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22 ADHERENCE TO AND PERSISTENCE WITH AN ORAL METRONOMIC CHEMOTHERAPY WITH CAPECITABINE IN HEAVILY PRETREATED METASTATIC BREAST CANCER (MBC) PATIENTS
Abstracts / Cancer Treatment Reviews 36S3 (2010) S95–S119
histochemical expression of HER-2 growth factor. With a median follow-up of 18 months (range 11–35) there were 16 pts (70%) with no evidence of disease; 4 patients (17%) were alive with disease; and 3 patients (13%) died of the disease. Relapse was detected in 7 women (30%), lung, brain, and chest wall recurrence being the most common sites of metastasis. Among those 7 cases, 5 are triple negative and one patient had obtained a complete pathological response. Conclusions: Our data suggest an improvement in locoregional control in patients treated by surgery, in conjunction with chemotherapy based on antracycline and radiotherapy, for LABD. Moreover, patients with triple-negative disease are a poor prognosis and at high incidence of early metastatic recurrence. 21 DUCTAL CARCINOMA IN SITU OF BREAST: ANALYSIS OF 232 CASES T.P. Latiano1 , C. D’Addetta1 , L. Lombardi1 , M. Morritti1 , A. Piano1 , R. Murgo2 , M. El Jaouni3 , M. Copetti4 , E. Maiello1 . 1 Oncology Unit, 2 Surgery Unit, 3 Unit of Radiotherapy, 4 Unit of Biostatistics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy Background: Ductal carcinoma in situ (DCIS) is a heterogeneous, unicentric precursor of invasive breast cancer, which is frequently identified through mammographic breast screening programs. The prognostic factors of DCIS include anatomo-pathologic factors, age and molecular factors. Methods: Two-hundred-thirty-two woman with DCIS were retrospectively reviewed between 1996 and 2009 in our Institution. The main characteristics of these pts were: median age 53 years (range 23–78), menopause 154 pts (66.3%), fertility 192 pts (82.7%); 50 pts (21.5%) were treated with mastectomy, 182 (78.4%) with breast conservation, and 171 (93.3%) received radiotherapy. Moreover, 106 pts (45.6%) received tamoxifen. Results: With median follow-up of 55 months (range 4–170), recurrence rate was 4.7% (11 pts: 8 ipsilateral, 2 controlateral and 1 ipsilateral + controlateral synchronous). Median relapse free survival was 44.5 months (range 23–68). Approximately 90% of these recurrence have received a breast conservation developing invasive cancer. All these pts had more than 40 years (range 40–66; median 49) and 6/11 were between 40 and 50 yrs. Histologically, 10/11 pts presented comedocarcinoma and 8/11 positive surgical margins. Nine of these woman underwent breast irradiation (90%) and only four pts (36%) ormonal therapy with tamoxifen. The overall survival of all group was 98.2%. Conclusions: Our retrospective analysis confirm the usefulness of mastectomy for patients with DCIS: in fact, breast radical surgery was associated with optimal local control. Furthermore, we observed that pts with 40–50 yrs and comedocarcinoma histology might be considered at high risk of local recurrence and therefore the age and the histology might be considerate as predictors of relapse of disease. 22 ADHERENCE TO AND PERSISTENCE WITH AN ORAL METRONOMIC CHEMOTHERAPY WITH CAPECITABINE IN HEAVILY PRETREATED METASTATIC BREAST CANCER (MBC) PATIENTS E. Mazzoni1 , P. Fedele1 , L. Orlando1 , A. Marino1 , M. D’Amico1 , F. Sponziello1 , A. Nacci1 , N. Calvani1 , P. Schiavone1 , P. Rizzo1 , M.C. Chetri’1 , S. Cinieri1 . 1 UOC and Breast Unit, Ospedale “Antonio Perrino”, Brindisi, Italy Background: Self-administered oral antitumoral medications have played a marginal role in anticancer treatment, compared with parenteral ones. In the past decade there has been a sudden increase in the number of the available oral antineoplastic drugs, thus determining an increasing attention about the arguments of drug delivery and patient preference and adherence. Capecitabine, administred in a metronomic fashion, due to its pharmacokinetic characteristics and low toxicity profile, is the ideal drug to measure patients adherence and persistence to oral chemotherapy. Methods: Since October 2006 to April 2010 we tested objective responses, clinical benefit and safety of capecitabine administred with a metronomic schedule of 500 mg thrice daily in heavily pretreated metastatic breast cancer patients. Adherence and
S101
persistence were measured with patients report, pill counts and prescription database analysis. According to ISPOR (International Society for Pharmacoeconomics and Outcome Research) adherence is the degree or extent of conformity to the recommendations about day-to-day treatment by the provider with respect to timing, dosage and frequency; persistence is the duration of time from the initiation to the discontinuation of treatment. A patient was counted as adherent with a self reported tablet intake of 80% or more and if a medication possession ratio of 80% or more was achieved. Results: Among 55 enrolled patients, 44 were evaluable. ECOG performance status (PS) is 0–3, median age 60 years (range 36–82), HER-2/neu overexpression in 23%; bone plus visceral disease in 41% of cases. All the patients were pretreated with at least 2 endocrine therapy lines (range 1–3) and a median of 3 chemotherapy regimens (range 1–6). Metronomic capecitabine was administered for a median duration of 28 weeks (range 12–144). All women reported to be adherent; but 90% were adherent as measured by the prescription control; adherence did not vary by cycle. We observed 10 partial responses (PR: 23%), 26 (59%) stable disease (SD) and 8 patients with progressive disease. Additional long term disease stabilization (SD > or = 24 weeks) occurred in 19 patients for an overall clinical benefit (CR+PR+ SD > or = 24 weeks) of 59%. Median time to progression was 28 weeks (95% CI, 12 to 144 weeks). Neither grade 2–4 hematological or clinical side effects were recorded and only 4 patients experienced grade 1 hand foot syndrome. We found no significant predictor for adherence and persistence. Conclusions: Our study reveals an high rate of adherence and persistence with metronomic capecitabine in heavily pretreated metastatic breast cancer patients. Easier of dispensation and reduction of side effects were the most important aspects patients expected of an oral therapy. 23 ZOLEDRONIC ACID BLOCKS THE INTERACTION BETWEEN MESENCHYMAL STEM CELLS AND BREAST CANCER CELLS N. Normanno1 , M. Gallo1 , L. Lamura1 , A. De Luca1 . 1 Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy Background: Bone-marrow-derived mesenchymal stem cell (MSCs) are recruited to the stroma of developing tumors, where they increase the metastatic potential of cancer cells by secreting chemokines that induce cell motility and invasion. In addition, MSCs sustain the growth and the survival of cancer cells within the bone microenvironment. Zoledronic acid (ZA) has been recently shown to increase the progression free-survival of estrogen receptor (ER)positive breast cancer patients by reducing both loco-regional and distant metastases. Methods: Since ZA very rapidly concentrates in the bone following intravenous administration, we assessed the effects of ZA on the interaction between MSCs and breast cancer cells. Results: We observed that treatment with ZA produced marginal effects on MSCs proliferation, with an approximately 25% growth inhibition following treatment with 20 mM ZA for 48 hours. In contrast, similar concentrations of ZA significantly reduced the ability of MSCs to migrate (~45% inhibition), and this phenomenon was associated with a considerable reduction in the levels of activation of AKT and ERK1/2. Conditioned medium (CM) from ZAtreated MSCs showed a reduced ability to promote the migration of ER-positive MCF-7 breast cancer cells as compared with conditioned medium from untreated MSCs. We identified two factors whose secretion was significantly reduced in CM of MSC following treatment with ZA: RANTES/CCL5 (~90% reduction) and IL-6 (~50% reduction). RANTES and IL-6 transcripts were also significantly reduced in MSCs following exposure to ZA. Blocking anti-RANTES and anti-IL-6 antibodies, alone or in combination, almost completely abolished the migration of MCF-7 cells induced by CM from untreated MSCs. Human recombinant RANTES and IL-6 significantly induced the migration of MCF-7 cells and their combination showed a synergistic effect. Similar results were observed in a panel of breast cancer cell lines of different histological subtype. Conclusions: These data suggest that ZA might exert its antitumor activity in the bone marrow microenvironment by inhibiting the
histochemical expression of HER-2 growth factor. With a median follow-up of 18 months (range 11–35) there were 16 pts (70%) with no evidence of disease; 4 patients (17%) were alive with disease; and 3 patients (13%) died of the disease. Relapse was detected in 7 women (30%), lung, brain, and chest wall recurrence being the most common sites of metastasis. Among those 7 cases, 5 are triple negative and one patient had obtained a complete pathological response. Conclusions: Our data suggest an improvement in locoregional control in patients treated by surgery, in conjunction with chemotherapy based on antracycline and radiotherapy, for LABD. Moreover, patients with triple-negative disease are a poor prognosis and at high incidence of early metastatic recurrence. 21 DUCTAL CARCINOMA IN SITU OF BREAST: ANALYSIS OF 232 CASES T.P. Latiano1 , C. D’Addetta1 , L. Lombardi1 , M. Morritti1 , A. Piano1 , R. Murgo2 , M. El Jaouni3 , M. Copetti4 , E. Maiello1 . 1 Oncology Unit, 2 Surgery Unit, 3 Unit of Radiotherapy, 4 Unit of Biostatistics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy Background: Ductal carcinoma in situ (DCIS) is a heterogeneous, unicentric precursor of invasive breast cancer, which is frequently identified through mammographic breast screening programs. The prognostic factors of DCIS include anatomo-pathologic factors, age and molecular factors. Methods: Two-hundred-thirty-two woman with DCIS were retrospectively reviewed between 1996 and 2009 in our Institution. The main characteristics of these pts were: median age 53 years (range 23–78), menopause 154 pts (66.3%), fertility 192 pts (82.7%); 50 pts (21.5%) were treated with mastectomy, 182 (78.4%) with breast conservation, and 171 (93.3%) received radiotherapy. Moreover, 106 pts (45.6%) received tamoxifen. Results: With median follow-up of 55 months (range 4–170), recurrence rate was 4.7% (11 pts: 8 ipsilateral, 2 controlateral and 1 ipsilateral + controlateral synchronous). Median relapse free survival was 44.5 months (range 23–68). Approximately 90% of these recurrence have received a breast conservation developing invasive cancer. All these pts had more than 40 years (range 40–66; median 49) and 6/11 were between 40 and 50 yrs. Histologically, 10/11 pts presented comedocarcinoma and 8/11 positive surgical margins. Nine of these woman underwent breast irradiation (90%) and only four pts (36%) ormonal therapy with tamoxifen. The overall survival of all group was 98.2%. Conclusions: Our retrospective analysis confirm the usefulness of mastectomy for patients with DCIS: in fact, breast radical surgery was associated with optimal local control. Furthermore, we observed that pts with 40–50 yrs and comedocarcinoma histology might be considered at high risk of local recurrence and therefore the age and the histology might be considerate as predictors of relapse of disease. 22 ADHERENCE TO AND PERSISTENCE WITH AN ORAL METRONOMIC CHEMOTHERAPY WITH CAPECITABINE IN HEAVILY PRETREATED METASTATIC BREAST CANCER (MBC) PATIENTS E. Mazzoni1 , P. Fedele1 , L. Orlando1 , A. Marino1 , M. D’Amico1 , F. Sponziello1 , A. Nacci1 , N. Calvani1 , P. Schiavone1 , P. Rizzo1 , M.C. Chetri’1 , S. Cinieri1 . 1 UOC and Breast Unit, Ospedale “Antonio Perrino”, Brindisi, Italy Background: Self-administered oral antitumoral medications have played a marginal role in anticancer treatment, compared with parenteral ones. In the past decade there has been a sudden increase in the number of the available oral antineoplastic drugs, thus determining an increasing attention about the arguments of drug delivery and patient preference and adherence. Capecitabine, administred in a metronomic fashion, due to its pharmacokinetic characteristics and low toxicity profile, is the ideal drug to measure patients adherence and persistence to oral chemotherapy. Methods: Since October 2006 to April 2010 we tested objective responses, clinical benefit and safety of capecitabine administred with a metronomic schedule of 500 mg thrice daily in heavily pretreated metastatic breast cancer patients. Adherence and
S101
persistence were measured with patients report, pill counts and prescription database analysis. According to ISPOR (International Society for Pharmacoeconomics and Outcome Research) adherence is the degree or extent of conformity to the recommendations about day-to-day treatment by the provider with respect to timing, dosage and frequency; persistence is the duration of time from the initiation to the discontinuation of treatment. A patient was counted as adherent with a self reported tablet intake of 80% or more and if a medication possession ratio of 80% or more was achieved. Results: Among 55 enrolled patients, 44 were evaluable. ECOG performance status (PS) is 0–3, median age 60 years (range 36–82), HER-2/neu overexpression in 23%; bone plus visceral disease in 41% of cases. All the patients were pretreated with at least 2 endocrine therapy lines (range 1–3) and a median of 3 chemotherapy regimens (range 1–6). Metronomic capecitabine was administered for a median duration of 28 weeks (range 12–144). All women reported to be adherent; but 90% were adherent as measured by the prescription control; adherence did not vary by cycle. We observed 10 partial responses (PR: 23%), 26 (59%) stable disease (SD) and 8 patients with progressive disease. Additional long term disease stabilization (SD > or = 24 weeks) occurred in 19 patients for an overall clinical benefit (CR+PR+ SD > or = 24 weeks) of 59%. Median time to progression was 28 weeks (95% CI, 12 to 144 weeks). Neither grade 2–4 hematological or clinical side effects were recorded and only 4 patients experienced grade 1 hand foot syndrome. We found no significant predictor for adherence and persistence. Conclusions: Our study reveals an high rate of adherence and persistence with metronomic capecitabine in heavily pretreated metastatic breast cancer patients. Easier of dispensation and reduction of side effects were the most important aspects patients expected of an oral therapy. 23 ZOLEDRONIC ACID BLOCKS THE INTERACTION BETWEEN MESENCHYMAL STEM CELLS AND BREAST CANCER CELLS N. Normanno1 , M. Gallo1 , L. Lamura1 , A. De Luca1 . 1 Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy Background: Bone-marrow-derived mesenchymal stem cell (MSCs) are recruited to the stroma of developing tumors, where they increase the metastatic potential of cancer cells by secreting chemokines that induce cell motility and invasion. In addition, MSCs sustain the growth and the survival of cancer cells within the bone microenvironment. Zoledronic acid (ZA) has been recently shown to increase the progression free-survival of estrogen receptor (ER)positive breast cancer patients by reducing both loco-regional and distant metastases. Methods: Since ZA very rapidly concentrates in the bone following intravenous administration, we assessed the effects of ZA on the interaction between MSCs and breast cancer cells. Results: We observed that treatment with ZA produced marginal effects on MSCs proliferation, with an approximately 25% growth inhibition following treatment with 20 mM ZA for 48 hours. In contrast, similar concentrations of ZA significantly reduced the ability of MSCs to migrate (~45% inhibition), and this phenomenon was associated with a considerable reduction in the levels of activation of AKT and ERK1/2. Conditioned medium (CM) from ZAtreated MSCs showed a reduced ability to promote the migration of ER-positive MCF-7 breast cancer cells as compared with conditioned medium from untreated MSCs. We identified two factors whose secretion was significantly reduced in CM of MSC following treatment with ZA: RANTES/CCL5 (~90% reduction) and IL-6 (~50% reduction). RANTES and IL-6 transcripts were also significantly reduced in MSCs following exposure to ZA. Blocking anti-RANTES and anti-IL-6 antibodies, alone or in combination, almost completely abolished the migration of MCF-7 cells induced by CM from untreated MSCs. Human recombinant RANTES and IL-6 significantly induced the migration of MCF-7 cells and their combination showed a synergistic effect. Similar results were observed in a panel of breast cancer cell lines of different histological subtype. Conclusions: These data suggest that ZA might exert its antitumor activity in the bone marrow microenvironment by inhibiting the