Laura Orlando

Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors

BACKGROUND We recently demonstrated that in premenopausal patients with estrogen receptors (ER)-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. These data indicate a different responsiveness to chemotherapy for tumors not expressing hormone receptors. To test this hypothesis we evaluated the responsiveness to preoperative chemotherapy in patients with ER and progesterone receptors (PgR)-absent tumors. PATIENTS AND METHODS Patients with biopsy-proven T2-T3, N0-2 breast cancer treated at a single institution from January 1995 to August 1999 with preoperative chemotherapy were retrospectively evaluated. ER and PgR were determined immunohistochemically and classified for this purpose as absent (0% of the cells positive) or positive (> or = 1% of the cells). RESULTS On 117 evaluable patients 72 had an objective response (61%). A significant difference in response was observed for patients with ER and PgR absent compared with those with ER and/or PgR-positive tumors (82% vs. 57%, P = 0.03 Fisherss exact test). Pathological complete remission rates were also significantly different in the two groups (23% vs. 7%, respectively; P = 0.04). CONCLUSIONS The different degree of response according to hormone receptors expression supports the hypothesis that tumors not expressing both ER and PgR might represent a different clinical entity in terms of chemotherapy responsiveness.

Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer

BackgroundHER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC).MethodsBetween April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM).ResultsThe 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5–40%), 10 stable disease (SD) (46%, 95% CI 24–68%), and 8 PD (36%, CI 17–59%). The clinical benefit (RP plus RC plus SD for ≥ 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24–68%) and 27% (95% CI, 6–61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade ≥2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively.ConclusionThe combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.

Adjuvant colon cancer chemotherapy: where we are and where we'll go.

Many patients with early-stage colon cancer are cured with surgery alone, even if the standard of care remains an uniform approach to adjuvant chemotherapy based primarily on tumour stage. Consequently, it is important to individualize decision-making in this subset of patients with the aim to identify potential prognostic and predictive markers in colon cancer. While 5-fluorouracil, leucovorin, and oxaliplatin are widely known as gold treatment in the post-operative of stage III, well-validated molecular markers might help define which patients with stage II disease are likely to benefit from adjuvant therapy as well. Herein we review the use of adjuvant chemotherapy in colon cancer and analyzed the date on the clinical development of molecular markers to individualize another therapeutic approach in colon cancer.

Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: Where are we now and where are we going?

Endocrine therapy is the most important systemic therapy for hormone receptor positive breast cancer; however, some patients with ER+ breast cancer show intrinsic resistance to endocrine therapy, whereas others develop acquired resistance. Preclinical models have shown that endocrine resistance is associated with enhanced expression of membrane growth factor pathways or activation of various intracellular pathways involved in signal transduction and cell survival. Despite encouraging preclinical data, clinical trials investigating the combination of endocrine therapy with trastuzumab or the TKIs gefitinib, erlotinib and lapatinib have yielded varied results. This may be related to some limitations in the studies conducted so far: lack of appropriate patient selection and stratification based on previous endocrine exposure and/or sensitivity; lack of identification of a molecular biomarker; lack of appropriate clinical endpoints in the trial design. More promising results come from clinical studies which have focused on novel agents such as the mTOR inhibitor everolimus. The two randomized trials (BOLERO-2 and TAMRAD) evaluating everolimus±endocrine therapy in a selected subgroup of HR-positive metastatic breast cancer patients have demonstrated a significant improvement in progression free survival for the combination compared to the endocrine therapy alone. The data reported so far show that the combination of target agents with endocrine therapy is effective in overcoming acquired resistance in patients with hormone receptor positive metastatic breast cancer. However, this therapeutic strategy is not yet a standard treatment for this patients. Application of more rigorous trial design, tumor and patient selection criteria will be important to better understand the complexity of endocrine resistance.

Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity

The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR ⩾10% T2–T4a-c, N0–N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70–95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, −82%, −62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.

Topoisomerase IIα gene status and prediction of pathological complete remission after anthracycline-based neoadjuvant chemotherapy in endocrine non-responsive Her2/neu-positive breast cancer

PURPOSE Topoisomerase IIalpha (Topo II) is a potential marker of responsiveness to anthracycline-based therapy. We analyzed the role of Topo II gene status in the prediction of pathological complete remission (pCR) after primary anthracycline-based chemotherapy in non- endocrine responsive breast cancers overexpressing Her2/neu. METHODS Twenty-three patients, with T2-T4, ER and PgR absent, overexpressing Her2/neu breast cancers treated with anthracycline-based chemotherapy were evaluated. Topo II gene status was assessed by FISH in pre-treatment tumor specimens and the results were correlated to pathological and clinical responses. RESULTS Overall, six patients had a pCR (26%). Topo II was amplified in 5 (22%) of the tumors. In all patients with Topo II amplification, Her2/neu gene amplification was also detected. Among patients without amplification, one had polysomia of chromosome (Cr) 17 and four patients had deletion of the Topo II gene. A higher probability of pCR was observed when Topo II amplification and Cr 17 polysomy were present: pCR was reported in 3 of 5 amplified tumors (60%), in the polysomic tumor (amplified plus polysomic 67%) and in only 2 out of 13 tumors without alteration of Topo II status (15%). If we compare the frequency of pCR in tumors with amplification or polysomy versus the frequency of tumors with not amplification (deletion or no modification), a significant difference was detected (p=0.02). One progressive disease (PD) was reported in one tumor with Topo II deletion (1/4, 25%) and one in tumor without any modification of Topo II gene status (1/13, 8%). CONCLUSIONS In patients with endocrine unresponsive and Her2 overexpressing tumors, Topo II amplification or the presence of chromosome 17 polysomy correlate with a significantly high probability of achieving pCR after neoadjuvant, anthracycline-based chemotherapy. Further prospective studies in order to more clearly define the predictive role of Topo II status in this subgroup of patients are warranted.

Incidence of venous thromboembolism in breast cancer patients during chemotherapy with vinorelbine, cisplatin, 5-fluorouracil as continuous infusion (ViFuP regimen): is prophylaxis required?

Cancer patients have an increased risk of venous thromboembolism (VTE). Previous published reports indicated an incidence of cancer-related VTE between 1%-11% [1]. Pathogenesis of VTE is multifactorial depending upon procoagulant activity of tumor cells, procoagulant host-response and upon co-morbidity factors, which involve vascular damage. Moreover, chemotherapy and endocrine therapy, as well as implanted central venous catheters further increase the incidence of VTE [2, 3]. We retrospectively analyzed the incidence of VTE in 182 consecutive breast cancer patients treated in one institution (European Institute of Oncology) between January 1997 and April 1999 with the ViFuP regimen (Navelbine 20 mg tot i.v. on days 1 and 3, cisplatin 60 mg/m i.v. on day 1 and 5-fluorouracil (5-FU) 200 mg/m i.v. daily as continuous infusion) through a permanent central venous device (CVC; Dome Port®, Bard). Seventy-eight patients had early or locally advanced (T2-T4) and 104 patients had metastatic breast cancer. Sixty-one patients (58.6%) in the metastatic group and twenty patients (25%) in the neoadjuvant setting were postmenopausal. Median age was 48 years (range 23-72). All patients had performance status 0-1. In a previous series of 333 patients with a permanent central venous device treated at the same institution we observed a low incidence of symptomatic VTE (1.5%) and therefore we did not consider the use of prophylactic anticoagulation [4]. The median follow-up was 15 months (range 1-27+) for the metastatic group and 8 months (range 1-15+) for the patients treated in the neoadjuvant setting. We observed 14 episodes of VTE (7.7%; 95% confidence interval (95% CI): 4.3%-12.6%), similarly distributed among patients with overt metastases (8 out of 104 patients, 7.7%; 95% CI: 3.4%-14.6%) and those with early or locally advanced disease (6 out of 78 patients, 7.7%; 95% CI: 2.9%-16%). All patients experienced VTE during chemotherapy. Median time from surgery for implant of central venous device to thrombosis was 2 months (range 1-4 months). Only one woman had a history of previous thromboembolic disease. Two women had VTE of the lower limb and one of them developed pulmonary embolism while all other VTE involved veins next to implantation site. Three patients had no symptoms (21%) and diagnosis was occasionally made during evaluation of response to treatment. After diagnosis of VTE, all patients received five days of low molecular weight heparin at the dose of 100 mg/kg twice a day plus oral warfarin to maintain an INR between 2.0-3.0. Despite maintenance anticoagulation, two patients experienced a new episode of VTE. All patients who had VTE treated in the neoadjuvant setting stopped the chemotherapy and were candidates to surgery. The incidence of VTE observed in patients receiving the ViFuP regimen is not negligible. Similar incidence of VTE have been reported in breast cancer patients treated with combination chemotherapies in the adjuvant setting and with advanced disease [5]. Weiss reported an incidence of 5%-7% in 433 patients treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) [2]. An increased thromboembolism (17%) in stage IV breast cancer treated with CMF and vincristine was also reported [3]. Patients with metastatic disease seemed to be at a higher risk of thrombosis than patients treated in the adjuvant setting, although in our series the incidence of thrombotic events in the two groups was similar. Limited data are available on the incidence of thrombosis in patients treated with 5-FU as continuous infusion for whom an incidence of VTE ranging from 4%—16% has been described [2]. The issue of antithrombotic prophylaxis in cancer patients was addressed in some randomized studies. Levine et al. demonstrated that very low-dose warfarin decreases the incidence of VTE in metastatic breast cancer patients treated with chemotherapy [5]. The daily use of low dose warfarin (lmg) or low molecular weight heparin (2500 UI) was protective in terms of catheter-related thrombosis in several studies [6, 7], while some reported lack of reduced risk of VTE with these treatments. There is limited information on the preoperative setting, and specifically for regimens delivered as continuos infusion. Smith observed a 10% catheter-related thrombosis in 50 breast cancer patients treated with a neoadjuvant infusional chemotherapy, despite the use of 1 mg of warfarin [8]. The routine use of anticoagulant prophylaxis during continuous infusion of 5-FU is theoretically hampered by a potential interaction between warfarin and this drug. Prolonged 5-FU half-life and increased INR were reported, thought to be due to interference with the synthesis of hepatic cytochrome 450 and impaired metabolism of warfarin and 5-FU [9, 10]. More information is needed on the proper anticoagulant regimen during infusional treatment containing 5-FU.

Infusional fluorouracil, epirubicin, and cisplatin followed by weekly paclitaxel plus bevacizumab in locally advanced breast cancer with unfavorable prognostic features.

The objective of this study was to evaluate the clinical and biological activities of bevacizumab in combination with preoperative anthracyclines and taxane-based chemotherapy in locally advanced breast cancer selected for unfavorable prognostic features. Patients with cT2–4c, cN0–2, estrogen and progesterone receptors less than 10% of the cells or cT4d and any estrogen/progesterone receptors expression received four courses of ECF-chemotherapy (epirubicin, cisplatin, fluorouracil as continuous infusion) followed by three courses of weekly paclitaxel in combination with bevacizumab. Thirty patients were included in the study. An objective response, either complete or partial, was observed in 26 patients (87%; 95% confidence interval: 69–96%), stable disease was observed in two patients (7%), and two patients (7%) progressed. A pathological complete response was obtained in 10 patients (33%; 95% confidence interval: 17–53%). Side effects related to bevacizumab with grade ≥2 included headache and hypertension. A nonstatistical significant decrease in the median value of circulating endothelial cells was observed at surgery (3.0/μl vs. 5.7/μl, P=0.19). In conclusion, high rates of both clinical and pathological responses with anthracycline-containing chemotherapy followed by weekly paclitaxel plus bevacizumab were observed in locally advanced breast cancer with unfavorable prognostic features. A non-negligible rate of progressive disease was observed, suggesting careful monitoring of the patients. Further studies evaluating the potential benefit of bevacizumab in neoadjuvant treatment need to be tested.

Subsequent Pregnancy After Breast Cancer

Approximately 213,000 new cases of breast cancer were diagnosed in the US during 2006. Of these, 25% and 10% occurred in women younger than 50 and 40 years, respectively (Howe et al. 2006). As women are delaying childbearing for personal reasons, including cultural, educational, and professional reasons (Ventura 1989), there has been an increasing number of patients in whom breast cancer occurs before the completion of their reproductive project.

Recent advances in the treatment of hormone receptor positive HER2 negative metastatic breast cancer

Endocrine therapy is the recommended systemic therapy for hormone receptor (HR) positive metastatic breast cancer (MBC). However so far the limited number of endocrine agents and the onset of endocrine resistance have severely limited the therapeutic options for this patients. In the last years many targeted agents have been investigated to prevent or overcome endocrine resistance; only a few of them have been found effective in HR positive MBC, such as everolimus, CK4/6 inhibitors and HDAC inhibitors. Furthermore, translational medicine studies using next generation sequencing technologies have evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with targeted agents benefit. In some studies predictive biomarkers have been identified and many ongoing studies are evaluating the efficacy of targeted drugs in HR positive MBC patients selected for biomarkers or stratified by pathways amplification.