided CIs and one-sided P values for planned comparisons were calculated. Ten-year estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% v 75%; HR = 1.09; 95% CI, 0.94 to 1.27). CAF had slightly better OS than CMF (85% v 82%, HR = 1.19 for CMF v CAF; 95% CI, 0.99 to 1.43); values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with TAM. Overall, TAM had no benefit (DFS, P = .16; OS, P = .37), but the TAM effect differed by HR groups. For HR-positive patients, TAM was beneficial (DFS, HR = 1.32 for no TAM v TAM; 95% CI, 1.09 to 1.61; P = .003; OS, HR = 1.26; 95% CI, 0.99 to 1.61; P = .03), but not for HR-negative patients (DFS, HR = 0.81 for no TAM v TAM; 95% CI, 0.64 to 1.03; OS, HR = 0.79; 95% CI, 0.60 to 1.05). CAF did not improve DFS compared with CMF; there was a slight effect on OS. Given greater toxicity, we cannot conclude CAF to be superior to CMF. TAM is effective in HR-positive disease, but not in HR-negative disease.