Giulia Peruzzotti

Chemotherapy Is More Effective in Patients with Breast Cancer Not Expressing Steroid Hormone Receptors A Study of Preoperative Treatment

Purpose: The purpose of this research was to identify factors predicting response to preoperative chemotherapy. Experimental Design: In a large volume laboratory using standard immunohistochemical methods, we reviewed the pretreatment biopsies and histologic specimens at final surgery of 399 patients with large or locally advanced breast cancer (cT2-T4, N0–2, M0) who were treated with preoperative chemotherapy. The incidence of pathological complete remission and the incidence of node-negative status at final surgery were assessed with respect to initial pathological and clinical findings. Menopausal status, estrogen receptor status, progesterone receptor status [absent (0% of the cells positive) versus expressed], clinical tumor size, histologic grade, Ki-67, Her-2/neu expression, and type and route of chemotherapy were considered. Results: High rates of pathological complete remission were associated with absence of estrogen receptor and progesterone receptor expression (P < 0.0001), and grade 3 (P = 0.001). Significant predictors of node-negative status at surgery were absence of estrogen receptor and progesterone receptor expression (P < 0.0001), clinical tumor size <5 cm (P < 0.001), and use of infusional regimens (P = 0.003). The chance of obtaining pathological complete remission or node-negative status for patients with endocrine nonresponsive tumors compared with those having some estrogen receptor or progesterone receptor expression was 4.22 (95% confidence interval, 2.20–8.09, 33.3% versus 7.5%) and 3.47 (95% confidence interval, 2.09–5.76, 42.9% versus 21.7%), respectively. Despite the significantly higher incidence of pathological complete remission and node-negative status achieved by preoperative chemotherapy for patients with estrogen receptor and progesterone receptor absent disease, the disease-free survival was significantly worse for this cohort compared with the low/positive expression cohort (4-year disease-free survival %: 41% versus 74%; hazard ratio 3.22; 95% confidence interval, 2.28–4.54; P < 0.0001). Conclusions: Response to preoperative chemotherapy is significantly higher for patients with endocrine nonresponsive tumors. New chemotherapy regimens or combinations should be explored in this cohort of patients with poor outcome. For patients with endocrine responsive disease, the role of preoperative endocrine therapies should be studied.

Depression and degree of acceptance of adjuvant cytotoxic drugs

An interaction between psychological attitude and outcome in early-stage breast cancer has been postulated, with a possible explanation related to the presumed tendency of depressed patients to be less proactive in obtaining health care. We report on the degree of acceptance of adjuvant chemotherapy in patients with breast cancer who have concomitant depression. Only 20 (51.3%) of the study group accepted and received the proposed chemotherapy compared with 75 (92.2%) of the control group (p<0.0001). Treatment of depression might be essential for tailoring adjuvant treatments with chemotherapy.

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.

Serum EGFR and Serum HER-2/neu Are Useful Predictive and Prognostic Markers in Metastatic Breast Cancer Patients Treated With Metronomic Chemotherapy

Metronomic chemotherapy has been demonstrated to be of value in patients with advanced breast cancer. No reliable markers of response are available. In breast tumor, HER‐2/neu is a prognostic factor, whereas no definite data exist for EGFR. The aim of the study was to evaluate the prognostic and predictive role of serum HER‐2/neu and serum EGFR in breast cancer patients treated with low‐dose chemotherapy.

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.

Factor V Leiden Mutation in Patients with Breast Cancer with a Central Venous Catheter: Risk of Deep Vein Thrombosis

BACKGROUND The objective of this study was to analyze the influence of the prothrombotic factor V Leiden (FVL) and G20210A prothrombin mutations on the frequency of the first episode of catheter-related deep vein thrombosis (DVT) in a cohort of patients with locally advanced or metastatic breast cancer during continuous venous insult (infusion of 5-fluorouracil-based chemotherapy). PATIENTS AND METHODS Between January 1999 and February 2001, we retrospectively analyzed the incidence of first DVT in 300 consecutive patients with locally advanced or metastatic breast cancer treated at a single institution with a combination of chemotherapy administered continuously through a totally implanted access port. We identified 25 women (study group) with catheter-related DVT. For each of the 25 patients, we selected 2 women eligible for identical chemotherapy who had similar age, stage of disease, and prognostic features as a control group. The prothrombotic FVL and prothrombin mutation G20210A genotype analyses were performed in all patients. Analyses were performed on blinded samples, and all patients signed a specific informed consent form. A total of 25 cases (with thrombosis) and 50 frequency-matched controls were evaluated for FVL. RESULTS Five cases and 2 controls were found with the mutation in the FVL, for incidences of 20% (95% CI, 9%-39%) and 4% (95% CI, 1%-14%), respectively. Thus, the frequency of the mutation was significantly higher in the cases than in controls (P = 0.04), and a logistic regression analysis, adjusted by age, yielded an odds ratio of 6.1 (95% CI, 1.1%-34.3%; P = 0.04). Time from start of infusion chemotherapy to thrombosis was not significantly different between those with the mutation (median, 31 days) and without the mutation (median, 43 days; P = 0.6). Only 1 subject (in the case group) was found with the G20210A mutation in the prothrombin gene. CONCLUSION Factor V Leiden carriers with locally advanced or metastatic breast cancer are at high risk of catheter-related DVT during chemotherapy. Clinicians should be aware of this increased risk, and alternative cytotoxic treatments not requiring continuous infusions should be considered for these patients.

Role of Endocrine Responsiveness and HER2/neu Overexpression in Inflammatory Breast Cancer Treated with Multimodality Preoperative Therapy

Abstract:  We analyzed the role of endocrine responsiveness and HER2/neu overexpression in inflammatory breast cancer treated with multimodality preoperative therapy. Thirty‐eight patients (estrogen receptor [ER] and/or progesterone receptor [PgR] ≥10% of the cells 21, premenopausal 14, Ki‐67 expression ≥20% of the cells 30, HER2/neu overexpressed 11) were treated with six courses of epirubicin, cisplatin and fluorouracil (FU) as continuous infusion, perioperative FU as continuous infusion, mastectomy and loco‐regional radiotherapy. In endocrine‐responsive patients, endocrine treatment (letrozole, either alone or if premenopausal with triptorelin) was given preoperatively and as adjuvant treatment. There were 32 objective responders (84.2%; 95% CI 70.0–94.6%), three of whom had pathologic complete remission. At the multivariate analysis disease‐free survival was significantly worse in patients with ER and PgR absent tumors compared with the positive expression cohort (hazards ratio [HR]: 5.91; 95% CI 1.69–20.7; p = 0.005), in particular if HER2/neu overexpression was detected (HR: 16.5; 95% CI 4.24–64.5; p < 0.0001). New multimodality and targeted strategies should be explored in endocrine nonresponsive breast cancer.

Preoperative concurrent chemo- and endocrine therapies for women with large operable breast cancer expressing steroid hormone receptors

Preoperative chemotherapy and endocrine therapy yielded low pathological complete remission (pCR) rates in patients with endocrine responsive breast cancer. Patients with large operable (cT2-T3, N0-2, M0), ER > or =10% breast cancer were treated in two consecutive studies with preoperative chemotherapy (Study I: six courses of either fluorouracil, leucovorin, vinorelbine (FLN), or vinorelbine, cisplatin, and continuous infusion of fluorouracil (ViFuP), at the discretion of the treating physician; Study II: capecitabine and oral vinorelbine (CAVINO)). Concurrent letrozole (in association with triptorelin if premenopause) was given. Sixty-five (58 evaluable) and 55 (all evaluable) patients were enrolled in the two studies. In Study I there were 43 objective responders (74%, 95% CI 63-85%), three of whom had pCR. Thirty-nine objective responses (91%) and all pCR were observed in patients with tumors expressing ER > or =50%. In Study II 34 patients (62%, 95% CI 49-75%) had an objective response. Endocrine therapy administered together with new intravenous, containing regimens should be explored in the preoperative treatment of endocrine responsive breast cancer.

Systemic effects of surgery: Quantitative analysis of circulating basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-β) in patients with breast cancer who underwent limited or extended surgery

BACKGROUND To assess if feature, extent and duration of surgery could influence levels of systemic proangiogenic cytokines vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor beta (TGF-beta). PATIENTS AND METHODS We collected blood samples from 82 consecutive breast cancer patients who underwent various types of surgery, classified according to the magnitude of tissue injury in: minimal (quadrantectomy), moderate (mastectomy without reconstruction), and heavy [mastectomy followed by reconstruction with transversus recto-abdominal muscle cutaneous flap (TRAM)]. Samples were collected one day before surgery (D(-1)), at the end of surgical tumor removal (D0), and on 1st (D(+1)), 2nd (D(+2)) and 5th (D(+5)) day after surgery. Serum VEGF, bFGF and TGF-beta levels were measured by the enzyme immunoassay method. RESULTS On average a continuous decrease was observed for all growth factors from the day before operation to the 5th day after operation. On day (D(+5)) an increase was observed for patients who underwent extended respect to moderate surgery. These differences were found statistically significant for bFGF and VEGF (p = 0.05 and p = 0.025 respectively). A statistically different trend for type of operation was observed also for TGF-beta at 24-48 h: a minor reduction, compared to time of operation, was observed for minimal surgery, an intermediate reduction for moderate surgery and a higher decrease for extended surgery. CONCLUSIONS Angiogenic cytokines perioperative levels could be increased on 5th day (D(+5)) by extent of surgery and should induce perioperative stimulation of residual cancer cells. A better understanding of the time interval during which the sequelae of events in wound healing occur may be the basis for defining new therapeutic strategies that can interfere with tumor outgrowth sparing wound healing processes.

Multiple primary non-breast tumors in breast cancer survivors

PurposeThe aim of this study was to assess the frequency of second primary non-breast cancer after breast cancer diagnosis and treatment, and its correlation with clinicopathological features.MethodsData from 21,527 patients with primary breast cancer were collected retrospectively in a single cancer centre; 4.1% of the women developed a second non-breast cancer. The most frequently observed second primary tumor affected the digestive tract (27.8%). The frequency of observed cancers was similar to that expected in the general population, excepting for an excess of melanoma [SIR 1.98 (1.52–2.53)], uterine cancers [SIR 1.44 (1.17–1.74)], ovarian cancers [SIR 1.67 (1.31–2.10)], thyroid tumors [SIR 1.54 (1.23–1.92)], and leukemia [SIR 1.57 (1.11–2.16)].ResultsClinicopathological breast cancer stratification showed a general increased risk of developing a second cancer in older patients, excluding ovarian cancer. An increased risk of developing ovarian cancer after breast cancer diagnosis was observed, in particular, in triple-negative [HR 3.47 (1.91–6.29)], G3 tumors [HR 2.54 (1.10–5.83)] and in positive breast cancer family history [HR 2.19 (1.22–3.94)]. Breast cancer survivors in hormonal therapy treatment are at higher risk for developing a second thyroid cancer [HR 4.00 (1.46–10.9)]. Conversely, adjuvant chemotherapy offered a protective effect on thyroid cancer risk development [HR 0.46 (0.28–0.76)].ConclusionsOlder age represents the major risk of developing a second primary non-breast cancer, excluding ovarian cancer. Clinical surveillance is required to prevent ovarian and thyroid cancers, respectively, in patients with positive family history, triple negative, G3 breast cancer and during hormonal therapy treatment in postmenopausal status.