Anna Cardillo

Size of Breast Cancer Metastases in Axillary Lymph Nodes: Clinical Relevance of Minimal Lymph Node Involvement

BACKGROUND Overt ipsilateral axillary lymph node metastases of breast cancer are the most significant prognostic indicators for women who have undergone surgery, yet the clinical relevance of minimal involvement (isolated tumor cells and micrometastases) of these nodes is uncertain. PATIENTS AND METHODS We evaluated biologic features, adjuvant treatment recommendations, and prognosis for 1,959 consecutive patients with pT1-3, pN0, minimal lymph node involvement (pN1mi or pN0i+), or pN1a (single positive node) and M0, who were operated on and counseled for medical therapy from April 1997 to December 2000. RESULTS Patients with pN1a and pN1mi/pN0i+, when compared with patients with pN0 disease, were more often prescribed anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively; P < .0001) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001). At the multivariate analysis, a statistically significant difference in disease-free survival (DFS) and in the risk of distant metastases was observed for patients with pN1a versus pN0 disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases) and for patients with pN1mi/pN0i+ versus pN0 disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases). CONCLUSION Even minimal involvement of a single axillary node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Further studies are required before widespread modification of clinical practice.

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.

Outcome of special types of luminal breast cancer

BACKGROUND The identification of special types of breast cancer might be of value in assessing prognosis and predicting response to therapy. METHODS A total of 7372 consecutive patients with immunohistochemically defined luminal invasive breast cancer operated at the European Institute of Oncology between 1997 and 2005 were included. We then explored patterns of recurrence by histological type. Median follow-up was 5.8 years. RESULTS Tumors from 5707 patients were classified as invasive ductal cancer (IDC) not otherwise specified (NOS), 851 lobular, 338 mixed ductal and lobular, 250 cribriform, 143 mucinous and 83 tubular carcinomas. Compared with IDC NOS disease-free survival (DFS) was significantly longer in patients with cribriform tumors [5-year DFS 97.9% versus 87.4%; hazard ratio (HR) = 0.48; P = 0.015) and in pooled cribriform plus tubular carcinomas (5-year DFS 98.7% versus 87.4%; HR = 0.45; P = 0.005). Mucinous tumors presented similar DFS if compared with IDC (5-year DFS 93 % versus 87.4%; HR = 1.03; P = 0.91). Conversely, DFS was poorer for patients with lobular carcinoma (5-year DFS 86.8% versus 87.4%; HR = 1.27; P = 0.01). CONCLUSIONS The diagnosis of tubular, cribriform and lobular carcinomas carry distinct prognostic implications. The identification of these special types has a significant utility in luminal breast cancer and should be considered in therapeutic algorithms.

A nomogram based on the expression of Ki-67, steroid hormone receptors status and number of chemotherapy courses to predict pathological complete remission after preoperative chemotherapy for breast cancer

BACKGROUND Tools able to predict pathological complete response (pCR) to preoperative chemotherapy might improve treatment outcome. PATIENTS AND METHODS Data from 783 patients with invasive ductal carcinoma treated with preoperative chemotherapy and operated at the European Institute of Oncology were used to develop a nomogram using logistic regression model based on both categorical (clinical T and N, HER2/neu, grade and primary therapy) and continuous variables (age, oestrogen receptor (ER), progesterone receptor (PgR), Ki-67 expression and number of chemotherapy courses). The performance of the resulting nomogram was internally evaluated through bootstrapping methods. Finally the model was externally validated on a patient set treated in other institutions and subsequently operated at the EIO. RESULTS At multivariable analysis the probability of pCR was directly associated with Ki-67 expression (OR for 10% increase in the percentage of positive cells, 1.15, 95% confidence interval (CI), 1.03, 1.29) and number of chemotherapy courses (OR for one cycle increase, 1.31, 95% CI, 1.12, 1.53) and inversely associated with ER and PgR expression (ORs for 10% increase in the percentage of positive cells, 0.86, 95% CI 0.79, 0.93 and 0.82, 95% CI 0.69, 0.99, respectively). The nomogram for pCR based on these variables had good discrimination in training as well in validation set (AUC, 0.78 and 0.77). CONCLUSION The use of a nomogram based on the number of preoperative courses, degree of Ki-67 and steroid hormone receptors expression may be useful for predicting the probability of pCR and for the design of the proper therapeutic algorithm in locally advanced breast cancer.

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.

Outcome of male breast cancer: a matched single-institution series.

BACKGROUND Breast cancer occurs rarely in men, accounting for approximately 1% of all breast carcinomas. Data on prognosis principally derive from retrospective studies and from extrapolation of female breast cancer series. PATIENTS AND METHODS A total of 99 men with invasive breast cancer were matched with 198 women with breast cancer who had surgery at the same institution from 1999 to 2010. Matching variables were year of surgery, age, primary tumor size, nodal involvement, hormone receptor status, status of HER2 (human epidermal growth factor receptor 2 [ERBB2]), Ki-67, and grade. Median follow-up was 8.6 years. RESULTS Disease-free survival (DFS) was significantly poorer in the men (10-year DFS, 51.7% vs. 66.5%; hazard ratio [HR], 1.79; 95% CI, 1.19-2.68; P = .004). Similar results were observed for overall survival (OS) (10-year OS, 70.7% vs. 84.2%; HR, 1.79; 95% CI, 1.01-3.15; P = .043). The cumulative incidence of death for causes not related to the primary breast cancer was significantly higher for men than for women (HR, 2.87; 95% CI, 1.58-5.22; P = .001), whereas the breast cancer-specific survival (BCSS) was similar between the 2 groups (10-year BCSS, 81.5% vs. 88%; HR, 1.27; 95% CI, 0.62-2.59; P = .517). CONCLUSION This comparative series found that men with breast cancer had a poorer DFS and OS when compared with women. The men also had a higher risk of contralateral tumors and second primaries. Appropriate counseling, surveillance, and prevention are recommended to improve survival for these individuals.

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.

Survival Outcomes in Breast Cancer Patients With Low Estrogen/Progesterone Receptor Expression

INTRODUCTION The prognostic value of low estrogen and progesterone receptors expression (ER/PgR 1%-10%) in early breast cancer patients is still unclear. PATIENTS AND METHODS We retrospectively analyzed 1424 consecutive patients with HER2/neu-negative and low endocrine receptors expression early breast cancer, submitted to surgery at the European Institute of Oncology between January 1995 and December 2009. Patients were classified according to the percentage of ER/PgR expression using immunohistochemistry. Group 1 with ER/PgR < 1%, and group 2 with ER/PgR 1% to 10%. RESULTS Group 1 (ER/PgR < 1%) included 1300 patients, and group 2 (ER/PgR 1%-10%) 124 patients. Median follow-up time was 74 months (range, 3-192 months). The 5-year disease-free survival (DFS) rate was 74% (95% confidence interval [CI], 72%-77%) for group 1, and 79% (95% CI, 70%-86%) for group 2 (P = .16). The 5-year overall survival (OS) rate was 86% (95% CI, 84%-88%) in group 1 and 90% (95% CI, 83%-95%) in group 2 (P = .13). In patients without lymph node involvement, the 5-year OS rate was 92% (95% CI, 89.5%-93.6%) for group 1 and 98% (95% CI, 90.2%-99.8%) for group 2 (P = .061). One hundred ten patients received endocrine therapy with no significant effect on DFS (P = .36) and OS (P = .30). CONCLUSION The ER/PgR 1%-10% group had a slight, but not statistically significant, better prognosis than the ER/PgR <1% group. Further studies are needed to identify the appropriate clinical approach in this subset of patients with low ER/PgR expression (ER/PgR 1%-10%), HER2-negative early breast cancer.

Phase II Trial of Combination of Pegylated Liposomal Doxorubicin, Cisplatin, and Infusional 5-Fluorouracil (CCF) Plus Trastuzumab as Preoperative Treatment for Locally Advanced and Inflammatory Breast Cancer

BACKGROUND Pegylated liposomal doxorubicin (PLD) was shown as active but less toxic compared to doxorubicin in advanced breast cancer. Given its low cardiotoxicity, the combination of PLD and trastuzumab appears most attractive in the treatment of human epidermal factor receptor 2 (HER2)-positive breast cancer. PATIENTS AND METHODS We investigated the activity of 8 courses of PLD in combination with cisplatin and infusional 5-fluorouracil (CCF) plus 3-week trastuzumab in patients with primary or recurrent cT2-T4 a-d, N0-3, M0 any estrogen receptor (ER), HER2-positive breast cancer. Patients with ER and/or progesterone receptor (PgR) ≥ 10% tumors received also letrozole (plus triptorelin if premenopausal). The principal endpoint was clinical response rate; secondary endpoints were the pathologic complete response rate (pCR) and the cardiac safety of the combination. RESULTS Thirty-two patients were enrolled in the study and all are evaluable for response and toxicity. Fifteen patients (47%) had ER-positive tumors, 15 patients and 2 patients had ER absent and ER poor tumors, respectively. Thirteen patients (41%) had inflammatory breast cancer (IBC) and 84% of patients had clinically positive nodes. A clinical response rate of 94% (95% CI, 79%-99%) and a pCR rate of 41% (95% CI, 24%-59%) were observed. Fifty-four percent of patients with IBC obtained a pCR. Eleven patients discontinued treatment before completing 8 courses as planned. No patient developed relevant cardiac toxicity. CONCLUSION In this series of very locally advanced breast cancer, the combination of CCF and trastuzumab was very active obtaining an impressive rate of pCR, particularly in IBC, which merits further investigation in larger series.

Safety and efficacy study of metronomic vinorelbine, cyclophosphamide plus capecitabine in metastatic breast cancer: A phase II trial

In a phase II study we assessed the safety and efficacy of metronomic oral chemotherapy with vinorelbine, cyclophosphamide capecitabine in patients with metastatic breast cancer, either as first-line (naïve group) or second-line or greater therapy (pre-treated group). Eligible patients had histologically or cytologically proven, hormone-receptor positive metastatic breast cancer. The primary end point was median time to progression (TTP). A total of 43 patients in the naïve group and 65 in the pre-treated group were enrolled. The median TTP was 25.1 months in the naïve group and 11.2 months in the pre-treated group. The most frequently reported grade 2 treatment-related adverse events were leukopenia and hand and foot syndrome. Metronomic combination of cyclophosphamide, capecitabine and vinorelbine showed significant activity and good tolerability in patients hormonal receptor positive, metastatic breast cancer patients.