Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis

TLDR: In this paper, the authors compared the three most commonly used definitions of pathological complete response (ypT0 ypN0, ypT0/is ypNs0, and ypTsN0/IsYPN0) for their association with EFS and overall survival in clinical trials of neoadjuvant treatment of breast cancer.

About: This article is published in The Lancet.The article was published on 2014-07-12 and is currently open access. It has received 2793 citations till now. The article focuses on the topics: Surrogate endpoint & Breast cancer.

Figures

Figure 6: Trial-level correlation between treatment eff ect on pathological complete response and event-free survival or overall survival Each circle corresponds to one randomised comparison and the size of the circle represents the sample size. A=GeparQuattro (epirubicin plus cyclophosphamide followed by docetaxel then capecitabine vs epirubicin plus cyclophosphamide followed by docetaxel). B=GeparDuo. C=GeparQuattro (epirubicin plus cyclophosphamide followed by docetaxel and capecitabine vs epirubicin plus cyclophosphamide followed by docetaxel). D=EORTC 10994/BIG 1-00. E=PREPARE. F=NSABP B-27. G=responders in GeparTrio. H=non-responders in GeparTrio. I=AGO 1. J=NOAH.

Figure 1: Study profi le

Figure 3: Associations between three defi nitions of pathological complete response and event-free survival and overall survival We compared event-free survival and overall survival between patients who did and did not achieve a pathological complete response according to one of three defi nitions. Patients who did not achieve a pathological complete response are not shown. Number of patients who achieved a pathological complete response is listed for each pathological complete response defi nition. Patients could achieve pathological complete response according to more than one defi nition. ypT0 ypN0=absence of invasive cancer and in-situ cancer in the breast and axillary nodes. ypT0/is ypN0=absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ. ypT0/is=absence of invasive cancer in the breast, irrespective of ductal carcinoma in situ or nodal involvement. HR=hazard ratio.

Figure 2: Associations between pathological complete response and event-free survival and overall survival ypT0/is ypN0 defi nition of pathological complete response (ie, absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ). HR=hazard ratio.

Figure 4: Percentage of patients achieving pathological complete response (A) and HRs for overall survival (B), by subgroup Information about clinical tumour stage available for 11 869 patients, about clinical nodal status for 11 807 patients, about histological type for 10 263 patients, about tumour grade for 8035 patients, and about clinical tumour subtype for 5694 patients. ypT0/is ypN0 defi nition of pathological complete response used. No multiplicity adjustment was made. HR=hazard ratio.

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "Pathological complete response and long-term clinical benefit in breast cancer: the ctneobc pooled analysis" ?

Cortazar, Lijun Zhang, Michael Untch, Keyur Mehta, Joseph P Costantino, Norman Wolmark, Hervé Bonnefoi, David Cameron, Luca Gianni, Pinuccia Valagussa, Sandra M Swain, Tatiana Prowell, Sibylle Loibl, D Lawrence Wickerham, Jan Bogaerts, Jose Baselga, Charles Perou, Gideon Blumenthal, Jens Blohmer, Eleftherios P Mamounas, Jonas Bergh, Robert Justice, 

Q2. What future works have the authors mentioned in the paper "Pathological complete response and long-term clinical benefit in breast cancer: the ctneobc pooled analysis" ?

Standardisation of the defi nition of pathological complete response would allow planning and inter pretation of future neoadjuvant clinical trials intended to support drug approval. In the HER2-positive subgroup, the authors noted that the addition of one trial with increased treatment eff ects ( NOAH ) decreased the slope of the curve, suggesting a trial-level correlation between frequency of pathological complete response and long-term outcome could be identifi ed in future trials with more homogeneous populations and incorporation of targeted therapies. The authors propose four potential explanations for the fi nding that an increase in frequency of pathological complete response between treatment groups did not predict improved EFS and OS. As previously suggested,6,27 an acceptable surrogate endpoint should be correlated with outcome at both the individual and trial levels. 

Q3. What is the endpoint of choice for adjuvant trials?

The endpoint of choice for adjuvant trials has been disease-free survival, refl ecting the fact that patients are disease free at the time of randomisation. 

Q4. Why did the authors exclude patients with lowgrade, hormone-receptor-positive tumours?

The authors excluded patients with lowgrade, hormone-receptor-positive tumours because of low frequency of pathological complete response. 

Q5. How many patients were included in the pooled analysis?

1087 (55%) of 1989 patients with HER2-positive tumours included in the pooled analysis did not receive 1 year of adjuvant trastuzumab because they were treated before adjuvant trastuzumab trials were reported. 

Q6. How many patients were eligible for this study?

To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemo therapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. 

Q7. what is the eff ect on neoadjuvant chemotherapy?

The eff ect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. 

Q8. What is the definition of a pooled analysis?

The CTNeoBC pooled analysis is the fi rst large analysis in which primary source data has been used to assess the association between pathological complete response and EFS and OS at a trial level. 

Q9. What was the hazard ratio for the TECHNO trial?

Patients in the NOAH16 trial were randomly assigned to preoperative chemotherapy with or without trastuzumab, and those in the TECHNO22 trial received trastuzumab and chemo therapy followed by 1 year of adjuvant trastuzumab. 

Q10. what was the coefficient of determination between improvement in pathological complete response and OS?

The coeffi cient of determination (R²) between improvement in pathological complete response and EFS was 0·03 (95% CI 0·00–0·25), and that between improvement in pathological complete response and OS was 0·24 (0·00–0·70). 

Q11. What was the frequency of pathological complete responses in patients with low-grade, hormone-re?

As expected, frequency of pathological complete responses in patients with low-grade, hormone-receptorpositive tumours was low, and more than doubled in the high-grade hormone-receptor-positive subgroup (fi gure 4A). 

Q12. What was the frequency of pathological complete response in HER2-positive tumours?

Within the HER2-positive population, pathological com plete response was more common for hormone-receptor-negative tumours than for hormonereceptor-positive tumours, and with the addition of trastuzumab (fi gure 4A). 

Q13. What was the search strategy for breast cancer trials?

The authors searched PubMed, Embase, and Medline for reports of clinical trials of neoadjuvant treatment of breast cancer published between Jan 1, 1990, and Aug 1, 2011.