- Email: [email protected]
Molecular Changes and Targeted Therapy in Inflammatory Breast Cancer
Annals of Oncology 23 (Supplement 11): xi17–xi18, 2012 doi:10.1093/annonc/mds549
IS2
1
MOLECULAR CHANGES AND TARGETED THERAPY IN INFLAMMATORY BREAST CANCER
N. T. Ueno1,2 1 Morgan Welch Inflammatory Breast Cancer Program and Clinic, 2Section of the Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center
IS2
2
P53 EXPRESSION IN NODE-POSITIVE BREAST CANCER PATIENTS RECEIVING DOCETAXEL-BASED ADJUVANT CHEMOTHERAPY
H. J. An1, H.-J. Lee2, G. Gong2, K.-P. Kim1, J.-H. Ahn1, K. H. Jung1, J. E. Kim1, B. H. Son3, S.-H. Ahn3, S.-B. Kim1 1 Departments of Medical Oncology, 2Pathology, 3Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Background: Taxene-based adjuvant chemotherapy is widely accepted in lymph node (LN)-positive breast cancer, but few biomarkers exist to predict clinical outcomes. We prospectively investigate the role of potential biomarkers in LN-positive breast cancer population homogenously treated with docetaxel-containing adjuvant chemotherapy. Methods: From 2007 to 2008, 218 patients with LN-positive breast cancer who received adjuvant chemotherapy (four cycles of adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2 followed by four cycles of docetaxel 100 mg/m2) were enrolled in this analysis. Immunohistochemical stainings for ER, PR, p53, topoisomerase-IIα, β-III tubulin, Tau, CYP3A4 and Her2/neu were carried out in formalin-fixed, paraffin-embedded tissue section and their relationships with prognosis were investigated. Results: With a median follow-up of 58.3 months (range, 10.9–62.9), p53 and topoisomerase-IIα overexpression were associated with poor relapse-free survival (RFS) and overall survival (OS) along with tumor size >2 cm, number of positive LN
IS2
3
TRANSARTERIAL CHEMOEMBOLIZATION FOR SYMPTOMATIC PALLIATION OF ADVANCED BREAST CANCER: A PILOT STUDY FOR EFFICACY AND SAFETY
J. H. Kim1, D. H. Lee2, T. Okuno3 1 Departments of Radiology, 2Medical oncology, Integrative Cancer Cener, SAM Hospital, Anyang, South Korea, 3Clinical ET, Yokohama, Japan Background: Advanced breast cancers may be associated with serious clinical symptoms corrupting proper quality of life. Traditional treatment including medication and radiotherapy have been preferentially applied to control them, but might be insufficient or useless. This study was aimed to evaluate the efficacy and safety of transarterial chemoembolization in the symptomatic palliation of advanced breast cancer patients. Methods: Total 20 patients were enrolled (From 2008 June to 2011 December). All patients complained of intractable clinical manifestations corrupting proper quality of life—severe pain (n = 16 in breast, mastectomy site, bones), uncontrolled bloody and/or non-bloody discharge from skin or soft tissue of the breast or mastectomy site (n = 7), intractable pleural effusion (n = 4), limit of motion (n = 2), general discomfort (n = 7). Thirteen patients had two or more than two intractable symptoms. Correlating clinical symptoms with findings on CT or PET-CT, arterial suppliers to problematic lesions were selected. Cocktail of chemoagents (gemcitabine 200 mg, oxaliplatine 50 mg, adriamycin 10 mg mixed in glycirrhyzinic acid 40 ml) was infused, followed by embolization with micro-particles (40–50 µm) when it was needed. This treatment was repeated per 4–8 weeks according to the patients’ response and clinical condition. Results: A significant reduction of pain grading score was demonstrated in 11 patients (more than 4 in pain grading score, reduction of analgesics dose). Discharge was significantly controlled in five patients. Pleural effusion was reduced in four patients (reduction of daily drainage >50%). The limit of motion was improved in one patient. General discomfort was improved in four patients. The time to maximum clinical improvement ranged from 2 to 8 days. The duration maintaining clinical improvement ranged from 2 to 6 weeks. Conclusions: In advanced breast cancer patients with intractable clinical manifestations, transarterial chemoembolization is helpful for restoring proper quality of life. However, the improvement maintaining duration is limited with individual variation, which makes the repetition of the procedure needed for clinical maintenance.
IS2
4
THE FIRST-TWO LINES OF CHEMOTHERAPY FOR DE NOVO METASTATIC BREAST CANCER: EFFICACY STUDY BETWEEN ANTHRACYCLINES AND NON-ANTHRACYCLINES
W.-W. Chen1,2, D.-Y. Chang2, C.-H. Lin2, C. Hsu2,3, A.-L. Cheng2,3,4, Y.-S. Lu2 1 Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan, 2Departments of Oncology and, 3Internal Medicine, 4Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan Background: For de novo metastatic breast cancer (DNMBC) patients, past evidence indicated that anthracyclines are beneficial in the first-two lines of palliative chemotherapy but with considerable toxic effects. However, with the provision of
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Simon Fraser University on April 23, 2015
Inflammatory breast cancer (IBC) is one of the most aggressive subtypes of breast cancer. IBC represents 2%–4% of breast cancer, but it represents 10% of breast cancer-related mortality. Despite multimodality approaches, the prognosis for patients with this disease remains poor. Although we are making efforts to improve treatment for IBC, IBC research remains to be limited because this is a rare disease and there are few defined targets for IBC due to undefined IBC biology. To improve this situation, we require insights from clinical trials and epidemiologic studies investigating IBC biology. Molecular targets such as vasculolymphatic, proliferation, and metastatic process has been identified, but all of these unique targets require clinical validation by clinical trials. Molecular targets in cell proliferation processes have been investigated the most and have yielded promising clinical results leading to improved outcomes for patients with IBC. These cell proliferation targets include HER2 and EGFR. As was the case in non-IBC, the HER2 antibody trastuzumab dramatically changed the prognosis of patients with HER2-overexpressing IBC. Lapatinib, which inhibits both HER2 and EGFR, also showed benefit in patients with HER2-positive breast cancer, including IBC, in clinical trials. Additional cell proliferation targets—WISP3, RhoC GTPase, and p27kip1—have also been studied in IBC. Molecules involved in metastasis processes may have a unique role in IBC owing to the aggressiveness of this disease. E-cadherin has been observed to be overexpressed in IBC, and loss of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT). Although this E-cadherin overexpression might be a transient phenomenon, we may be able to target this unique feature. Other potential candidate is the EGFR pathway. We have been investigating the role of this pathway and the possibility of EGFR-targeted therapy for IBC. We are conducting a clinical trial with panitumumab, a human EGFR antibody, plus chemotherapy (nab-paclitaxel and carboplatin) as a preoperative regimen in patients with HER2-negative IBC. In summary, further extensive preclinical and clinical work based on molecular findings is needed to improve outcomes in patients with IBC.
(≥4), high tumor grade (G3), and negativity of hormone receptor in univariate analyses. However, in multivariate analyses, the number of positive LN ≥4 (HR = 2.47; 95% CI, 1.07–5.74; P = 0.035), high tumor grade (HR = 2.76; 95% CI, 1.08–7.09, P = 0.034), and overexpression of p53 (HR = 6.55; 95% CI, 2.40–17.85, P < 0.001) were independent poor prognostic factors for RFS. p53 overexpression were also related to poor OS (HR = 3.93; 95% CI, 1.04–14.81, P = 0.044). Patients with high p53 expression (>10% of positive cells) tended to have tumors with large size, higher grade and lower hormone receptor positivity compared with those of low p53 expression. Conclusions: p53 overexpression along with a number of positive LN and tumor grade was found to be a useful biomarker to predict poor outcomes in patients with LN-positive breast cancer receiving docetaxel-based adjuvant chemotherapy.
abstracts
International Session 2: ‘Breast cancer’
abstracts
IS2
5
PHASE II TRIAL OF TS-1 IN COMBINATION WITH OXALIPLATIN (SOX) IN PATIENTS WITH METASTATIC BREAST CANCER (MBC) PREVIOUSLY TREATED WITH ANTHRACYCLINE AND TAXANE CHEMOTHERAPY [TORCH] [KOREAN CANCER STUDY GROUP (KCSG) BR07-03]
S.-A. Im1, K. H. Lee1, D.-Y. Oh1, K. S. Lee2, J.-H. Ahn3, J. Sohn4, J. S. Ahn5, J. H. Kim6, M. H. Lee7, K. E. Lee8, S.-Y. Kim9, S. B. Kim3, Y.-H. Im5, J. Ro2, H.-S. Park10 1 Seoul National University Hospital, 2National Cancer Center, 3Asan Medical Center, 4Yonsei University College of Medicine, Severance Hospital, 5Samsung Medical Center, 6Seoul National University Bundang Hospital, 7Inha University Hospital, 8Ewha Womans University Medical Center, 9Kyung-Hee University Hospital, 10Soon Chun Hyang University Hospital Background: Oxaliplatin, a platinum analogue, is an active drug in advanced anthracycline and taxane-pretreated breast cancer patients as a single agent and with 5-fluorouracil (5-FU) combination. TS-1 was developed by the scientific theory of both potentiating antitumor activity of 5-FU and reducing gastrointestinal toxicity. This trial was carried out to evaluate the efficacy and safety of TS-1 in combination with oxaliplatin in metastatic breast cancer (MBC) patients previously treated with anthracycline (A) and taxane (T) chemotherapy (CTx). Methods: Between October 2007 and October 2009, MBC patients were enrolled in this prospective multicenter trial. Eligible criteria included age >18 years, at least one measurable lesion, prior treatment with A and T CTx, and ECOG PS 0-2. TS-1 40 mg/m2 bid on D1-14 with oxaliplatin 130 mg/m2 on D1 were administered every 3 weeks till disease progression. Primary end-point was response rate (RR), and secondary end-points were time-to-progression (TTP), overall survival (OS), duration of response (DOR) and toxic effects. Response was evaluated every 6 weeks according to the RECIST criteria v.1.0 and toxicity was assessed with NCICTCAE v.3.0. (ClinicalTrials.gov identifier NCT00527930.) Results: A total of 87 patients were enrolled. Median age was 48 (range 30–71) years. Nineteen patients (21.8%) had de novo stage IV and 68 patients (78.2%) had recurrent disease. Forty-eight patients (55.2%) had ≥3 disease sites. Fifty-four patients (62.1%) were hormone receptor positive, and 25 patients (28.7%) were triple negative. Five patients received prior anti-HER2 therapy. A total of 525 cycles were administered (median 6, range: 1–22+ cycle). In per-protocol analysis, the overall RR was 38.5% (CR 0%, PR 38.5%) and the disease control rate (CR, PR, and SD) was 67.9%. Median TTP, OS, and DOR were 6.0, 19.4, 6.6 months, respectively. The RR did not differ by triple negativity (39.1% in TNBC versus 38.2% in non-TNBC, P = 0.361). Reported grade 3 or 4 toxic effects ( per cycle) were neutropenia (10.3%), thrombocytopenia (5.5%), diarrhea (1.9%), vomiting (1.9%), and stomatitis (0.2%). There was no treatment-related death. Conclusions: SOX is an effective regimen in anthracycline and taxane pretreated MBC patients with manageable toxic effects.
xi | abstracts
IS2
6
BOLERO-2: A RANDOMIZED PHASE III STUDY OF EVEROLIMUS IN COMBINATION WITH EXEMESTANE: RESULTS OF THE JAPANESE SUBGROUP ANALYSIS
Y. Ito1, N. Masuda2, H. Iwata3, H. Mukai4, J. Horiguchi5, Y. Tokuda6, K. Kuroi7, H. Iwase8, H. Inaji9, S. Ohsumi10, T. Nakayama11, S. Ohno12, T. Sahmoud13, N. Ohno14, S. Noguchi11 1 Cancer Institute Hospital of JFCR, 2National Hospital Organization Osaka National Hospital, 3Aichi Cancer Center Hospital, 4National Cancer Center Hospital East, 5Gunma University Hospital, 6Tokai University Hospital, 7Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, 8 Kumamoto University Hospital, 9Osaka Medical Center for Cancer and Cardiovascular Diseases, 10National Hospital Organization Shikoku Cancer Center, 11Osaka University Hospital, 12National Kyushu Cancer Center, 13 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 14Novartis Pharma K.K. Background: BOLERO-2, an international, phase III study in patients with locally advanced or metastatic breast cancer refractory to non-steroidal aromatase inhibitor therapy, previously reported that the addition of everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) (6.9 versus 2.8 months; HR = 0.43; P < 0.001) versus EXE alone by local assessment (Baselga J, et al. N Eng J Med 2011). This report presents data from the Japanese subpopulation. Methods: Eligible patients were randomized (2:1) to EVE (10 mg/day) or matching placebo (PBO), with both arms receiving EXE (25 mg/day). Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was PFS by local assessment. Secondary end points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety. Results: Of the 724 patients from 24 countries enrolled in this study, 106 patients were Japanese, of whom 71 and 35 were assigned to EVE + EXE or PBO + EXE, respectively. Data from this Japanese subpopulation are presented. The addition of EVE to EXE prolonged median PFS (8.4 months versus 4.1 months; P = 0.025), increased ORR (16.9% versus 0%), and CBR (43.7% versus 25.7%) compared with EXE alone. In the EVE + EXE arm, most common grade 3/4 adverse events included stomatitis (9.9%), anemia (5.6%), and aspartate aminotransferase increased (4.2%). The incidence of non-infective lung-related adverse events was 31.0%, which was higher than in the overall population. The majority of these events were grade 1 or 2. Most patients showed recovery or relief after dose reduction or interruption, administration of corticosteroids, or oxygen therapy. Conclusion: Japanese patients in the BOLERO-2 trial treated with EVE + EXE showed similar PFS benefits as the overall population and a manageable safety profile. Thus, EVE + EXE is a promising new therapeutic option for Japanese women with advanced breast cancer.
IS2
7
CLINICAL EVALUATION OF PERTUZUMAB, A NEW HER2 TARGETED AGENT, IN BREAST CANCER
Y. Sasaki Division of Medical Oncology, Department of Medicine, Showa University School of Medicine Trastuzumab improves the outcome in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, most patients with advanced disease eventually progress and new treatment options for trastuzumab-resistant population are warranted. Pertuzumab, a humanized monoclonal antibody, prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. In addition, pertuzumab has complementary mechanism of action with that of trastuzumab. A combination of pertuzumab and trastuzumab showed more potent anti-tumor activity in a HER2-positive breast cancer xenograft model KPL-4 than either pertuzumab or trastuzumab alone. Thus, the combination strategy of the two antibodies is expected to have higher efficacy in HER2-positive breast cancer patients. Since a phase II study of pertuzumab–trastuzumab combination regimen showed meaningful efficacy (ORR 24.2%) in HER2-positive MBC patients who had progressed during trastuzumab treatment, a phase III study (CLEOPATRA) was conducted. The study compares the efficacy and safety of pertuzumab + trastuzumab + docetaxel with those of placebo + trastuzumab + docetaxel, in the first-line setting for patients with HER2-positive MBC. The primary end point was independently assessed progression-free survival (PFS). The median PFS of the pertuzumab arm was 18.5 months and was significantly longer than that of the control arm, 12.4 months. The interim analysis of overall survival showed a strong trend in favor of the pertuzumab group. Although the rates of febrile neutropenia and diarrhea of grade 3 or greater were higher in the pertuzumab group than in the control group, adding pertuzumab to trastuzumab and docetaxel had an acceptable tolerability profile with no increase in left ventricular systolic dysfunction. Pertuzumab is currently being studied in early breast cancer in combination with trastuzumab, and also in first-line metastatic breast cancer in combination with T-DM1, an antibody drug conjugate of trastuzumab and a maytansinoid, DM1.
Volume 23 | Supplement 11 | October 2012
Downloaded from http://annonc.oxfordjournals.org/ at Simon Fraser University on April 23, 2015
newer chemotherapies, comparative studies addressing the efficacy between anthracyclines and non-anthracyclines in the first-two lines of palliative chemotherapy for DNMBC were lacking. Methods: We collected clinicopathological characteristics of DNMBC patients who had received palliative chemotherapy in National Taiwan University Hospital between 2001 and 2006. Patients were classified as anthracycline or non-anthracycline group according to the first-two lines of chemotherapy. Kaplan–Meier method and log-rank test were used for the estimation and comparison of both overall survival (OS) and time to treatment failure of the first-two lines (TTF2). Cox proportional hazard model was used for OS and TTF2. Best composite response rate (BCRR) were compared with the logistic regression test. Results: A total of 121 patients, 58 (47.9%) in the anthracycline group and 63 (52.1%) in the non-anthracycline group, were analyzed. Between these two groups, the distributions of clinicopathological variables were generally similar. The median OS (33.1 versus 36.7 months, P = 0.91), median TTF2 (13.6 versus 17.2 months, P = 0.80), and BCRR (67.2 versus 66.7%; odds ratio 1.03, 95% CI 0.48–2.19, P = 0.95) were not significantly different. In multivariate analysis, early treatment with anthracyclines (anthracycline group) did not translated into improvements in OS (HR 1.02, 95% CI 0.64–1.63, P = 0.93) and TTF2 (HR 1.12, 95% CI 0.70–1.79, P = 0.65). Conclusion: Our study is the first study to demonstrate that anthracyclines may not be mandatory in the first-two lines of palliative chemotherapy for DNMBC. Future prospective studies are needed to evaluate the most proper early palliative chemotherapy for DNMBC patients in terms of both efficacy and toxicity.
Annals of Oncology
IS2
1
MOLECULAR CHANGES AND TARGETED THERAPY IN INFLAMMATORY BREAST CANCER
N. T. Ueno1,2 1 Morgan Welch Inflammatory Breast Cancer Program and Clinic, 2Section of the Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center
IS2
2
P53 EXPRESSION IN NODE-POSITIVE BREAST CANCER PATIENTS RECEIVING DOCETAXEL-BASED ADJUVANT CHEMOTHERAPY
H. J. An1, H.-J. Lee2, G. Gong2, K.-P. Kim1, J.-H. Ahn1, K. H. Jung1, J. E. Kim1, B. H. Son3, S.-H. Ahn3, S.-B. Kim1 1 Departments of Medical Oncology, 2Pathology, 3Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Background: Taxene-based adjuvant chemotherapy is widely accepted in lymph node (LN)-positive breast cancer, but few biomarkers exist to predict clinical outcomes. We prospectively investigate the role of potential biomarkers in LN-positive breast cancer population homogenously treated with docetaxel-containing adjuvant chemotherapy. Methods: From 2007 to 2008, 218 patients with LN-positive breast cancer who received adjuvant chemotherapy (four cycles of adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2 followed by four cycles of docetaxel 100 mg/m2) were enrolled in this analysis. Immunohistochemical stainings for ER, PR, p53, topoisomerase-IIα, β-III tubulin, Tau, CYP3A4 and Her2/neu were carried out in formalin-fixed, paraffin-embedded tissue section and their relationships with prognosis were investigated. Results: With a median follow-up of 58.3 months (range, 10.9–62.9), p53 and topoisomerase-IIα overexpression were associated with poor relapse-free survival (RFS) and overall survival (OS) along with tumor size >2 cm, number of positive LN
IS2
3
TRANSARTERIAL CHEMOEMBOLIZATION FOR SYMPTOMATIC PALLIATION OF ADVANCED BREAST CANCER: A PILOT STUDY FOR EFFICACY AND SAFETY
J. H. Kim1, D. H. Lee2, T. Okuno3 1 Departments of Radiology, 2Medical oncology, Integrative Cancer Cener, SAM Hospital, Anyang, South Korea, 3Clinical ET, Yokohama, Japan Background: Advanced breast cancers may be associated with serious clinical symptoms corrupting proper quality of life. Traditional treatment including medication and radiotherapy have been preferentially applied to control them, but might be insufficient or useless. This study was aimed to evaluate the efficacy and safety of transarterial chemoembolization in the symptomatic palliation of advanced breast cancer patients. Methods: Total 20 patients were enrolled (From 2008 June to 2011 December). All patients complained of intractable clinical manifestations corrupting proper quality of life—severe pain (n = 16 in breast, mastectomy site, bones), uncontrolled bloody and/or non-bloody discharge from skin or soft tissue of the breast or mastectomy site (n = 7), intractable pleural effusion (n = 4), limit of motion (n = 2), general discomfort (n = 7). Thirteen patients had two or more than two intractable symptoms. Correlating clinical symptoms with findings on CT or PET-CT, arterial suppliers to problematic lesions were selected. Cocktail of chemoagents (gemcitabine 200 mg, oxaliplatine 50 mg, adriamycin 10 mg mixed in glycirrhyzinic acid 40 ml) was infused, followed by embolization with micro-particles (40–50 µm) when it was needed. This treatment was repeated per 4–8 weeks according to the patients’ response and clinical condition. Results: A significant reduction of pain grading score was demonstrated in 11 patients (more than 4 in pain grading score, reduction of analgesics dose). Discharge was significantly controlled in five patients. Pleural effusion was reduced in four patients (reduction of daily drainage >50%). The limit of motion was improved in one patient. General discomfort was improved in four patients. The time to maximum clinical improvement ranged from 2 to 8 days. The duration maintaining clinical improvement ranged from 2 to 6 weeks. Conclusions: In advanced breast cancer patients with intractable clinical manifestations, transarterial chemoembolization is helpful for restoring proper quality of life. However, the improvement maintaining duration is limited with individual variation, which makes the repetition of the procedure needed for clinical maintenance.
IS2
4
THE FIRST-TWO LINES OF CHEMOTHERAPY FOR DE NOVO METASTATIC BREAST CANCER: EFFICACY STUDY BETWEEN ANTHRACYCLINES AND NON-ANTHRACYCLINES
W.-W. Chen1,2, D.-Y. Chang2, C.-H. Lin2, C. Hsu2,3, A.-L. Cheng2,3,4, Y.-S. Lu2 1 Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan, 2Departments of Oncology and, 3Internal Medicine, 4Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan Background: For de novo metastatic breast cancer (DNMBC) patients, past evidence indicated that anthracyclines are beneficial in the first-two lines of palliative chemotherapy but with considerable toxic effects. However, with the provision of
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Simon Fraser University on April 23, 2015
Inflammatory breast cancer (IBC) is one of the most aggressive subtypes of breast cancer. IBC represents 2%–4% of breast cancer, but it represents 10% of breast cancer-related mortality. Despite multimodality approaches, the prognosis for patients with this disease remains poor. Although we are making efforts to improve treatment for IBC, IBC research remains to be limited because this is a rare disease and there are few defined targets for IBC due to undefined IBC biology. To improve this situation, we require insights from clinical trials and epidemiologic studies investigating IBC biology. Molecular targets such as vasculolymphatic, proliferation, and metastatic process has been identified, but all of these unique targets require clinical validation by clinical trials. Molecular targets in cell proliferation processes have been investigated the most and have yielded promising clinical results leading to improved outcomes for patients with IBC. These cell proliferation targets include HER2 and EGFR. As was the case in non-IBC, the HER2 antibody trastuzumab dramatically changed the prognosis of patients with HER2-overexpressing IBC. Lapatinib, which inhibits both HER2 and EGFR, also showed benefit in patients with HER2-positive breast cancer, including IBC, in clinical trials. Additional cell proliferation targets—WISP3, RhoC GTPase, and p27kip1—have also been studied in IBC. Molecules involved in metastasis processes may have a unique role in IBC owing to the aggressiveness of this disease. E-cadherin has been observed to be overexpressed in IBC, and loss of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT). Although this E-cadherin overexpression might be a transient phenomenon, we may be able to target this unique feature. Other potential candidate is the EGFR pathway. We have been investigating the role of this pathway and the possibility of EGFR-targeted therapy for IBC. We are conducting a clinical trial with panitumumab, a human EGFR antibody, plus chemotherapy (nab-paclitaxel and carboplatin) as a preoperative regimen in patients with HER2-negative IBC. In summary, further extensive preclinical and clinical work based on molecular findings is needed to improve outcomes in patients with IBC.
(≥4), high tumor grade (G3), and negativity of hormone receptor in univariate analyses. However, in multivariate analyses, the number of positive LN ≥4 (HR = 2.47; 95% CI, 1.07–5.74; P = 0.035), high tumor grade (HR = 2.76; 95% CI, 1.08–7.09, P = 0.034), and overexpression of p53 (HR = 6.55; 95% CI, 2.40–17.85, P < 0.001) were independent poor prognostic factors for RFS. p53 overexpression were also related to poor OS (HR = 3.93; 95% CI, 1.04–14.81, P = 0.044). Patients with high p53 expression (>10% of positive cells) tended to have tumors with large size, higher grade and lower hormone receptor positivity compared with those of low p53 expression. Conclusions: p53 overexpression along with a number of positive LN and tumor grade was found to be a useful biomarker to predict poor outcomes in patients with LN-positive breast cancer receiving docetaxel-based adjuvant chemotherapy.
abstracts
International Session 2: ‘Breast cancer’
abstracts
IS2
5
PHASE II TRIAL OF TS-1 IN COMBINATION WITH OXALIPLATIN (SOX) IN PATIENTS WITH METASTATIC BREAST CANCER (MBC) PREVIOUSLY TREATED WITH ANTHRACYCLINE AND TAXANE CHEMOTHERAPY [TORCH] [KOREAN CANCER STUDY GROUP (KCSG) BR07-03]
S.-A. Im1, K. H. Lee1, D.-Y. Oh1, K. S. Lee2, J.-H. Ahn3, J. Sohn4, J. S. Ahn5, J. H. Kim6, M. H. Lee7, K. E. Lee8, S.-Y. Kim9, S. B. Kim3, Y.-H. Im5, J. Ro2, H.-S. Park10 1 Seoul National University Hospital, 2National Cancer Center, 3Asan Medical Center, 4Yonsei University College of Medicine, Severance Hospital, 5Samsung Medical Center, 6Seoul National University Bundang Hospital, 7Inha University Hospital, 8Ewha Womans University Medical Center, 9Kyung-Hee University Hospital, 10Soon Chun Hyang University Hospital Background: Oxaliplatin, a platinum analogue, is an active drug in advanced anthracycline and taxane-pretreated breast cancer patients as a single agent and with 5-fluorouracil (5-FU) combination. TS-1 was developed by the scientific theory of both potentiating antitumor activity of 5-FU and reducing gastrointestinal toxicity. This trial was carried out to evaluate the efficacy and safety of TS-1 in combination with oxaliplatin in metastatic breast cancer (MBC) patients previously treated with anthracycline (A) and taxane (T) chemotherapy (CTx). Methods: Between October 2007 and October 2009, MBC patients were enrolled in this prospective multicenter trial. Eligible criteria included age >18 years, at least one measurable lesion, prior treatment with A and T CTx, and ECOG PS 0-2. TS-1 40 mg/m2 bid on D1-14 with oxaliplatin 130 mg/m2 on D1 were administered every 3 weeks till disease progression. Primary end-point was response rate (RR), and secondary end-points were time-to-progression (TTP), overall survival (OS), duration of response (DOR) and toxic effects. Response was evaluated every 6 weeks according to the RECIST criteria v.1.0 and toxicity was assessed with NCICTCAE v.3.0. (ClinicalTrials.gov identifier NCT00527930.) Results: A total of 87 patients were enrolled. Median age was 48 (range 30–71) years. Nineteen patients (21.8%) had de novo stage IV and 68 patients (78.2%) had recurrent disease. Forty-eight patients (55.2%) had ≥3 disease sites. Fifty-four patients (62.1%) were hormone receptor positive, and 25 patients (28.7%) were triple negative. Five patients received prior anti-HER2 therapy. A total of 525 cycles were administered (median 6, range: 1–22+ cycle). In per-protocol analysis, the overall RR was 38.5% (CR 0%, PR 38.5%) and the disease control rate (CR, PR, and SD) was 67.9%. Median TTP, OS, and DOR were 6.0, 19.4, 6.6 months, respectively. The RR did not differ by triple negativity (39.1% in TNBC versus 38.2% in non-TNBC, P = 0.361). Reported grade 3 or 4 toxic effects ( per cycle) were neutropenia (10.3%), thrombocytopenia (5.5%), diarrhea (1.9%), vomiting (1.9%), and stomatitis (0.2%). There was no treatment-related death. Conclusions: SOX is an effective regimen in anthracycline and taxane pretreated MBC patients with manageable toxic effects.
xi | abstracts
IS2
6
BOLERO-2: A RANDOMIZED PHASE III STUDY OF EVEROLIMUS IN COMBINATION WITH EXEMESTANE: RESULTS OF THE JAPANESE SUBGROUP ANALYSIS
Y. Ito1, N. Masuda2, H. Iwata3, H. Mukai4, J. Horiguchi5, Y. Tokuda6, K. Kuroi7, H. Iwase8, H. Inaji9, S. Ohsumi10, T. Nakayama11, S. Ohno12, T. Sahmoud13, N. Ohno14, S. Noguchi11 1 Cancer Institute Hospital of JFCR, 2National Hospital Organization Osaka National Hospital, 3Aichi Cancer Center Hospital, 4National Cancer Center Hospital East, 5Gunma University Hospital, 6Tokai University Hospital, 7Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, 8 Kumamoto University Hospital, 9Osaka Medical Center for Cancer and Cardiovascular Diseases, 10National Hospital Organization Shikoku Cancer Center, 11Osaka University Hospital, 12National Kyushu Cancer Center, 13 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 14Novartis Pharma K.K. Background: BOLERO-2, an international, phase III study in patients with locally advanced or metastatic breast cancer refractory to non-steroidal aromatase inhibitor therapy, previously reported that the addition of everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) (6.9 versus 2.8 months; HR = 0.43; P < 0.001) versus EXE alone by local assessment (Baselga J, et al. N Eng J Med 2011). This report presents data from the Japanese subpopulation. Methods: Eligible patients were randomized (2:1) to EVE (10 mg/day) or matching placebo (PBO), with both arms receiving EXE (25 mg/day). Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was PFS by local assessment. Secondary end points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety. Results: Of the 724 patients from 24 countries enrolled in this study, 106 patients were Japanese, of whom 71 and 35 were assigned to EVE + EXE or PBO + EXE, respectively. Data from this Japanese subpopulation are presented. The addition of EVE to EXE prolonged median PFS (8.4 months versus 4.1 months; P = 0.025), increased ORR (16.9% versus 0%), and CBR (43.7% versus 25.7%) compared with EXE alone. In the EVE + EXE arm, most common grade 3/4 adverse events included stomatitis (9.9%), anemia (5.6%), and aspartate aminotransferase increased (4.2%). The incidence of non-infective lung-related adverse events was 31.0%, which was higher than in the overall population. The majority of these events were grade 1 or 2. Most patients showed recovery or relief after dose reduction or interruption, administration of corticosteroids, or oxygen therapy. Conclusion: Japanese patients in the BOLERO-2 trial treated with EVE + EXE showed similar PFS benefits as the overall population and a manageable safety profile. Thus, EVE + EXE is a promising new therapeutic option for Japanese women with advanced breast cancer.
IS2
7
CLINICAL EVALUATION OF PERTUZUMAB, A NEW HER2 TARGETED AGENT, IN BREAST CANCER
Y. Sasaki Division of Medical Oncology, Department of Medicine, Showa University School of Medicine Trastuzumab improves the outcome in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, most patients with advanced disease eventually progress and new treatment options for trastuzumab-resistant population are warranted. Pertuzumab, a humanized monoclonal antibody, prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. In addition, pertuzumab has complementary mechanism of action with that of trastuzumab. A combination of pertuzumab and trastuzumab showed more potent anti-tumor activity in a HER2-positive breast cancer xenograft model KPL-4 than either pertuzumab or trastuzumab alone. Thus, the combination strategy of the two antibodies is expected to have higher efficacy in HER2-positive breast cancer patients. Since a phase II study of pertuzumab–trastuzumab combination regimen showed meaningful efficacy (ORR 24.2%) in HER2-positive MBC patients who had progressed during trastuzumab treatment, a phase III study (CLEOPATRA) was conducted. The study compares the efficacy and safety of pertuzumab + trastuzumab + docetaxel with those of placebo + trastuzumab + docetaxel, in the first-line setting for patients with HER2-positive MBC. The primary end point was independently assessed progression-free survival (PFS). The median PFS of the pertuzumab arm was 18.5 months and was significantly longer than that of the control arm, 12.4 months. The interim analysis of overall survival showed a strong trend in favor of the pertuzumab group. Although the rates of febrile neutropenia and diarrhea of grade 3 or greater were higher in the pertuzumab group than in the control group, adding pertuzumab to trastuzumab and docetaxel had an acceptable tolerability profile with no increase in left ventricular systolic dysfunction. Pertuzumab is currently being studied in early breast cancer in combination with trastuzumab, and also in first-line metastatic breast cancer in combination with T-DM1, an antibody drug conjugate of trastuzumab and a maytansinoid, DM1.
Volume 23 | Supplement 11 | October 2012
Downloaded from http://annonc.oxfordjournals.org/ at Simon Fraser University on April 23, 2015
newer chemotherapies, comparative studies addressing the efficacy between anthracyclines and non-anthracyclines in the first-two lines of palliative chemotherapy for DNMBC were lacking. Methods: We collected clinicopathological characteristics of DNMBC patients who had received palliative chemotherapy in National Taiwan University Hospital between 2001 and 2006. Patients were classified as anthracycline or non-anthracycline group according to the first-two lines of chemotherapy. Kaplan–Meier method and log-rank test were used for the estimation and comparison of both overall survival (OS) and time to treatment failure of the first-two lines (TTF2). Cox proportional hazard model was used for OS and TTF2. Best composite response rate (BCRR) were compared with the logistic regression test. Results: A total of 121 patients, 58 (47.9%) in the anthracycline group and 63 (52.1%) in the non-anthracycline group, were analyzed. Between these two groups, the distributions of clinicopathological variables were generally similar. The median OS (33.1 versus 36.7 months, P = 0.91), median TTF2 (13.6 versus 17.2 months, P = 0.80), and BCRR (67.2 versus 66.7%; odds ratio 1.03, 95% CI 0.48–2.19, P = 0.95) were not significantly different. In multivariate analysis, early treatment with anthracyclines (anthracycline group) did not translated into improvements in OS (HR 1.02, 95% CI 0.64–1.63, P = 0.93) and TTF2 (HR 1.12, 95% CI 0.70–1.79, P = 0.65). Conclusion: Our study is the first study to demonstrate that anthracyclines may not be mandatory in the first-two lines of palliative chemotherapy for DNMBC. Future prospective studies are needed to evaluate the most proper early palliative chemotherapy for DNMBC patients in terms of both efficacy and toxicity.
Annals of Oncology