Alessandra Rubagotti

Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis

BACKGROUNDnFor more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2-3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years.nnnMETHODSnWe did a meta-analysis of three clinical trials--the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies--in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2-3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy.nnnFINDINGSnPatients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratio 0.59 [95% CI 0.48-0.74]; p<0.0001), event-free survival (0.55 [0.42-0.71]; p<0.0001), distant recurrence-free survival (0.61 [0.45-0.83]; p=0.002), and overall survival (0.71 [0.52-0.98]; p=0.04).nnnINTERPRETATIONnOur results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2-3 years to anastrozole.

Cyclophosphamide, Methotrexate, and Fluorouracil Versus Tamoxifen Plus Ovarian Suppression as Adjuvant Treatment of Estrogen Receptor–Positive Pre-/Perimenopausal Breast Cancer Patients: Results of the Italian Breast Cancer Adjuvant Study Group 02 Randomized Trial

PURPOSEnTo compare the efficacy of chemotherapy versus that of tamoxifen plus ovarian suppression in pre-/perimenopausal estrogen receptor-positive patients with early breast cancer.nnnPATIENTS AND METHODSnPatients were randomly assigned to receive either six cycles of a standard regimen of cyclophosphamide 100 mg/m(2) orally days 1 to 14, methotrexate 40 mg/m(2) intravenously (IV) days 1 and 8, and fluorouracil 600 mg/m(2) IV days 1 and 8 (CMF), with all drugs restarted on day 29, or 5 years of tamoxifen, 30 mg/d, plus ovarian suppression with surgical oophorectomy, ovarian irradiation, or monthly goserelin 3.6-mg injections. Disease-free survival was the main study end point. Overall survival and toxicity were additional end points.nnnRESULTSnBetween 1989 and 1997, 120 patients were assigned to CMF and 124 to tamoxifen and ovarian suppression (oophorectomy, n = 6; ovarian irradiation, n = 31; and goserelin injections, n = 87). At the time of analysis (median follow-up time, 76 months; range, 9 to 121 months), 82 patients had relapsed and 39 had died. No difference between groups had emerged with respect to either disease-free or overall survival. Treatments were comparable even in respect to age, tumor size, and nodal status, although a nonsignificant trend favored patients with poorly differentiated tumors treated with CMF. Leukopenia, nausea, vomiting, stomatitis, and alopecia were significantly more common in patients treated with CMF. There were few patients who developed benign gynecologic changes in either group, and numbers were comparable.nnnCONCLUSIONnThe combination of tamoxifen with ovarian suppression seems to be safe and to yield comparable results relative to standard CMF.

Estrogen-Like Action of Tamoxifen on Vaginal Epithelium in Breast Cancer Patients

The action of prolonged administration of Tamoxifen on the vaginal epithelium in postmenopausal breast cancer patients has been investigated by means of exfoliative cytology. Our study gives quite convincing evidence of a clear-cut estrogenic effect of Tamoxifen on vaginal epithelium. The relationship between estrogenic properties of Tamoxifen and breast cancer management is discussed.

Evaluation of Tamoxifen and Anastrozole in the Prevention of Gynecomastia and Breast Pain Induced by Bicalutamide Monotherapy of Prostate Cancer

PURPOSEnTo determine whether tamoxifen or anastrozole prevents gynecomastia and breast pain caused by bicalutamide (150 mg) without compromising efficacy, safety, or sexual functioning.nnnPATIENTS AND METHODSnA double-blind, placebo-controlled trial was performed in patients with localized, locally advanced, or biochemically recurrent prostate cancer. Patients (N = 114) were randomly assigned to either bicalutamide (150 mg/d) plus placebo or in combination with tamoxifen (20 mg/d) or anastrozole (1 mg/d) for 48 weeks. Gynecomastia, breast pain, prostate-specific antigen (PSA), sexual functioning, and serum levels of hormones were assessed.nnnRESULTSnGynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-tamoxifen group, and 51% of patients in the bicalutamide-anastrozole group (P < .001); breast pain developed in 39%, 6%, and 27% of patients, respectively (P = .006). Baseline PSA level decreased by > or = 50% in 97%, 97%, and 83% of patients in the bicalutamide, bicalutamide-tamoxifen, and bicalutamide-anastrozole groups, respectively (P = .07); and adverse events were reported in 37%, 35%, and 69% of patients, respectively (P = .004). There were no major differences among treatments in sexual functioning parameters from baseline to month 6. Elevated testosterone levels occurred in each group; however, free testosterone levels remained unchanged in the bicalutamide-tamoxifen group because of increased sex hormone-binding globulin levels.nnnCONCLUSIONnAnastrozole did not significantly reduce the incidence of bicalutamide-induced gynecomastia and breast pain. In contrast, tamoxifen was effective, without increasing adverse events, at least in the short-term follow-up. These data support the need for a larger study to determine any effect on mortality.

Sequential Tamoxifen and Aminoglutethimide Versus Tamoxifen Alone in the Adjuvant Treatment of Postmenopausal Breast Cancer Patients: Results of an Italian Cooperative Study

PURPOSEnTo determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued.nnnPATIENTS AND METHODSnThree hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years.nnnRESULTSnAt a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P =.02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P =.005) and breast cancer-specific survival (P =.06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P =.0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm.nnnCONCLUSIONnSwitching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

An Open, Randomised, Multicentre, Phase 3 Trial Comparing the Efficacy of Two Tamoxifen Schedules in Preventing Gynaecomastia Induced by Bicalutamide Monotherapy in Prostate Cancer Patients

BACKGROUNDnBicalutamide monotherapy is a valuable option for prostate cancer (PCa) patients who wish to avoid the consequences of androgen deprivation; however, this treatment induces gynaecomastia and mastalgia in most patients. Tamoxifen is safe and effective in preventing breast events induced by bicalutamide monotherapy without affecting antitumor activity, but possible interference between bicalutamide and tamoxifen remains a matter of concern. To reduce the exposure to tamoxifen, we considered the putative advantages of weekly administration.nnnOBJECTIVEnTo compare the efficacy of two different schedules of tamoxifen in preventing breast events. Toxicity, prostate-specific antigen behaviour, and sexual-functioning scores were also evaluated.nnnDESIGN, SETTING, AND PARTICIPANTSnThis was a noninferiority trial. From December 2003 to February 2006, 80 patients with localised/locally advanced or biochemically recurrent PCa who were also candidates for bicalutamide single therapy were randomised to receive two different schedules of tamoxifen: daily (n=41) and weekly (n=39). Median follow-up was 24.2 mo.nnnINTERVENTIONnDaily bicalutamide (150 mg) plus daily tamoxifen 20mg continuously (daily group) or the same but with tamoxifen at 20mg weekly after the first 8 wk of daily treatment (weekly group). Three patients in the weekly group and one in the daily group were discontinued for adverse events.nnnMEASUREMENTSnFor gynaecomastia, we used ultrasonography. For mastalgia and sexual functioning, we used questionnaires.nnnRESULTS AND LIMITATIONSnGynaecomastia developed in 31.7% of patients in the daily group and in 74.4% of patients in the weekly group (p<0.0001), and it was more severe in patients who switched to weekly tamoxifen (p=0.001). Mastalgia occurred in 12.2% and 46.1% of patients, respectively (p=0.001). There were no major differences among treatment schedules relative to sexual functioning scores and incidence and severity of adverse events. No differences between groups in PSA behaviour and disease progression have been detected so far.nnnCONCLUSIONSnThis study demonstrated that tamoxifen 20mg/wk is inferior to tamoxifen 20mg/d in preventing the incidence and severity of bicalutamide-induced breast events. The safety and efficacy of tamoxifen at the common daily dose of 20mg for the prophylaxis of bicalutamide-induced breast events were confirmed.

Serum enterolactone levels and mortality outcome in women with early breast cancer: A retrospective cohort study

We previously demonstrated that high serum enterolactone levels are associated with a reduced incidence of breast cancer in healthy women. The present study was aimed at investigating whether a similar association might be found between serum enterolactone levels and the mortality of women with early breast cancer. The levels of enterolactone in cryopreserved serum aliquots obtained from 300 patients, operated on for breast cancer, were measured using a time-resolved fluoro-immunoassay. Levels were analyzed in respect to the risk of mortality following surgery. Cox proportional hazard regression models were used to check for prognostic features, to estimate hazard ratios for group comparisons and to test for the interaction on mortality hazards between the variables and enterolactone concentrations. The Fine and Gray competing risk proportional hazard regression model was used to predict the probabilities of breast cancer-related and breast cancer-unrelated mortalities. At a median follow-up time of 23xa0years (range 0.6–26.1), 180 patients died, 112 of whom died due to breast cancer-related events. An association between a decreased mortality risk and enterolactone levels ≥10xa0nmol/l was found in respect to both all-cause and breast cancer-specific mortality. The difference in mortality hazards was statistically significant, but it appeared to decrease and to lose significance after the first 10xa0years, though competing risk analysis showed that breast cancer-related mortality risk remained constantly lower in those patients with higher enterolactone levels. Our findings are consistent with those of most recent literature and provide further evidence that mammalian lignans might play an important role in reducing all-cause and cancer-specific mortality of the patients operated on for breast cancer.

Periostin: A Novel Prognostic and Therapeutic Target For Genitourinary Cancer?

Many of the cellular abnormalities present in solid tumors are structural in nature and involve the proteins of the extracellular matrix (ECM). Periostin is a protein produced and secreted by the fibroblasts as a component of the ECM where it is involved in regulating intercellular adhesion. The expression of periostin has an important physiological role during embryogenesis and growth, namely at the level of bone, dental, and cardiac tissues. Many studies indicate that periostin plays an important role for tumor progression in various types of cancer, such as colon, lung, head and neck, breast, ovarian, and prostate. To the best of our knowledge, a limited number of studies have investigated periostin expression in urogenital cancer, such as prostate, bladder, penile, and renal cancer, and no studies were performed in testis cancer. In this review article, we summarize the most recent knowledge of periostin, its genetic and protein structure, and the role of the different isoforms identified and sequenced so far. In particular, we focus our attention on the role of this protein in genitourinary tumors, trying to emphasize the role not only as a possible prognostic marker, but also as a possible target for the development of future anticancer therapies.

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Long term results of the Italian Tamoxifen Anastrozole trial

The Italian Tamoxifen Anastrozole (ITA) trial investigated the efficacy of switching to anastrozole for women who were already on adjuvant tamoxifen since 2-3years. Relapse-free survival (RFS) was the primary end-point; event-free survival (EFS), overall survival (OS) and safety were secondary end-points. Herein, we report an update on the long term results of this trial. At a median follow-up time of 128 months (range 14-168 months), 94 events have been recorded in the tamoxifen group compared with 71 events in the anastrozole group (hazard ratio (HR)=0.71; 95% confidence interval (CI), 0.52-0.97; p=0.03). RFS was also significantly longer in the anastrozole group (HR=0.64; 95% CI, 0.44-0.94; p=0.023); no statistically significant difference between study arms concerning OS was shown, but the trial was not powered enough in respect to this end-point. The incidence of serious adverse events (SAE) like bone fractures was comparable (four in each arm), while gynaecological problems were still significantly more numerous among the women continued on tamoxifen (21 patients developed a SAE in this group, including eight endometrial cancers, compared to three patients who suffered from a SAE, including one endometrial cancer, in the anastrozole group: p<0.000). Present data confirm that switch is safe and can provide long-term gain in terms both of RFS and of EFS, which persists even several years since treatment discontinuation.

Complement C3f serum levels may predict breast cancer risk in women with gross cystic disease of the breast

UNLABELLEDnGross cystic disease (GCDB) is a breast benign condition predisposing to breast cancer. Cryopreserved sera from GCDB patients, some of whom later developed a cancer (cases), were studied to identify potential risk markers. A MALDI-TOF mass spectrometry analysis found several complement C3f fragments having a significant increased abundance in cases compared to controls. After multivariate analysis, the full-length form of C3f maintained a predictive value of breast cancer risk. Higher levels of C3f in the serum of women affected by a benign condition like GCDB thus appears to be correlated to the development of breast cancer even 20 years later.nnnBIOLOGICAL SIGNIFICANCEnIncreased complement system activation has been found in the sera of women affected by GCDB who developed a breast cancer, even twenty or more years later. C3f may predict an increased breast cancer risk in the healthy population and in women affected by predisposing conditions.