1. Response-Guided Neoadjuvant Chemotherapy for Breast Cancer Gunter von Minckwitz, Jens Uwe Blohmer, Serban Dan Costa, Carsten Denkert, Holger Eidtmann Journal of clinical oncology 2013 Vol. 31 R2 박현영 / Prof. 김시영 R2 박현영 / Prof. 김시영

2. Introduction Response to systemic treatment in early breast cancer can be monitored if treatment is given before surgery Response to systemic treatment in early breast cancer can be monitored if treatment is given before surgery Neoadjuvant, compared with adjuvant approaches, have so far failed to produce long-term advantages for patients Neoadjuvant, compared with adjuvant approaches, have so far failed to produce long-term advantages for patients

3. Introduction French study French study Survival of patients not responding to an initial neoadjuvant regimen, but responding to a different second neoadjuvant regimen Survival of patients not responding to an initial neoadjuvant regimen, but responding to a different second neoadjuvant regimen Similar to the survival of responders to the initial regimen Similar to the survival of responders to the initial regimen Survival in nonresponders to either regimen was worst Survival in nonresponders to either regimen was worst The Aberdeen phase II study The Aberdeen phase II study neoadjuvant treatment with docetaxel for patients initially receiving anthracycline-based neoadjuvant treatment neoadjuvant treatment with docetaxel for patients initially receiving anthracycline-based neoadjuvant treatment The pathologic complete response (pCR) rate was highest in responders who switched to docetaxel and lowest in nonresponders The pathologic complete response (pCR) rate was highest in responders who switched to docetaxel and lowest in nonresponders

4. Introduction GeparTrio study GeparTrio study Clinical responders to the initial two cycles of anthracycline-taxane– based chemotherapy were considered chemosensitive and were therefore randomly assigned to an additional four or six cycles of the same regimen. Clinical responders to the initial two cycles of anthracycline-taxane– based chemotherapy were considered chemosensitive and were therefore randomly assigned to an additional four or six cycles of the same regimen. Nonresponders were considered resistant to this initial regimen and were therefore randomly assigned to remain on the same regimen or switch to a non–cross-resistant regimen Nonresponders were considered resistant to this initial regimen and were therefore randomly assigned to remain on the same regimen or switch to a non–cross-resistant regimen Study’s long-term survival data according to early tumor response and biologically defined subtypes Study’s long-term survival data according to early tumor response and biologically defined subtypes

5. RESEARCH DESIGN AND METHODS Primary objectives Primary objectives Compare pCR rates in responders and clinical response rates in nonresponders Compare pCR rates in responders and clinical response rates in nonresponders Secondary objectives Secondary objectives Disease-free survival (DFS) and overall survival (OS) determination Disease-free survival (DFS) and overall survival (OS) determination

6. RESEARCH DESIGN AND METHODS Histologic confirmation of the diagnosis by core biopsy Histologic confirmation of the diagnosis by core biopsy Age less than 36 years Age less than 36 years Clinical tumor size more than 5cm Clinical tumor size more than 5cm Estrogen receptor (ER) and progesterone receptor (PR) negativity Estrogen receptor (ER) and progesterone receptor (PR) negativity Clinical axillary node involvement Clinical axillary node involvement Undifferentiated tumor grade Undifferentiated tumor grade

7. RESEARCH DESIGN AND METHODS All patients started treatment with two cycles of docetaxel 75 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (TAC) All patients started treatment with two cycles of docetaxel 75 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (TAC) Clinical response was determined preferably by sonography or another clinical method Clinical response was determined preferably by sonography or another clinical method Early responders were randomly assigned to either four or six cycles of TAC Early responders were randomly assigned to either four or six cycles of TAC Nonresponders were assigned to either four cycles of TAC or four cycles of vinorelbine 25 mg/m2 on days 1 and 8 plus capecitabine 1,000 mg/m2 orally twice a day on days 1 through 14, every 3 weeks (NX) Nonresponders were assigned to either four cycles of TAC or four cycles of vinorelbine 25 mg/m2 on days 1 and 8 plus capecitabine 1,000 mg/m2 orally twice a day on days 1 through 14, every 3 weeks (NX)

8. RESEARCH DESIGN AND METHODS Clinical response was assessed by palpation, ultrasound, and mammography at the end of the second cycle and before surgery. Clinical response was assessed by palpation, ultrasound, and mammography at the end of the second cycle and before surgery. Reduction 50% in the product of the two largest perpendicular diameters of the primary tumor Reduction 50% in the product of the two largest perpendicular diameters of the primary tumor pCR was defined as no residual invasive and no noninvasive disease in any excised breast or regional node tissue pCR was defined as no residual invasive and no noninvasive disease in any excised breast or regional node tissue

9. Statistical analysis χ2 tests χ2 tests Fisher’s exact test Fisher’s exact test Kaplan-Meier product limit method Kaplan-Meier product limit method Cox proportional hazards model Cox proportional hazards model Multivariate Cox proportional hazards model Multivariate Cox proportional hazards model

10. Result

17. Discussion This is the first phase III study investigating response- guided neoadjuvant chemotherapy in early breast cancer This is the first phase III study investigating response- guided neoadjuvant chemotherapy in early breast cancer Both strategies, prolonging treatment of early responders with the same but prolonged chemotherapy and switching early nonresponders to non–cross-resistant chemotherapy, improve DFS Both strategies, prolonging treatment of early responders with the same but prolonged chemotherapy and switching early nonresponders to non–cross-resistant chemotherapy, improve DFS Further exploratory subgroup DFS and OS analysis reveals that the main beneficiaries of this strategy are patients with hormone receptor–positive tumors Further exploratory subgroup DFS and OS analysis reveals that the main beneficiaries of this strategy are patients with hormone receptor–positive tumors

18. Discussion we do not know whether the two strategies we explored would not also be active in the opposite response group we do not know whether the two strategies we explored would not also be active in the opposite response group Second, information on pretreatment HER2 status was unavailable in almost 20% and Ki-67 in almost 50% of patients, and all biomarkers were not assessed centrally Second, information on pretreatment HER2 status was unavailable in almost 20% and Ki-67 in almost 50% of patients, and all biomarkers were not assessed centrally Third, analysis by subgroups was planned retrospectively. Third, analysis by subgroups was planned retrospectively.

19. Discussion Fourth, because treatment effect was mainly observed in hormone receptor positive tumors, 5-year follow-up was probably too short to show similar effects on OS, which is longer in such patients Fourth, because treatment effect was mainly observed in hormone receptor positive tumors, 5-year follow-up was probably too short to show similar effects on OS, which is longer in such patients Fifth, we had to combine both response-guided and both conventional treatment groups for further exploratory analysis as sample size was calculated to show differences in pCR but not in survival Fifth, we had to combine both response-guided and both conventional treatment groups for further exploratory analysis as sample size was calculated to show differences in pCR but not in survival Finally, we do not know whether our results would have been different if HER2-positive patients had received today’s standard treatment with trastuzumab Finally, we do not know whether our results would have been different if HER2-positive patients had received today’s standard treatment with trastuzumab

20. Discussion The various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy. The various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy.

21. Conclusions This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor–positive tumors. If confirmed, the response-guided approach could provide a clinically meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer. This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor–positive tumors. If confirmed, the response-guided approach could provide a clinically meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer.