PURPOSE To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. METHODS A literature search identified relevant ...randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER) -positive invasive tumors. Women < or = 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making.
Selective estrogen receptor modulators (SERMs) reduce the risk of recurrence of invasive breast cancer and the incidence of first breast cancers in women who are at increased risk. Multiple, ...randomized clinical trials have shown both the efficacy and safety of SERMs in reducing the risk of breast cancer. Long-term follow-up as long as 20 years in the randomized trials shows persistent efficacy with acceptable safety. Hormone replacement therapy given concurrently with tamoxifen abrogates its preventive effect, but women with atypical hyperplasia derive particular benefit from SERM therapy. Aromatase inhibitors also reduce the risk of developing invasive breast cancer, but the experience with them for risk reduction is limited to few trials. National organizations have made recommendations to use SERMs and aromatase inhibitors to reduce the risk of breast cancer in high-risk women and additional efforts should be made to increase their use in clinical practice, where the number of women needed to treat to prevent one case of breast cancer conforms to accepted standards of preventive medicine.
Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. ...Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors.
We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials.
In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression.
These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.
Patients with early-stage, hormone receptor-positive breast cancer have considerable residual risk for recurrence after completing 5 years of adjuvant tamoxifen. In May 2001, the National Surgical ...Adjuvant Breast and Bowel Project (NSABP) initiated accrual to a randomized, placebo-controlled, double-blind clinical trial to evaluate the steroidal aromatase inhibitor exemestane as extended adjuvant therapy in this setting.
Postmenopausal patients with clinical T(1-3)N(1)M(0) breast cancer who were disease free after 5 years of tamoxifen were randomly assigned to 5 years of exemestane (25 mg/d orally) or 5 years of placebo. Our primary aim was to test whether exemestane prolongs disease-free survival (DFS). In October 2003, results of National Cancer Institute of Canada (NCIC) MA.17 showing benefit from adjuvant letrozole in this setting necessitated termination of accrual to B-33, unblinding, and offering of exemestane to patients in the placebo group.
At the time of unblinding, 1,598 patients had been randomly assigned; 72% in the exemestane group continued on exemestane and 44% in the placebo group elected to receive exemestane. With 30 months of median follow-up, original exemestane assignment resulted in a borderline statistically significant improvement in 4-year DFS (91% v 89%; relative risk RR = 0.68; P = .07) and in a statistically significant improvement in 4-year relapse-free survival (RFS; 96% v 94%; RR = 0.44; P = .004). Toxicity, assessed up to time of unblinding, was acceptable for the adjuvant setting.
Despite premature closure and crossover to exemestane by a substantial proportion of patients, original exemestane assignment resulted in non-statistically significant improvement in DFS and in statistically significant improvement in RFS.
We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer.
The National ...Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel.
By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831.
Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.)
PurposeThe clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated ...cancers can help inform assessments of clinical utility.MethodsWhole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient-participants and their clinicians. We queried patient-participants' electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient-participants of eligible age who had begun risk management.ResultsThirty-seven MyCode patient-participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer-including a stage 1C fallopian tube cancer-via these procedures.ConclusionScreening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.
Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis.
To compare the relative ...effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes.
The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% SD, 2.17%). Data reported are based on a cutoff date of December 31, 2005.
Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years.
Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events.
There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio RR, 1.02; 95% confidence interval CI, 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death.
Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs.
clinicaltrials.gov Identifier: NCT00003906.
Garlic-derived organosulfides (OSCs) including diallyl trisulfide (DATS) are highly effective in affording protection against chemically induced cancer in animals. Evidence is also mounting to ...indicate that some naturally occurring OSCs can suppress proliferation of cancer cells by causing apoptosis, but the sequence of events leading to proapoptotic effect of OSCs is poorly defined. Using PC-3 and DU145 human prostate cancer cells as a model, we now demonstrate that DATS is a significantly more potent apoptosis inducer than diallyl sulfide (DAS) or diallyl disulfide (DADS). DATS-induced apoptosis in PC-3 cells was associated with phosphorylation of Bcl-2, reduced Bcl-2 : Bax interaction, and cleavage of procaspase-9 and -3. Bcl-2 overexpressing PC-3 cells were significantly more resistant to apoptosis induction by DATS compared with vector-transfected control cells. DATS treatment resulted in activation of extracellular-signal regulated kinase 1/2 (ERK1/2) and c-jun N-terminal kinase 1 (JNK1) and/or JNK2, but not p38 mitogen-activated protein kinase. Phosphorylation of Bcl-2 in DATS-treated PC-3 cells was fully blocked in the presence of JNK-specific inhibitor SP600125. Moreover, JNK inhibitor afforded significant protection against DATS-induced apoptosis in both cells. DATS-induced Bcl-2 phosphorylation and apoptosis were partially attenuated by pharmacological inhibition of ERK1/2 using PD98059 or U0126. Overexpression of catalase inhibited DATS-mediated activation of JNK1/2, but not ERK1/2, and apoptosis induction in DU145 cells suggesting involvement of hydrogen peroxide as a second messenger in DATS-induced apoptosis. In conclusion, our data point towards important roles for Bcl-2, JNK and ERK in DATS-induced apoptosis in human prostate cancer cells.
In premenopausal women, tamoxifen for 5 years reduces the risk of estrogen receptor (ER) - positive breast cancer for at least 10 years. Women < 50 years of age experience fewer serious side effects. ...Vascular and vasomotor events do not persist after treatment regardless of age. Raloxifene use is consistently associated with a reduction in breast cancer risk. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive breast cancer with equal efficacy, but raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in breast cancer risk from either agent translates into reduced breast cancer mortality. Overall quality of life is similar with raloxifene or tamoxifen, but the incidence of dyspareunia, weight gain, and musculoskeletal complaints is higher with raloxifene use, whereas vasomotor symptoms, bladder incontinence, gynecologic symptoms, and leg cramps were higher with tamoxifen use. Ongoing randomized, placebo-controlled trials investigating the use of third-generation aromatase inhibitors in the chemoprevention of breast cancer in postmenopausal women include the NCIC Clinical Trials Group MAP3 (ExCel) Trial (Exemestane in Preventing Cancer in Postmenopausal Women at Increased Risk of Developing Breast Cancer), and the IBIS-II trial.71 The North American MAP3 study randomized patients to exemestane or placebo in patients who refuse treatment with a SERM, and the international IBIS-II trial compares anastrozole for 5 years versus placebo for chemoprevention in patients at increased risk.
Premenopausal women with breast cancer receiving adjuvant chemotherapy are at risk for amenorrhea. The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history (MH) ...and quality-of-life (QOL) studies to compare treatments on these outcomes.
Patients were randomly assigned to sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T; AC→T), concurrent TAC, or AT, which varied in duration (24, 12, 12 weeks, respectively), and use of C. Endocrine therapy was prescribed for women with hormone receptor-positive tumors. MH and QOL were assessed with standardized questionnaires at baseline; cycle 4, day 1; and every 6 months through 24 months. Prespecified analyses examined rates of amenorrhea by treatment arm, the relationship between amenorrhea and QOL, and QOL by treatment arm.
Amenorrhea 12 months after random assignment was significantly different between treatment groups: 69.8% for AC→T, 57.7% for TAC, and 37.9% for AT (P < .001). The AT group without tamoxifen had the lowest rate of amenorrhea. QOL was poorer for patients receiving AC→T at 6 months but similar to others by 12 months. Post-treatment symptoms were increased above baseline for all treatments. Multivariable repeated measures modeling demonstrated that treatment arm, time point, age, and tamoxifen use were significantly associated with symptom severity (all P values < .002).
Amenorrhea rates differed significantly by treatment arm, with the AT arm having the lowest rate. Patients treated with longer duration therapy (AC→T) had greater symptom severity and poorer QOL at 6 months, but did not differ from shorter duration treatments at 12 months.
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