Giorgio Mustacchi

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.

Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial

BACKGROUNDnLonger duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting.nnnMETHODSnWe did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients with HER2-negative measurable metastatic breast cancer; each received three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75-100 mg/m(2)) every 3 weeks. Progression-free patients were randomly assigned with an interactive voice-response system by block (size four) randomisation (1:1) to receive either bevacizumab and capecitabine or bevacizumab only (bevacizumab 15 mg/kg on day 1; capecitabine 1000 mg/m(2) twice per day on days 1-14, every 3 weeks) until progression, stratified by oestrogen receptor status (positive vs negative), visceral metastases (present vs absent), response status (stable disease vs response vs non-measurable), and lactate dehydrogenase concentration (≤1·5 vs >1·5u2008×u2008upper limit of normal). Neither patients nor investigators were masked to allocation. The primary endpoint was progression-free survival (from randomisation) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00929240.nnnFINDINGSnBetween July 16, 2009, and March 7, 2011 (when enrolment was prematurely terminated), 284 patients received initial bevacizumab and docetaxel; 185 (65%) were randomly assigned (91 to bevacizumab and capecitabine versus 94 to bevacizumab only). Progression-free survival was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (median 11·9 months [95% CI 9·8-15·4] vs 4·3 months [3·9-6·8]; stratified hazard ratio 0·38 [95% CI 0·27-0·55]; two-sided log-rank p<0·0001), as was overall survival (median 39·0 months [95% CI 32·3-not reached] vs 23·7 months [18·5-31·7]; stratified HR 0·43 [95% CI 0·26-0·69]; two-sided log-rank p=0·0003). Results for time to progression were consistent with those for progression-free survival. 78 (86%) patients in the bevacizumab and capecitabine group and 72 (77%) in the bevacizumab only group had an objective response. Clinical benefit was recorded in 92 (98%) patients in the bevacizumab alone group and 90 (99%) in the bevacizumab and capecitabine group. Mean change from baseline in global health score did not differ significantly between groups. Grade 3 or worse adverse events during the maintenance phase were more common with bevacizumab and capecitabine than with bevacizumab only (45 [49%] of 91 patients vs 25 [27%] of 92 patients). The most common grade 3 or worse events were hand-foot syndrome (28 [31%] in the bevacizumab and capecitabine group vs none in the bevacizumab alone group), hypertension (eight [9%] vs three [3%]), and proteinuria (three [3%] vs four [4%]). Serious adverse events were reported by ten (11%) patients in the bevacizumab and capecitabine group and seven (8%) patients in the bevacizumab only group.nnnINTERPRETATIONnDespite prematurely terminated accrual and the lack of information about post-progression treatment, both progression-free survival and overall survival were significantly improved with bevacizumab and capecitabine compared with bevacizumab alone as maintenance treatment. These results might inform future maintenance trials and current first-line treatment strategies for HER2-negative metastatic breast cancer.nnnFUNDINGnF Hoffmann-La Roche.

Gene expression profiling in breast cancer: A clinical perspective

Gene expression profiling tests are used in an attempt to determine the right treatment for the right person with early-stage breast cancer that may have spread to nearby lymph nodes but not to distant parts of the body. These new diagnostic approaches are designed to spare people who do not need additional treatment (adjuvant therapy) the side effects of unnecessary treatment, and allow people who may benefit from adjuvant therapy to receive it. In the present review we discuss in detail the major diagnostic tests available such as MammaPrint dx, Oncotype dx, PAM50, Mammostrat, IHC4, MapQuant DX, Theros-Breast Cancer Gene Expression Ratio Assay, and their potential clinical applications.

Modulating effect of lonidamine on response to doxorubicin in metastatic breast cancer patients: Results from a multicenter prospective randomized trial

Previous results from our preclinical studies have shown that lonidamine (LND) can positively modulate the antiproliferative activity of doxorubicin (DOX) on breast cancer cell lines. To evaluate the effect of LND in a clinical setting, a multicenter randomized trial was carried out on patients with advanced breast cancer. From September 1991 to July 1993, 181 patients were enrolled in the trial and received an initial treatment of DOX at 75 mg/m2 for 3 cycles. The 137 patients who reached complete remission, partial remission, or stable disease were randomized to receive either DOX alone (75 mg/m2 day 1) (arm A) or DOX plus LND (600 mg orally/day) (arm B).The patients enrolled in the two arms were fairly homogeneous in terms of major clinical characteristics. Toxicity was similar in both arms except for myalgia: WHO grade ≥ 2 was observed in 57% of arm B patients. Overall response rate to DOX + LND was 50% and to DOX alone 38% in evaluable patients, and 48% vs 37% in all registered patients, as determined by an intention-to-treat analysis. The differences did not reach statistical significance. Conversely, in agreement with previous findings, we observed a significant difference in response rate in the subgroup of patients with liver metastases, regardless of the extent of hepatic involvement (DOX + LND 68% vs DOX 33%, p=0.03). This observation makes LND an important tool in association with anthracyclines in the treatment of this subgroup of patients.

Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma : Pooled analysis of 2 consecutive trials

The superiority of new generation aromatase inhibitors over tamoxifen in the adjuvant treatment of early breast carcinoma has emerged from several randomized trials. However, until now not all previous studies have shown a mortality benefit.

The role of taxanes in triple-negative breast cancer: literature review

Breast cancer (BC) is the most frequent tumor worldwide. Triple-negative BCs are characterized by the negative estrogen and progesterone receptors and negative HER2, and represent 15% of all BCs. In this review, data on the use of taxanes in triple-negative BCs are analyzed, concluding they are effective in any clinical setting (neoadjuvant, adjuvant, and metastatic). Further, the role of nab-paclitaxel (formulation of albumin-bound paclitaxel) in these tumors is also evaluated. The available data show the clinical potential of nab-paclitaxel based combinations in terms of long-duration response, increased survival, and better quality of life of patients with triple-negative metastatic BC. The ongoing trials will give further information on the better management of this type of tumor.

Biology, prognosis and response to therapy of breast carcinomas according to HER2 score

BACKGROUNDnThe standardization of the HER2 score and recent changes in therapeutic modalities points to the need for a reevaluation of the role of HER2 in recently diagnosed breast carcinoma.nnnPATIENTS AND METHODSnA multicenter, retrospective study of 1794 primary breast carcinomas diagnosed in Italy in 2000/2001 and scored in HER2 four categories according to immunohistochemistry was conducted.nnnRESULTSnDuctal histotype, vascular invasion, grade, MIB1 positivity, estrogen and progesterone receptor expression differed significantly in HER2 3+ tumors compared with the other categories. HER2 2+ tumors almost showed values intermediate between those of the negative and the 3+ subgroups. The characteristics of HER2 1+ tumors were found to be in between those of HER2 0 and 2+ tumors. With a median follow-up of 54 months, HER2 3+ status was associated with higher relapse rates in node-positive and node-negative subgroups, while HER2 2+ only in node positive. Analysis of relapses according to type of therapy provided evidence of responsiveness of HER2-positive tumors to chemotherapy, especially taxanes.nnnCONCLUSIONSnThe present prognostic significance of HER2 is correlated to receptor expression level and points to the need to consider HER2 2+ and HER2 3+ tumors as distinct diseases with different outcomes and specific features.

Biological Characteristics and Medical Treatment of Breast Cancer in Young Women—A Featured Population: Results from the NORA Study

Background. The present paper described the biological characteristics and clinical behavior of young women in the cohort NORA study Patients and Methods. From 2000–2002, patients (N > 3500) were enrolled at 77 Italian hospitals. Women aged ≤50 years (N = 1013) were stratified into age groups (≤35, 36–40, 41–45, and 46–50 years). The relationship between age and patient characteristics, cancer presentation, and treatment was analyzed. Results. Younger women more frequently had tumors with ER/PgR-negative(χ 2 = 7.07; P = .008), HER2 amplification (χ 2 = 5.76; P = .01), and high (≥10%) Ki67 labelling index (χ 2 = 9.53; P = .002). Positive nodal status, large tumors, and elevated Ki67 all associated with the choice for chemotherapy followed by endocrine therapy in hormone receptor-positive patients (P < .0001). At univariate analysis, ER-ve status, chemotherapy and age resulted as the only statistically significant variables (HR = 2.02, P = .004, and >40 versus ≤40, P < .0001, resp.). At multivariate analysis, after adjustment for significant clinical and pathological factors, age remains a significant prognostic variable (HR = 0.93, P = .0021). Conclusion. This cohort study suggests that age per sè is an important prognostic factor. The restricted role of early diagnosis and the aggressive behavior of cancer in this population make necessary the application of targeted medical strategies crucial.

Effect of adjuvant trastuzumab treatment in conventional clinical setting: an observational retrospective multicenter Italian study.

Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23xa0%) patients completed 1-year trastuzumab treatment. In 128 patients (12.77xa0%), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician’s decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32xa0months, 107 breast cancer relapses were recorded (overall frequency, 10.67xa0%), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (<18xa0months from the start of treatment) compared to recurrences in bone after the end of treatment and wash-out of the drug (>18xa0months from the start of treatment) (35.89 vs. 14.28xa0%, pxa0=xa00.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases.

Neo-adjuvant exemestane in elderly patients with breast cancer: a phase II, multicentre, open-label, Italian study

BACKGROUNDnThe steroidal aromatase inhibitor exemestane has demonstrated efficacy for the treatment of breast cancer in the metastatic and adjuvant settings. Smaller trials have also reported efficacy in the neo-adjuvant setting.nnnPATIENTS AND METHODSnThis phase II, open-label, multicentre study examined the efficacy and safety of neo-adjuvant exemestane in women aged >70 years with operable, receptor-rich breast cancer. Consecutive eligible patients received exemestane 25 mg/day for 6 months before planned surgery. The primary end point was clinical response.nnnRESULTSnOverall, 117 patients were recruited (median age 80 years). The objective response rate in 112 assessable patients (85 with clinical and mammographic evaluation; 27 with clinical evaluation only) was 69.6% (two complete responses; 76 partial responses). In patients who responded, median tumour size reduced from 4.81 to 2.12 cm. Seventy-seven patients (68.7%) continued to surgery. Of the 40 patients eligible for breast-conserving surgery, 34 (85%) deemed unfit for this procedure at baseline. Exemestane-related adverse events were unremarkable except for grade 3 allergic skin reactions in two patients (1.8%).nnnCONCLUSIONnNeo-adjuvant exemestane given for 6 months appears to be effective for receptor-rich breast cancer in older patients. There may now be sufficient evidence to support the use of neo-adjuvant in this patient population.