Underuse of anthracyclines in women with HER-2+ advanced breast cancer.

Anthracyclines are among the most active drugs in breast cancer. Because of excessive cardiotoxicity, their use in combination with trastuzumab has been discouraged in patients with human epidermal growth factor receptor (HER)-2(+) metastatic breast cancer. We sought to describe how this treatment paradigm influenced the use of anthracyclines in this patient setting. We analyzed a multi-institutional database containing the treatment history of 450 patients who received at least one trastuzumab-based regimen for HER-2(+) metastatic breast cancer. Patients were considered eligible for anthracyclines for metastatic disease if they were never exposed (NE) or had been previously exposed (PE) to an anthracycline in the neoadjuvant or adjuvant setting and had relapsed after 12 months from the last dose. We then assessed the use of anthracycline-based therapy after failure with the first trastuzumab-based regimen in eligible patients. Three-hundred twenty-one patients were considered eligible for anthracyclines. In total, 190 eligible patients developing disease progression during the initial trastuzumab-based therapy were analyzed. An anthracycline was administered as first salvage treatment in 14 NE and two PE patients. Another 15 NE and nine PE patients received an anthracycline as a further line of therapy. Of 119 eligible patients who died from breast cancer, only 30 received an anthracycline for metastatic disease. In conclusion, despite the fact that two thirds of the patients receiving trastuzumab-based therapy for HER-2 metastatic breast cancer are eligible for anthracyclines, these drugs are infrequently used nowadays to treat trastuzumab-refractory disease. A role for these compounds should be redefined in this patient subset.

Trastuzumab with either docetaxel or vinorelbine as first-line treatment for patients with HER2-positive advanced breast cancer: a retrospective comparison.

BACKGROUND: Combinations of trastuzumab with either docetaxel or vinorelbine are considered valuable treatment options for HER2-positive metastatic breast cancer patients. We performed a retrospective comparison of the clinical outcomes associated with either one of these combinations. METHODS: From a multi-institutional database we retrieved 179 patients treated with either docetaxel or vinorelbine plus trastuzumab as first-line therapy for HER2-positive advanced breast cancer. RESULTS: Docetaxel-trastuzumab was superior to vinorelbine-trastuzumab in terms of response rate (RR: 77 vs 57%, p = 0.01) and median overall survival (OS: 35 vs 23 months, p = 0.04), but not in median time to progression (TTP: 12 vs 10 months, p = 0.53). At multivariate analysis, type of treatment was not associated with TTP but was an independent predictor of OS, with a significant reduction in the risk of death in favor of docetaxel-trastuzumab (HR 0.474, 95% IC 0,303-0.742, p < 0.01). CONCLUSION: Docetaxel or vinorelbine, when combined with trastuzumab, provide excellent rates of tumor control in patients with previously untreated HER2-positive advanced breast cancer. Docetaxel may offer some advantage in terms of response rate and resulted in a significantly prolonged overall survival, which, because of the retrospective design of our study, deserves further investigation in prospective trials.

Retrospective evaluation of clinical outcomes in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy in the pre-lapatinib era.

BACKGROUND: Patients with HER2-positive breast cancer whose disease has become resistant to the anti-HER2 monoclonal antibody trastuzumab can benefit from lapatinib, a dual epidermal growth factor receptor/HER2 tyrosine kinase (TK) inhibitor. Before the availability of this compound, trastuzumab was often continued beyond disease progression, usually in addition to further chemotherapy, an approach which was not based on randomized studies. We sought to retrospectively compare the clinical outcomes of patients who, upon progression during an initial trastuzumab-based regimen, stopped or continued trastuzumab in addition to further chemotherapy. PATIENTS AND METHODS: From the clinical records of 407 patients with HER2-positive advanced breast cancer, we identified 279 patients progressing during an initial trastuzumab-based treatment. Of these patients, 83 continued trastuzumab in addition to chemotherapy, and 112 received chemotherapy alone. RESULTS: We found no difference in response rate (28% vs. 30%; P = .5), median time to second tumor progression (8.4 months vs. 7 months; P = .24), or median postprogression survival (20.6 months and 15.4 months; P = .29) according to whether patients continued or stopped trastuzumab. At multivariate analysis, continuation of trastuzumab was associated with a statistically insignificant trend toward reduced risk of second progression (hazard ratio, 0.753; P = .08). CONCLUSION: Patients with HER2-positive advanced breast cancer developing tumor progression during an initial trastuzumab-based regimen did not seem to benefit significantly from the continuation of trastuzumab in addition to chemotherapy. For these patients, there is evidence from a large randomized trial that effective HER2 targeting can be accomplished by inhibiting the HER2 TK activity with lapatinib.

Pathological classification of ductal carcinoma in situ of the breast correlates with surgical treatment and may be predicted by mammography.

In order to assess the correlation of pathological and radiological features of ductal carcinoma in situ (DCIS) of the breast and their association with surgical outcome, a consecutive series of 150 patients was retrospectively examined. Pathological slides from all patients were divided into three categories according to the pathological EPWG (European Pathologist Working Group) and DIN (Ductal Intraepithelial Neoplasia) classifications, which showed very good inter-correlation (r=0.99) (whole series). Mammographic images from 46 of these cases were blindly classified into five categories according to the level of radiological suspicion (R), morphology of calcifications (Ca) and preoperative results of needle biopsy (C/B) (limited series). No significant differences in the distribution of clinical and pathological variables were detected among whole and limited series. The lesions were grouped into two (low versus high) pathological (PRG), radiological (RRG and CaRG) and needle biopsy (C/BRG) risk groups. PRG was associated with both RRG (p=0.002) and CaRG (p=0000), but not with C/BRG. Correlations with surgical outcome were also explored, with lesions of high PRG being more likely to undergo re-excision for inadequate first wide local excision [odds ratio (OR)=2.1], mastectomy (OR=2.6) and nodal staging procedures (OR=3.8) in the whole series. Conversely, no significant correlation was found between PRG, RRG, CaRG and C/BRG with surgical outcome in the limited series. We suggest that pathological features of DCIS are associated with surgical outcome and may be predicted by mammography.

Comparison of two models for the prediction of nonsentinel node metastases in breast cancer.

BACKGROUND: It is debated whether all patients with a positive sentinel node dissection (SLND) should be submitted to axillary lymph node dissection (ALND). Models have been developed to estimate the likelihood of nonsentinel node (non-SLN) metastases. METHODS: The accuracy of the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram and MD Anderson scoring system for the prediction of non-SLN status was tested in a consecutive series of 186 SLN-positive breast cancer patients. A multivariate analysis was performed to assess which parameters independently predicted the presence of non-SLN metastases. RESULTS: The predictive accuracy of the MSKCC nomogram measured by the receiver operating characteristic curve was 0.71, and it was best in patients with <10% risk of non-SLN metastases (sensitivity 100% and specificity 96%). The MD Anderson score predicted non-SLN involvement with low accuracy because it classified 85% of the patients in the intermediate-risk groups. Only SLN macrometastases and tumor multifocality independently predicted non-SLNs involvement. CONCLUSIONS: The MSKCC nomogram can help individualize the surgical treatment of SLN-positive breast cancer when the likelihood of further axillary involvement is low or surgical risks are higher.

Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy.

We sought to describe patterns of treatment and clinical outcome in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy. One hundred eighty-four consecutive HER2-positive advanced breast cancer patients received trastuzumab-based therapy between September 1999 and September 2004. Patients were followed up until death or May 2005. For patients progressing on trastuzumab-based therapy, we calculated the response rate (RR) to the first post-progression treatment, overall survival (OS) from the first administration of trastuzumab, time to second progression (TT-SP), and post-progression survival (PPS), according to treatment. At the time of this analysis, 132 patients had progressed on trastuzumab-based therapy, and 89 had died. Of the progressing patients, 21 experienced rapid progression and could not receive additional anticancer treatments;40 patients continued trastuzumab either alone (12 patients with isolated central nervous system progression), with chemotherapy (23 patients), or with endocrine therapy (5 patients); and 71 stopped trastuzumab and received chemotherapy (61 patients) or endocrine therapy (10 patients) as the first post-progression treatment. Excluding patients with rapid progression, clinical outcomes were similar whether trastuzumab was continued or not, in terms of RR (18% and 27%, respectively), OS (31 and 30 months, respectively), TT-SP (6 and 7 months, respectively), and PPS (21 and 19 months, respectively). The clinical outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy might not be influenced by continuing trastuzumab. The optimal therapeutic strategy in this setting of patients needs evaluation in randomized trials.

Attitudes of Italian gynaecologists towards prophylactic oophorectomy at hysterectomy for non-malignant conditions.

OBJECTIVE: To compare the attitudes of Italian oncologic gynaecologists towards prophylactic oophorectomy at hysterectomy for a non-neoplastic reason. STUDY DESIGN: A four-item two-part questionnaire was submitted to 170 gynaecologists attending a national conference on gynaecologic oncology. RESULTS: About 92% of gynaecologists reported they would perform prophylactic oophorectomy in women over 50 years, but only 14% said they would in patients aged 45-50; a family history of cancer emerged as a major decision-making criterion for performing oophorectomy in the younger set of patients. CONCLUSION: Our brief survey confirms the wide variability in attitudes among gynaecologists towards performing prophylactic oophorectomy at hysterectomy for a non-neoplastic pathology in women aged 40-50.

Laparoscopic treatment of endometrial cancer: feasibility and results.

OBJECTIVE: The aim of this study was to compare laparoscopic and abdominal approach in the treatment of endometrial cancer in our department. STUDY DESIGN: From January 1999 to November 2002, 77 patients underwent surgery for stages I-III endometrial cancer. The first group of 36 patients had abdominal hysterectomy as well as salpingo-oophorectomy, with or without lymphadenectomy. The remaining 41 patients received laparoscopic assisted vaginal hysterectomy as well as salpingo-oophorectomy, with or without lymphadenectomy. In this retrospective study, we have compared the surgical results, the short- and long-term morbidity and the outcome of the two patient groups. RESULTS: Body mass index (BMI) was significantly higher in the laparoscopic group (27.3 versus 24.6; p=0.009). The average time for surgery was significantly longer for the laparoscopic group (143.6 min versus 109.7 min; p=0.0001), but lymphadenectomy was performed in more patients (63.4% versus 25%; p=0.001). Postoperative hospital stay was significantly longer in patients undergoing the abdominal approach (4.59 days versus 3.18 days; p<0.0001). No blood transfusions were performed and the rates of complications were similar in the two groups. No differences were found in recurrence and survival rate. CONCLUSIONS: In our experience, laparoscopic and abdominal surgery can achieve similar results in the treatment of endometrial cancer. In our series, even with the BMI and the number of lymphadenectomies being higher in the laparoscopic group, the rates of complications were similar in the two groups.

Antihormones in prevention and treatment of breast cancer.

Breast cancer has the highest incidence of all types of cancer in women. Age and family history are the strongest risk factors, but sex hormones also play an important role, as demonstrated by epidemiological studies reporting a consistent association by reproductive personal history and breast cancer risk. The acceptability of preventive strategies by healthy women is closely related to their lifetime risk of developing breast cancer. Although surgical prevention may be considered in carriers of BRCA1/2 mutation, this option cannot be advocated for the majority of women whose risk is only moderately increased. In these women, chemoprevention with tamoxifen may reduce the incidence of estrogen receptor (ER)-positive breast carcinoma by 30-50%. Other drugs such as raloxifen and aromatase inhibitors (AIs) are currently being tested in this setting. Tamoxifen has been the most successful hormonal treatment over the last 30 years and, until recently, the most active drug in endocrine-sensitive breast cancer. In premenopausal breast cancer, tamoxifen still represents the therapy of choice, alone or in association with ovarian suppression. Conversely, in postmenopausal women it has been overtaken by third-generation AIs as first-choice drugs both in the adjuvant and metastatic settings. Many other issues, such as the optimal sequence between tamoxifen and AIs, the duration of AIs treatment, and the association of ovarian suppression and AIs in premenopausal patients still await the completion of randomized clinical trials. Furthermore, it is likely that treatment tailoring will be increased by the definition of patient subgroups that could derive larger benefits from AIs (progesterone receptor-negative, HER-2-overexpressing) or other new drugs.

Vaginal oestrogen therapy after breast cancer: is it safe?

The increasing number of breast cancer patients who suffer from menopausal symptoms is mainly due to the extensive use of adjuvant treatments in the younger women. Both short and long-term side effects of oestrogen deficiency may severely impact on the quality of life of these women and should not be underestimated. Hormonal treatments are contraindicated in breast cancer survivors mainly due to the concern that dormant micrometastases may be stimulated to grow. Alternative non-hormonal remedies are now available to alleviate symptoms and to prevent chronic diseases associated with oestrogen deficiency. Urogenital atrophy is an important consequence of oestrogen deprivation that can be effectively treated by vaginal estrogens, although systemic absorption occurs with conventional doses. Preliminary data suggest that much lower doses of vaginal estrogens can alleviate urogenital atrophy without influencing serum estrogenic levels. Further research is warranted to confirm whether vaginal estrogens are safe in symptomatic breast cancer patients who are non-responsive to alternative treatments.

Pretreatment serum hemoglobin level and a preliminary investigation of intratumoral microvessel density in advanced ovarian cancer.

OBJECTIVE: The primary aim of this study was to evaluate the prognostic and predictive value of pretreatment serum hemoglobin level (Hb) in advanced ovarian cancer; second aim was to perform a preliminary investigation of intratumoral microvessel density (IMD). METHODS: The influence on survival and response to treatment of several clinico-pathological features, including Hb, was analyzed in 72 patients with advanced ovarian cancer. IMD was assessed in tumor specimens of 25 of the 72 patients to compare three different endothelial markers: anti-FactorVIII, anti-CD31 and anti-CD34. In this subgroup of patients, a preliminary analysis of the prognostic and predictive value of IMD, and its relationship with Hb and other clinico-pathological features, was performed. RESULTS: Hb >or= 12 g/dl was significantly associated with a better overall survival in univariate analysis (P = 0.0181) and was the only independent prognostic variable in multivariate analysis (P = 0.0160). Hb was directly related to progression-free survival (P = 0.0240) and complete response to treatment (P = 0.016). In the preliminary investigation of IMD, mean microvessel count did not show any significant difference among the three endothelial markers used, but anti-CD34 revealed a more consistent staining reaction. The relationship between IMD and complete response to treatment was found near to statistical significance (P = 0.05); Hb and IMD were inversely related (r = -0.47; P = 0.045). CONCLUSIONS: Hb has a prognostic and predictive value in advanced ovarian cancer. In our preliminary study, which was performed on a limited number of patients, we found anti-CD34 to be an optimal marker for IMD determination, IMD to be a possible predictive factor of complete response to treatment, and IMD and Hb to be inversely related.

Analysis of the evolution in the management of endometrial cancer in Italy: a CTF study.

OBJECTIVE: In 1994 we mailed questionnaires to referral centers in Italy in order to evaluate the different opinions concerning aspects of endometrial cancer treatment, which is still controversial. The data processing showed a significant nonhomogeneity in disease management and prompted the Italian Society of Gynecologic Oncology to define guidelines for endometrial cancer adjuvant treatment. In 2001, we mailed again the same questionnaire to the same referral Centers in Italy. The aim of the second enquiry was the evaluation of changes in endometrial cancer management and the effective impact of the guidelines published. METHODS: The enquiry used the same questionnaires mailed in 1994; actually, we mailed those questionnaires to the same referral centers in Italy twice: in December 2000 and March 2001. The results of both the enquiries were collected in a relational data base, and the statistical evaluations were calculated using SPSS-statistics (Window ver. 8). RESULTS: Endometrial cancer treatment consists in abdominal hysterectomy and bilateral salpingo-oophorectomy. The unique relevant difference as to 1994 consists in the systemic performing of peritoneal cytology in endometrial cancer staging. Unlike the previous enquiry, adjuvant radiotherapy is not systematically performed in disease at stage Ic because of the substantial absence of confirmed data demonstrating a real benefit in terms of survival rate. The comparison between the two enquiries shows a significant change in medical planning and diversification attitude according to patient age and menopausal state. The disease management changes in patients over 75 years old, mainly with respect to surgery and primary therapy. CONCLUSIONS: We noted a resistance of many centers to accept some trends actually widespread in the literature but not yet performed in practical clinical.