- Email: [email protected]
P125 Adriamycin–cytoxan followed by weekly taxol as neoadjuvant treatment in localised breast cancer
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Poster Session II. Neo-adjuvant (pre-op) systemic therapy
P122 A multicenter study of epirubicin-docetaxel (ET) as primary chemotherapy for patients with inflammatory breast cancer (IBC) K. Anan1 , S. Mitsuyama1 , K. Ikejiri2 , T. Ohchi3 , Y. Rai4 , T. Oikawa5 , M. Kudaka6 , R. Nishimura7 , S. Kuroki8 , K. Tamura9 . ET Study group in Kyushu of Japan. 1 Kitakyushu Municipal Medical Center, Surgery, Kitakyushu, Japan, 2 National Hospital Organization Kyushu Medical Center, Surgery, Fukuoka, Japan, 3 Miyazaki Prefectural Nobeoka Hospital, Surgery, Miyazaki, Japan, 4 Sagara Hospital, Surgery, Kagoshima, Japan, 5 Oikawa Hospital, Surgery, Fukuoka, Japan, 6 Naha City Hospital, Surgery, Okinawa, Japan, 7 Kumamoto City Hospital, Surgery, Kumamoto, Japan, 8 Kyushu University, Surgery, Fukuoka, Japan Background: IBC is a rare clinical entity but a most lethal form of locally advanced cancer. ET regimen is one of the most active chemotherapies for metastatic breast cancer. A Japanese phase I study demonstrated recommended dose of each epirubicin and docetaxel was 60 mg/m2 in every 3 week administration. Based on these data, this study was designed to evaluate survival, efficacy and safety of ET regimen as a primary chemotherapy for IBC. Patients and Methods: Patients between 20 and 75 years of age with acceptable organ function and newly-diagnosed IBC were included. Epirubicin 60 mg/m2 was given as i.v. bolus injection followed by a 1-hour infusion of docetaxel 60 mg/m2 every 3 weeks for 4 cycles unless disease progression occurred, in which case appropriate surgery was offered. Results: From July 2002 to April 2006, 19 patients were enrolled in the study. Median follow-up time was 16 months. Seventeen patients completed ET regimen and 1 patient was excluded because of no diffuse erythema leaving 16 patients evaluable for survival status and safety. Median age was 58 years (range: 31−69), ECOG Performance Status 0 was seen in 88% of patients. 31% of patients were either ER positive and/or PgR positive. 25% of patients were HER2 2+ or 3+. Grade 3−4 haematological toxicities were neutropenia (81%), febrile neutropenia (50%) and anaemia (19%). 69% of patients received granulocyte colony stimulating factor for observed neutropenia. However, all patients with febrile neutropenia were observed it only 1 cycle and obvious infection was not observed. Grade 3−4 nonhaematological toxicities were constipation (19%), nausea (13%), anorexia (13%), fatigue (6%), vomiting (6%), diarrhea (6%) and stomatitis (6%). The ET regimen was given to 81% of patients at the planned dose. Median cycles were 4 cycles (range: 2−4). Fourteen patients with measurable disease were evaluable for clinical response. The clinical response rate was 43% (95% confidence interval: 18−71%). Median survival was 19 months. Conclusions: As primary chemotherapy for IBC the ET regimen is tolerated and effective. The survival benefit has to be evaluated carefully, because of the extremely poor prognosis of IBC. We must study molecular mechanism of IBC and further develop new treatment strategy.
P123 Preoperative sequential chemotherapy of dose-dense epirubicin/cyclophosphamide followed by docetaxel/capecitabine in patients with stage II/IIIA breast cancer A. Grassadonia1 , E. Cianchetti2 , C. Ficorella3 , D. Angelucci1 , S. Grossi2 , E. Ricevuto3 , M. Zilli1 , N. Tinari1 , C. Natoli1 , S. Iacobelli1 . 1 University “G. D’Annunzio”, Oncology and Neurosciences, Chieti, Italy, 2 University “G. D’Annunzio”, Breast Surgery Unit, Chieti, Italy, 3 University “G. D’Annunzio”, Experimental Medicine, Chieti, Italy Purpose: To evaluate the activity and safety of a dose-dense, sequential chemotherapy of epirubicin/cyclophosphamide (EC) followed by docetaxel/capecitabine (DXe) given preoperatively in patients with stage II/IIIA breast cancer not candidate to breast-conserving surgery. Methods: This was a Simon’s two-step phase II study, recruiting 24 patients in the first step, and an additional 20 patients in the second step (total of 44 patients). Patients with histologically/cytologically confirmed primary breast cancer (T2−3, N0−2, M0) received four cycles of EC (cyclophosphamide, 600 mg/m2 and epirubicin, 90 mg/m2 ) q2 weeks followed by two cycles of DXe (docetaxel, 36 mg/m2 days 1, 8, and 15 and capecitabine, 1250 mg/m2 days 5−18) q 28 days, with pegfilgrastim prophylaxis. The primary end point of the study was the incidence of pCR defined as the absence of invasive or in situ cancer in the breast at definitive surgery. Forty-four women were enrolled; all had T2 or T3 lesions, 39% had clinically palpable lymph nodes, and 59% had steroid receptor positive tumors.
Friday, 16 March 2007 Results: Forty-one out of 44 enrolled patients were evaluable for response to treatment (one patient withdrew from the study for G4 neutropenia after the first EC cycle, two patients for therapy refusal after 1 EC cycle and after 4 EC cycles, respectively). Nine patients (22%) exhibited a pCR in the breast alone and 7 (17%) in both breast and lymph nodes. Interestingly, all but one of the 9 pCR cases showed hormone receptor-negative tumors. A clinical response (CR or PR) detected by palpation and by imaging was observed in 38 patients, for an overall response rate of 93%. Thirty-six patients (88%) underwent breast-conserving surgery. The treatment was well tolerated. One patient stopped capecitabine for G3 diarrhoea and five patients required a 25% dose reduction of capecitabine: 2 for G3 mucositis and 3 for hand-foot syndrome. There was no case of cardiac toxicity, thrombocytopenia or any other serious adverse event. Conclusion: The dose-dense sequential combination EC/DXe is endowed with good antitumor activity and limited toxicity, allowing a high rate of pCR and breast conservation.
P124 neo-ALTTO (neoadjuvant lapatinib and/or trastuzumab treatment optimisation) study [BIG 1-06/SOLTI/EGF106903]: a phase III translational study for Her2-overexpressing early breast cancer (BC) J. Baselga1 , M.J. Piccart-Gebhart2 , R.D. Gelber3 , S. di Cosimo1 , G. Viale4 , M. Koehler5 , F. Rojo1 . 1 Vall d’Hebron University Hospital, Bacelona, Spain, 2 Jules Bordet Institute, Brussels, Belgium, 3 Dana Farber Cancer Institute, Boston, USA, 4 European Institute of Oncology, Milan, Italy, 5 GlaxoSmithKline, Collegeville, USA Preoperative therapy in BC constitutes a valuable model for testing new treatments and offers the opportunity for rapid comparison of clinical and biological effects of novel drugs. Lapatinib (L), an oral, small molecule, dual inhibitor of EGFR and HER2 tyrosine kinases targeting HER2+ tumors, demonstrated activity in pts with trastuzumab (H) resistant or refractory disease, has the potential to be less cardiotoxic and has some activity against HER2+ BC brain metastases. Preclinical and clinical data demonstrate a relative lack of cross resistance between H and L. Different mechanisms of action and targets on the HER2 receptor by H (extracellular domain) and L (intracellular domain and EGFR) support combined H and L administration. L may be as effective as H and more acceptable to pts as oral therapy. We are conducting the neo-ALTTO (neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study, a randomized comparison of neoadjuvant H 4 mg/kg iv load followed by 2 mg/kg iv weekly, or L 1500 mg PO QD or both agents combined (identical to treatments in ALTTO adjuvant trial) for 6 weeks followed by the same 3 arms of HER2 inhibitors in combination with weekly paclitaxel (80 mg/m2 ) for 12 weeks before surgery in 450 women with HER2+ operable BC worldwide. After surgery, pts will receive 3 courses of adjuvant FEC chemotherapy followed by the same targeted therapy as in the neoadjuvant setting for 34 weeks, to complete 1 year of anti-HER2 therapy. Tumor tissue (for proteomic, genomic and RNA analysis) will be collected pretreatment, at 2 weeks, and at excision to assess if intermediate biological markers can predict for response, for differences in response between treatments, and when assessed in association with the ALTTO study, to determine if these markers predict long-term outcome (DFS and OS). A subset of pts will be evaluated at week 2 and 6 with PET-imaging to determine early response to anti-HER2 therapy and correlate with molecular tissue markers, pCR or DFS. The primary objective of this study is to compare the rate of pCR at the time of surgery. Secondary objectives include comparisons of safety and tolerability, objective tumor response rate, DFS and OS, conversion to breast conserving surgery and node-negative disease at surgery, and identification of molecular features of responding tumors. The study is being coordinated by the Breast International Group (BIG), SOLTI (Solid Tumor Intensification) Group and is sponsored by GlaxoSmithKline.
P125 Adriamycin–cytoxan followed by weekly taxol as neoadjuvant treatment in localised breast cancer M. Leviov1 , L. Leitzin1 , S. Keren1 , A. Rabkin1 , Z. Shklar1 , M. Steiner2 , A. Biterman3 , E. Shiloni4 . 1 Lin Medical Center, Oncology, Haifa, Israel, 2 Carmel Hospital, Oncology, Haifa, Israel, 3 Carmel Hospital, Surgery A, Haifa, Israel, 4 Carmel Hospital, Surgery B, Haifa, Israel During the last three years weekly taxol was added following the standard adriamycin based therapy as neoadjuvant treatment in localized breast can-
Friday, 16 March 2007 cer. The aim was to increase clinical and pathological complete response. The first induction phase consisted of Adriamycin-Cytoxan combination (60/600) x 4. Subsequently weekly Taxol 80 mg/m2 x 12 weeks was planned before definitive surgery. 52 patients entered the protocol. Median age was 50 years (34−75). 14/52 (27%) had T2 3 cm tumors, 21/52 (40%) had T3 lesions, 10/52 (19%) had T4 non inflammatory carcinoma, 6/52 (12%) suffered from inflammatory carcinoma and 1/52 (2%) presented with only massive axillary disease. Axillary lymph nodes were palpated in 26/52 patients (50%). After completing AC therapy, significant clinical response was seen in 39/52 (75%) patients (4 complete response, 35 partial response) minimal response or stable disease in 12/52 patients (27%) and rapid tumor progression in one patient (2%). 5 patients underwent surgery after AC therapy (4 who refused further chemotherapy and one developed Taxol hypersensitivity at first infusion) and 46/52 patients started weekly taxol. 35/46 patients finished the planned taxol therapy, two are still on treatment and 9 stopped after 2−10 weeks (median 9), 2 due to refusal and 7 due to Grade III toxicity (4 peripheral neuropathy, 2 nails toxicity and one interstitial lung fibrosis). All 44 evaluable patients (who had >6 weekly taxol treatments) had significant objective clinical response, complete response 14/44 (35%), and partial response 30/44 (65%). 42 patients were operated till now, 16 had lumpectomy and 26 mastectomy. Pathologic CR was documented in 4/42 (10%), in 1/42 patient (2%) only DCIS was found, microscopic foci of tumor cells were found in 7/42 (17%) and invasive cancer in 30/42 patients (71%). We concluded that the addition of weekly taxol after adriamycin based therapy increases significantly the clinical complete response rate (from 8% to 35%) Treatment is feasible although toxicity is not negligible. The low rate of pathologic complete response (10%) may be due to the high prevalence of T3−4 tumors (61%) in this group.
P126 Neoadjuvant treatment of stage II or III breast cancer with docetaxel and low dose capecitabine, with addition of trastuzumab for HER 2 amplified tumors Q.J. Khan1 , P. Sharma1 , B.F. Kimler2 , J. Baranda1 , J.C. Andersen3 , J. Klemp1 , C.J. Fabian1 . 1 University of Kansas Medical Center, Oncology–Hematology, Kansas City, USA, 2 University of Kansas Medical Center, Radiation Oncology, Kansas City, USA, 3 Northwest Cancer Spclsts, Oncology-Hematology, Portland, USA Background: Two simultaneous phase II pilot studies were initiated at the University of Kansas Medical Center to determine the efficacy of neoadjuvant (NA) docetaxel (D) and low dose capecitabine plus trastuzumab (T) in HER 2 + breast cancer and efficacy of D and low dose capecitabine in HER 2 − breast cancer. We here present the combined efficacy and toxicity data from both these studies. Patients and Methods: All patients (21 women) had 3 cm tumor and/or clinically palpable axillary lymphadenopathy. Inflammatory breast cancers were excluded. HER 2 testing by FISH was required. NA treatment consisted of four cycles of D 30 mg/m2 weekly for 3 weeks, repeated every 28 days and low dose capecitabine 1 g BID (fixed dose) d 1−14, repeated every 28 days. Women with HER 2 + tumors also received weekly T for 12 weeks. All patients received 4 cycles of adjuvant AC. In HER 2 + tumors, T was restarted after completion of AC and continued for 32 weeks. MUGA scans were obtained at baseline, after completion of NA treatment and at 12 months in women with HER 2 + tumors. Results: 8 women had HER 2 + tumors and received chemotherapy and T. Median age was 48, mean tumor size was 4.8 cm, 6/8 women were node + and 6/8 women were ER −. Six women were evaluable for response. Five achieved a complete clinical response (CCR), four had pathologic complete response (PCR) in the breast and five had PCR in axilla. Four women had PCR in both breast and axilla (PCR rate 50%). Thirteen women had HER 2 − tumors and received chemotherapy alone. Median age was 51, mean tumor size was 3.9 cm, 6/13 women were node + and 9/13 were ER −. There was no CCR, five women had clinical partial response, seven had clinical stable disease and one woman had clinical progression of disease. None achieved PCR. 50% of women who received T and chemotherapy had an asymptomatic drop in EF of 10 points or more from baseline to the end of neoadjuvant treatment. However, there was no further drop in EF at 12 months. Only three women had any grade 3 toxicity in the T study and four had grade 3 toxicities in the non-T study. There were no grade 4 toxicities. Conclusions: Neoadjuvant D and low dose capecitabine when administered with T is well tolerated and is associated with a high rate of PCR in HER 2 + tumors. The same chemotherapy administered in HER 2 tumors is
Poster Session II. Neo-adjuvant (pre-op) systemic therapy
S49
similarly well tolerated but is associated with a low rate of PCR. Our results suggest possible synergy between D/low dose capecitabine and T.
P127 Does neutropenia impose postponement of (neo)adjuvant chemotherapy? One year retrospective analysis in a single cancer centre M. Debled, N. Madranges, C. Donamaria, A. Floquet, M. Durand, ´ Regional Cancer Center, Medical Oncology, L. Mauriac. Institut Bergonie, Bordeaux Cedex, France In 2005, 224 patients were treated at Institut Bergonie´ (Bordeaux, France) for an invasive carcinoma in adjuvant (n = 162) or neo-adjuvant settings (n = 62), outside any clinical trial. Median age was 49.4 years (26.7−72.6). Chemotherapy regimens were either FEC 100 for 4 (n = 54) or 6 (n = 59) courses or a sequential association of 3 FEC 100 followed with 3 docetaxel without (n = 94) or with (n = 17) trastuzumab in case of overexpression or amplification of HER 2/neu. In total, 1238 courses were delivered. Haematologic control was systematically done every three weeks, with a blood count performed the day before administration of the scheduled chemotherapy. Relative dose intensities were 99% (75−101%), 97% (76−102%) and 99% (68−102%) for respectively 4 FEC 100, 6 FEC 100 and 3 FEC 100 followed with 3 docetaxel without/with trastuzumab. Relative dose intensities <85% occurred in 7%, 7% and 5%, respectively. Neutrophil count <1500/ml, the day before the scheduled chemotherapy, occurred in 171 cases (17% of blood counts). Three situations were observed: – Administration of chemotherapy without postponement and any new blood count in 69 cases. Median neutrophil count was 1300/ml. – Second early blood count control before chemotherapy administration within 2 days in 70 cases. In 54 cases blood count was normalised and chemotherapy delivered without any delay. In 16 cases neutrophil count was less than 1500, 7 cases >1200 and 6 cases <1200; in the first situation, chemotherapy was delivered and, in the second one, it was postponed for a mean delay of 5 days (1 to 8 days). – Second blood count performed after a 48 hour delay (mean 4.8 days) in 32 cases. In every cases blood count was normalised and chemotherapy delivered. In all the cases where chemotherapy was delivered with a neutrophil count <1500, no febrile neutropenia was observed. G-CSF prescription was done for 6 patients in 10 chemotherapy courses (0.8%) either for recurrent neutropenia or for infectious complication. In conclusion, in case of a neutrophil count <1500 performed the day before the scheduled chemotherapy, a new blood count within 2 days shows in most of the cases a normalisation of the neutrophil count allowing chemotherapy administration. This rapid normalisation of blood count and absence of clinical complication are strong arguments to deliver adjuvant chemotherapy without postponement and support treatments.
P128 Phase II trial with letrozole (2.8 mg) to maximal response as neoadjuvant endocrine therapy in postmenopausal patients with ER/PgR[+] operable breast cancer A. Lombart-Cussac1 , A. Galan ´ 2 , C. Fuster Diana1 , E. Buch2 , 3 1 V. Caranana ˜ , A. Rodriguez-Lescure4 , C. Vazquez ´ , A. Guerrero1 , A. Ruiz1 , V. Guilem Porta1 . 1 Instituto Valenciano de Oncolog´ıa, Dept. of Oncology, Valencia, Spain, 2 Hospital de Sagunto, Dept. of Oncology, Valencia, Spain, 3 Hospital Arnau de Vilanova, Dept. of Oncology, Valencia, Spain, 4 Hospital Universitario de Elche, Dept. of Oncology, Alicante, Spain Background: Randomized trials in postmenopausal patients with ER/PgR[+] operable breast cancer had shown that neoadjuvant therapy with an aromatase inhibitor (AI) is more effective than tamoxifen and equivalent to chemotherapy in terms of ORR and preserving breast surgery. However, trials were conducted with a predetermined length of 3 to 4 months of therapy, and no study has analyzed as yet the optimal duration of AI as induction therapy. In this study we assessed the safety and efficacy for letrozole (Femara® ), in postmenopausal women with ER and/or PgR[+] until maximal response. Material and Methods: An open, multicentric, phase II trial to evaluate the efficacy of letrozole over a preoperative period of 3 months to 1 year was conducted. Inclusion criteria required: Postmenopausal status, histological diagnosis (tru-cut) of infiltrating breast carcinoma, ER and/or PgR[+] (by
Poster Session II. Neo-adjuvant (pre-op) systemic therapy
P122 A multicenter study of epirubicin-docetaxel (ET) as primary chemotherapy for patients with inflammatory breast cancer (IBC) K. Anan1 , S. Mitsuyama1 , K. Ikejiri2 , T. Ohchi3 , Y. Rai4 , T. Oikawa5 , M. Kudaka6 , R. Nishimura7 , S. Kuroki8 , K. Tamura9 . ET Study group in Kyushu of Japan. 1 Kitakyushu Municipal Medical Center, Surgery, Kitakyushu, Japan, 2 National Hospital Organization Kyushu Medical Center, Surgery, Fukuoka, Japan, 3 Miyazaki Prefectural Nobeoka Hospital, Surgery, Miyazaki, Japan, 4 Sagara Hospital, Surgery, Kagoshima, Japan, 5 Oikawa Hospital, Surgery, Fukuoka, Japan, 6 Naha City Hospital, Surgery, Okinawa, Japan, 7 Kumamoto City Hospital, Surgery, Kumamoto, Japan, 8 Kyushu University, Surgery, Fukuoka, Japan Background: IBC is a rare clinical entity but a most lethal form of locally advanced cancer. ET regimen is one of the most active chemotherapies for metastatic breast cancer. A Japanese phase I study demonstrated recommended dose of each epirubicin and docetaxel was 60 mg/m2 in every 3 week administration. Based on these data, this study was designed to evaluate survival, efficacy and safety of ET regimen as a primary chemotherapy for IBC. Patients and Methods: Patients between 20 and 75 years of age with acceptable organ function and newly-diagnosed IBC were included. Epirubicin 60 mg/m2 was given as i.v. bolus injection followed by a 1-hour infusion of docetaxel 60 mg/m2 every 3 weeks for 4 cycles unless disease progression occurred, in which case appropriate surgery was offered. Results: From July 2002 to April 2006, 19 patients were enrolled in the study. Median follow-up time was 16 months. Seventeen patients completed ET regimen and 1 patient was excluded because of no diffuse erythema leaving 16 patients evaluable for survival status and safety. Median age was 58 years (range: 31−69), ECOG Performance Status 0 was seen in 88% of patients. 31% of patients were either ER positive and/or PgR positive. 25% of patients were HER2 2+ or 3+. Grade 3−4 haematological toxicities were neutropenia (81%), febrile neutropenia (50%) and anaemia (19%). 69% of patients received granulocyte colony stimulating factor for observed neutropenia. However, all patients with febrile neutropenia were observed it only 1 cycle and obvious infection was not observed. Grade 3−4 nonhaematological toxicities were constipation (19%), nausea (13%), anorexia (13%), fatigue (6%), vomiting (6%), diarrhea (6%) and stomatitis (6%). The ET regimen was given to 81% of patients at the planned dose. Median cycles were 4 cycles (range: 2−4). Fourteen patients with measurable disease were evaluable for clinical response. The clinical response rate was 43% (95% confidence interval: 18−71%). Median survival was 19 months. Conclusions: As primary chemotherapy for IBC the ET regimen is tolerated and effective. The survival benefit has to be evaluated carefully, because of the extremely poor prognosis of IBC. We must study molecular mechanism of IBC and further develop new treatment strategy.
P123 Preoperative sequential chemotherapy of dose-dense epirubicin/cyclophosphamide followed by docetaxel/capecitabine in patients with stage II/IIIA breast cancer A. Grassadonia1 , E. Cianchetti2 , C. Ficorella3 , D. Angelucci1 , S. Grossi2 , E. Ricevuto3 , M. Zilli1 , N. Tinari1 , C. Natoli1 , S. Iacobelli1 . 1 University “G. D’Annunzio”, Oncology and Neurosciences, Chieti, Italy, 2 University “G. D’Annunzio”, Breast Surgery Unit, Chieti, Italy, 3 University “G. D’Annunzio”, Experimental Medicine, Chieti, Italy Purpose: To evaluate the activity and safety of a dose-dense, sequential chemotherapy of epirubicin/cyclophosphamide (EC) followed by docetaxel/capecitabine (DXe) given preoperatively in patients with stage II/IIIA breast cancer not candidate to breast-conserving surgery. Methods: This was a Simon’s two-step phase II study, recruiting 24 patients in the first step, and an additional 20 patients in the second step (total of 44 patients). Patients with histologically/cytologically confirmed primary breast cancer (T2−3, N0−2, M0) received four cycles of EC (cyclophosphamide, 600 mg/m2 and epirubicin, 90 mg/m2 ) q2 weeks followed by two cycles of DXe (docetaxel, 36 mg/m2 days 1, 8, and 15 and capecitabine, 1250 mg/m2 days 5−18) q 28 days, with pegfilgrastim prophylaxis. The primary end point of the study was the incidence of pCR defined as the absence of invasive or in situ cancer in the breast at definitive surgery. Forty-four women were enrolled; all had T2 or T3 lesions, 39% had clinically palpable lymph nodes, and 59% had steroid receptor positive tumors.
Friday, 16 March 2007 Results: Forty-one out of 44 enrolled patients were evaluable for response to treatment (one patient withdrew from the study for G4 neutropenia after the first EC cycle, two patients for therapy refusal after 1 EC cycle and after 4 EC cycles, respectively). Nine patients (22%) exhibited a pCR in the breast alone and 7 (17%) in both breast and lymph nodes. Interestingly, all but one of the 9 pCR cases showed hormone receptor-negative tumors. A clinical response (CR or PR) detected by palpation and by imaging was observed in 38 patients, for an overall response rate of 93%. Thirty-six patients (88%) underwent breast-conserving surgery. The treatment was well tolerated. One patient stopped capecitabine for G3 diarrhoea and five patients required a 25% dose reduction of capecitabine: 2 for G3 mucositis and 3 for hand-foot syndrome. There was no case of cardiac toxicity, thrombocytopenia or any other serious adverse event. Conclusion: The dose-dense sequential combination EC/DXe is endowed with good antitumor activity and limited toxicity, allowing a high rate of pCR and breast conservation.
P124 neo-ALTTO (neoadjuvant lapatinib and/or trastuzumab treatment optimisation) study [BIG 1-06/SOLTI/EGF106903]: a phase III translational study for Her2-overexpressing early breast cancer (BC) J. Baselga1 , M.J. Piccart-Gebhart2 , R.D. Gelber3 , S. di Cosimo1 , G. Viale4 , M. Koehler5 , F. Rojo1 . 1 Vall d’Hebron University Hospital, Bacelona, Spain, 2 Jules Bordet Institute, Brussels, Belgium, 3 Dana Farber Cancer Institute, Boston, USA, 4 European Institute of Oncology, Milan, Italy, 5 GlaxoSmithKline, Collegeville, USA Preoperative therapy in BC constitutes a valuable model for testing new treatments and offers the opportunity for rapid comparison of clinical and biological effects of novel drugs. Lapatinib (L), an oral, small molecule, dual inhibitor of EGFR and HER2 tyrosine kinases targeting HER2+ tumors, demonstrated activity in pts with trastuzumab (H) resistant or refractory disease, has the potential to be less cardiotoxic and has some activity against HER2+ BC brain metastases. Preclinical and clinical data demonstrate a relative lack of cross resistance between H and L. Different mechanisms of action and targets on the HER2 receptor by H (extracellular domain) and L (intracellular domain and EGFR) support combined H and L administration. L may be as effective as H and more acceptable to pts as oral therapy. We are conducting the neo-ALTTO (neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study, a randomized comparison of neoadjuvant H 4 mg/kg iv load followed by 2 mg/kg iv weekly, or L 1500 mg PO QD or both agents combined (identical to treatments in ALTTO adjuvant trial) for 6 weeks followed by the same 3 arms of HER2 inhibitors in combination with weekly paclitaxel (80 mg/m2 ) for 12 weeks before surgery in 450 women with HER2+ operable BC worldwide. After surgery, pts will receive 3 courses of adjuvant FEC chemotherapy followed by the same targeted therapy as in the neoadjuvant setting for 34 weeks, to complete 1 year of anti-HER2 therapy. Tumor tissue (for proteomic, genomic and RNA analysis) will be collected pretreatment, at 2 weeks, and at excision to assess if intermediate biological markers can predict for response, for differences in response between treatments, and when assessed in association with the ALTTO study, to determine if these markers predict long-term outcome (DFS and OS). A subset of pts will be evaluated at week 2 and 6 with PET-imaging to determine early response to anti-HER2 therapy and correlate with molecular tissue markers, pCR or DFS. The primary objective of this study is to compare the rate of pCR at the time of surgery. Secondary objectives include comparisons of safety and tolerability, objective tumor response rate, DFS and OS, conversion to breast conserving surgery and node-negative disease at surgery, and identification of molecular features of responding tumors. The study is being coordinated by the Breast International Group (BIG), SOLTI (Solid Tumor Intensification) Group and is sponsored by GlaxoSmithKline.
P125 Adriamycin–cytoxan followed by weekly taxol as neoadjuvant treatment in localised breast cancer M. Leviov1 , L. Leitzin1 , S. Keren1 , A. Rabkin1 , Z. Shklar1 , M. Steiner2 , A. Biterman3 , E. Shiloni4 . 1 Lin Medical Center, Oncology, Haifa, Israel, 2 Carmel Hospital, Oncology, Haifa, Israel, 3 Carmel Hospital, Surgery A, Haifa, Israel, 4 Carmel Hospital, Surgery B, Haifa, Israel During the last three years weekly taxol was added following the standard adriamycin based therapy as neoadjuvant treatment in localized breast can-
Friday, 16 March 2007 cer. The aim was to increase clinical and pathological complete response. The first induction phase consisted of Adriamycin-Cytoxan combination (60/600) x 4. Subsequently weekly Taxol 80 mg/m2 x 12 weeks was planned before definitive surgery. 52 patients entered the protocol. Median age was 50 years (34−75). 14/52 (27%) had T2 3 cm tumors, 21/52 (40%) had T3 lesions, 10/52 (19%) had T4 non inflammatory carcinoma, 6/52 (12%) suffered from inflammatory carcinoma and 1/52 (2%) presented with only massive axillary disease. Axillary lymph nodes were palpated in 26/52 patients (50%). After completing AC therapy, significant clinical response was seen in 39/52 (75%) patients (4 complete response, 35 partial response) minimal response or stable disease in 12/52 patients (27%) and rapid tumor progression in one patient (2%). 5 patients underwent surgery after AC therapy (4 who refused further chemotherapy and one developed Taxol hypersensitivity at first infusion) and 46/52 patients started weekly taxol. 35/46 patients finished the planned taxol therapy, two are still on treatment and 9 stopped after 2−10 weeks (median 9), 2 due to refusal and 7 due to Grade III toxicity (4 peripheral neuropathy, 2 nails toxicity and one interstitial lung fibrosis). All 44 evaluable patients (who had >6 weekly taxol treatments) had significant objective clinical response, complete response 14/44 (35%), and partial response 30/44 (65%). 42 patients were operated till now, 16 had lumpectomy and 26 mastectomy. Pathologic CR was documented in 4/42 (10%), in 1/42 patient (2%) only DCIS was found, microscopic foci of tumor cells were found in 7/42 (17%) and invasive cancer in 30/42 patients (71%). We concluded that the addition of weekly taxol after adriamycin based therapy increases significantly the clinical complete response rate (from 8% to 35%) Treatment is feasible although toxicity is not negligible. The low rate of pathologic complete response (10%) may be due to the high prevalence of T3−4 tumors (61%) in this group.
P126 Neoadjuvant treatment of stage II or III breast cancer with docetaxel and low dose capecitabine, with addition of trastuzumab for HER 2 amplified tumors Q.J. Khan1 , P. Sharma1 , B.F. Kimler2 , J. Baranda1 , J.C. Andersen3 , J. Klemp1 , C.J. Fabian1 . 1 University of Kansas Medical Center, Oncology–Hematology, Kansas City, USA, 2 University of Kansas Medical Center, Radiation Oncology, Kansas City, USA, 3 Northwest Cancer Spclsts, Oncology-Hematology, Portland, USA Background: Two simultaneous phase II pilot studies were initiated at the University of Kansas Medical Center to determine the efficacy of neoadjuvant (NA) docetaxel (D) and low dose capecitabine plus trastuzumab (T) in HER 2 + breast cancer and efficacy of D and low dose capecitabine in HER 2 − breast cancer. We here present the combined efficacy and toxicity data from both these studies. Patients and Methods: All patients (21 women) had 3 cm tumor and/or clinically palpable axillary lymphadenopathy. Inflammatory breast cancers were excluded. HER 2 testing by FISH was required. NA treatment consisted of four cycles of D 30 mg/m2 weekly for 3 weeks, repeated every 28 days and low dose capecitabine 1 g BID (fixed dose) d 1−14, repeated every 28 days. Women with HER 2 + tumors also received weekly T for 12 weeks. All patients received 4 cycles of adjuvant AC. In HER 2 + tumors, T was restarted after completion of AC and continued for 32 weeks. MUGA scans were obtained at baseline, after completion of NA treatment and at 12 months in women with HER 2 + tumors. Results: 8 women had HER 2 + tumors and received chemotherapy and T. Median age was 48, mean tumor size was 4.8 cm, 6/8 women were node + and 6/8 women were ER −. Six women were evaluable for response. Five achieved a complete clinical response (CCR), four had pathologic complete response (PCR) in the breast and five had PCR in axilla. Four women had PCR in both breast and axilla (PCR rate 50%). Thirteen women had HER 2 − tumors and received chemotherapy alone. Median age was 51, mean tumor size was 3.9 cm, 6/13 women were node + and 9/13 were ER −. There was no CCR, five women had clinical partial response, seven had clinical stable disease and one woman had clinical progression of disease. None achieved PCR. 50% of women who received T and chemotherapy had an asymptomatic drop in EF of 10 points or more from baseline to the end of neoadjuvant treatment. However, there was no further drop in EF at 12 months. Only three women had any grade 3 toxicity in the T study and four had grade 3 toxicities in the non-T study. There were no grade 4 toxicities. Conclusions: Neoadjuvant D and low dose capecitabine when administered with T is well tolerated and is associated with a high rate of PCR in HER 2 + tumors. The same chemotherapy administered in HER 2 tumors is
Poster Session II. Neo-adjuvant (pre-op) systemic therapy
S49
similarly well tolerated but is associated with a low rate of PCR. Our results suggest possible synergy between D/low dose capecitabine and T.
P127 Does neutropenia impose postponement of (neo)adjuvant chemotherapy? One year retrospective analysis in a single cancer centre M. Debled, N. Madranges, C. Donamaria, A. Floquet, M. Durand, ´ Regional Cancer Center, Medical Oncology, L. Mauriac. Institut Bergonie, Bordeaux Cedex, France In 2005, 224 patients were treated at Institut Bergonie´ (Bordeaux, France) for an invasive carcinoma in adjuvant (n = 162) or neo-adjuvant settings (n = 62), outside any clinical trial. Median age was 49.4 years (26.7−72.6). Chemotherapy regimens were either FEC 100 for 4 (n = 54) or 6 (n = 59) courses or a sequential association of 3 FEC 100 followed with 3 docetaxel without (n = 94) or with (n = 17) trastuzumab in case of overexpression or amplification of HER 2/neu. In total, 1238 courses were delivered. Haematologic control was systematically done every three weeks, with a blood count performed the day before administration of the scheduled chemotherapy. Relative dose intensities were 99% (75−101%), 97% (76−102%) and 99% (68−102%) for respectively 4 FEC 100, 6 FEC 100 and 3 FEC 100 followed with 3 docetaxel without/with trastuzumab. Relative dose intensities <85% occurred in 7%, 7% and 5%, respectively. Neutrophil count <1500/ml, the day before the scheduled chemotherapy, occurred in 171 cases (17% of blood counts). Three situations were observed: – Administration of chemotherapy without postponement and any new blood count in 69 cases. Median neutrophil count was 1300/ml. – Second early blood count control before chemotherapy administration within 2 days in 70 cases. In 54 cases blood count was normalised and chemotherapy delivered without any delay. In 16 cases neutrophil count was less than 1500, 7 cases >1200 and 6 cases <1200; in the first situation, chemotherapy was delivered and, in the second one, it was postponed for a mean delay of 5 days (1 to 8 days). – Second blood count performed after a 48 hour delay (mean 4.8 days) in 32 cases. In every cases blood count was normalised and chemotherapy delivered. In all the cases where chemotherapy was delivered with a neutrophil count <1500, no febrile neutropenia was observed. G-CSF prescription was done for 6 patients in 10 chemotherapy courses (0.8%) either for recurrent neutropenia or for infectious complication. In conclusion, in case of a neutrophil count <1500 performed the day before the scheduled chemotherapy, a new blood count within 2 days shows in most of the cases a normalisation of the neutrophil count allowing chemotherapy administration. This rapid normalisation of blood count and absence of clinical complication are strong arguments to deliver adjuvant chemotherapy without postponement and support treatments.
P128 Phase II trial with letrozole (2.8 mg) to maximal response as neoadjuvant endocrine therapy in postmenopausal patients with ER/PgR[+] operable breast cancer A. Lombart-Cussac1 , A. Galan ´ 2 , C. Fuster Diana1 , E. Buch2 , 3 1 V. Caranana ˜ , A. Rodriguez-Lescure4 , C. Vazquez ´ , A. Guerrero1 , A. Ruiz1 , V. Guilem Porta1 . 1 Instituto Valenciano de Oncolog´ıa, Dept. of Oncology, Valencia, Spain, 2 Hospital de Sagunto, Dept. of Oncology, Valencia, Spain, 3 Hospital Arnau de Vilanova, Dept. of Oncology, Valencia, Spain, 4 Hospital Universitario de Elche, Dept. of Oncology, Alicante, Spain Background: Randomized trials in postmenopausal patients with ER/PgR[+] operable breast cancer had shown that neoadjuvant therapy with an aromatase inhibitor (AI) is more effective than tamoxifen and equivalent to chemotherapy in terms of ORR and preserving breast surgery. However, trials were conducted with a predetermined length of 3 to 4 months of therapy, and no study has analyzed as yet the optimal duration of AI as induction therapy. In this study we assessed the safety and efficacy for letrozole (Femara® ), in postmenopausal women with ER and/or PgR[+] until maximal response. Material and Methods: An open, multicentric, phase II trial to evaluate the efficacy of letrozole over a preoperative period of 3 months to 1 year was conducted. Inclusion criteria required: Postmenopausal status, histological diagnosis (tru-cut) of infiltrating breast carcinoma, ER and/or PgR[+] (by