Abstract

An intermediate endpoint is a surrogate marker of treatment efficacy assessed earlier than the true outcome of interest. A suitable intermediate endpoint in neoadjuvant trials of specific breast cancer subtypes is pathological complete response (pCR) rate, defined as no invasive (+/−noninvasive) residual cancer in breast and nodes at surgery. On the basis of available evidence, Food and Drug Administration the US allowed to use of pCR as a surrogate endpoint for accelerated approval process. However, surrogacy to long-term outcome remains an unresolved issue. Literature data provide indications that triple-negative, HER2-positive, and high-grade hormone receptor-positive breast cancer subtypes achieved the highest pCR rate; the prognostic impact of pCR on survival is established only for these aggressive subtypes. In the German experience, early response after two to four cycles of neoadjuvant treatment strongly correlated with both pCR rate and long-term outcome. Therefore, early response may be considered a predictive marker for pCR and used for driving clinical trial design.

Primary systemic therapy (PST) compared with adjuvant treatment offers potential advantages that include: increasing number of breast conserving surgery, assessment of early clinical and molecular response, and correlation between achieving clinical/pathological response and long-term outcome (1).

Definition of “intermediate endpoint”

An endpoint is a clinical/laboratory outcome measured in a patient after randomization that allows one to assess the effect of an independent variable (ie, a new drug) on a dependent variable (ie, survival). An intermediate endpoint is a surrogate marker of treatment efficacy assessed earlier than the true outcome of interest and it is hypothesized to be in the middle of the causal sequence relating the independent variable to the dependent variable (2).

Endpoints and Drug Approval

A recent analysis of DiMasi et al. (3) estimated that the clinical success rate of oncology drug approval in solid tumor indications is 9.8%. This relatively high failure rate could have different explanations: the less certainty regarding the correlation between intermediate endpoints and regulatory endpoints is a not negligible one.

Historically, new drugs for breast cancer have been approved on the basis of adequate clinical trials demonstrating a relevant clinical benefit, such as improvement in disease-free survival and overall survival (OS). However, choice of OS as a primary endpoint can greatly increase study size, duration, and costs.

Recent financial analyses showed that development cost has increased dramatically and the development approached used over the past decades is no more sustainable (4). Thus, intermediate endpoints reasonably likely to predict clinical benefit are used as primary endpoint in clinical trials (5).

The earliest indicator of treatment efficacy is a drug-induced tumor size decrease (6). However, clinical response is a weaker prognostic parameter than pathological complete response (pCR); thus, complete response rate after PST is frequently used as an intermediate endpoint in neoadjuvant setting (5).

Several meta-analyses indicated that the risk of death among patients who attain a pCR is lower than the risk of patients with residual tumor at the time of surgery; patients who achieved a pCR have a more favorable long-term outcome, such as disease-free survival and OS (7–10).

Even if data did not establish the surrogacy of pCR, the Food and Drug Administration allowed using pCR as a surrogate endpoint for accelerated approval process.

Definition of pCR

No standard definition of pCR exists among different studies. The German study groups defined pCR as no invasive or noninvasive residual cancer in breast and nodes (ypT0 ypN0) (11), but other international study groups allowed noninvasive residual in breast and/or infiltrated lymph nodes (ypT0/is ypN0/+) (12–14).

A recent pooled analysis of 6377 subjects (8) examined the impact on survival of different pCR definitions and demonstrated that patients who attained ypT0 ypN0 experienced better disease-free survival (hazard ratio [HR] = 1.74; 95% confidence interval [CI] = 1.28 to 2.36; P < .001) and a trend in better OS (HR = 1.41; 95% CI = 0.87 to 2.29; P = .166) compared with patients who attained ypTis ypN0. Moreover, patients with residual infiltrated lymph nodes experienced the worst long-term outcome (Table 1).

Table 1.

Prognostic impact of different definition of pCR on disease-free survival and overall survival assessed by von Minckwitz et al. (8)*

pCR definitions Patients No. of patients with event DFS No. of patients who died OS 
N HR 95% CI P value HR 95% CI P value 
GBG definition (11) All patients 3938          
ypT0 ypN0 645 16.4 58 1.0   16 1.0   
No pCR 3293 83.6 735 4.04 3.07 to 5.31 <.001 371 7.39 4.45 to 12.3 <.001 
MD Anderson definition (18) All patients 3938          
ypT0/is ypN0 854 21.7 92 1.0   26 1.0   
No pCR 3084 78.3 701 3.51 2.79 to 4.40 <.001 361 5.99 3.99 to 9.00 <.001 
NSABP definition (19) All patients 3938          
ypT0/is ypN0/+ 979 24.9 131 1.0   48 1.0   
No pCR 2959 75.1 662 2.77 2.27 to 3.38 <.001 339 3.66 2.67 to 5.01 <.001 
French definition (20) All patients 3938          
ypT0/is/mic ypN0/+ 1340 34.0 221 1.0   303 1.0   
No pCR 2598 66.0 572 2.11 1.78 to 2.49 <.001 84 2.80 2.17 to 3.60 <.001 
pCR definitions Patients No. of patients with event DFS No. of patients who died OS 
N HR 95% CI P value HR 95% CI P value 
GBG definition (11) All patients 3938          
ypT0 ypN0 645 16.4 58 1.0   16 1.0   
No pCR 3293 83.6 735 4.04 3.07 to 5.31 <.001 371 7.39 4.45 to 12.3 <.001 
MD Anderson definition (18) All patients 3938          
ypT0/is ypN0 854 21.7 92 1.0   26 1.0   
No pCR 3084 78.3 701 3.51 2.79 to 4.40 <.001 361 5.99 3.99 to 9.00 <.001 
NSABP definition (19) All patients 3938          
ypT0/is ypN0/+ 979 24.9 131 1.0   48 1.0   
No pCR 2959 75.1 662 2.77 2.27 to 3.38 <.001 339 3.66 2.67 to 5.01 <.001 
French definition (20) All patients 3938          
ypT0/is/mic ypN0/+ 1340 34.0 221 1.0   303 1.0   
No pCR 2598 66.0 572 2.11 1.78 to 2.49 <.001 84 2.80 2.17 to 3.60 <.001 

*CI = confidence interval; DFS = disease-free survival; GBG = German Breast Group; HR = hazard ratio; NSABP = National Surgical Adjuvant Breast and Bowel Project; OS = overall survival; pCR = pathological complete response; ypT0 = no invasive or noninvasive residual breast cancer in breast; ypTis = no invasive residual breast cancer in breast; ypT1mic = invasive residual breast cancer in breast < 0.1cm; ypN0 = no invasive or noninvasive residual breast cancer in lymph nodes; ypN+ = invasive residual breast cancer in lymph nodes.

The Authors concluded that the definition of pCR that demonstrated the largest hazard ration for survival between patients with and without a pCR and associated with the most favorable outcome is ypT0 ypN0.

PCR and Breast Cancer Subtypes

In the pooled analysis performed by Houssami et al. (7) on 11695 patients from 30 studies, the pCR (ypT0 ypN0) rate was 18.9%, with a great difference among breast cancer subtypes. The odds of pCR were highest in HER2-positive/hormone receptor (HR)-negative tumors (38.9%), compared with 31.1% in triple-negative (TN), 18.7% in HER2-positive/HR-positive, and 8.3% in HR-positive/HER2-negative subtypes (7).

von Minckwitz et al. (8) reported that low proliferating HR-positive tumors showed no prognostic impact of pCR (ypT0 ypN0), whereas higher aggressive tumors (high-grade HR positive, HR negative/HER2 positive, and TN) showed a significant prognostic impact of pCR. Similarly, the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) meta-analysis highlighted that the association of pCR (ypT0/is ypN0) and survival was stronger in patients with HER2-positive and TN tumors, compared with less aggressive tumor subtypes (such as low-grade HR positive) (10). Both analyses reported conflicting results regarding HR-positive/HER2-positive tumors, where the association with survival appears to be less obvious.

The CTNeoBC analysis could not find a linkage of improvements of pCR rates by a randomized treatment and improvement of survival by the same treatment, which might be explained by the low absolute increase in pCR rates achieved in the majority of the examined studies.

Early Assessment of Response

In the GeparTrio study, early clinical response was assessed after two cycles of docetaxel, doxorubicin, and cyclophosphamide; overall 22.2% of patients showing an early response achieved pCR, compared with 5.6% of those who have no response after two docetaxel, doxorubicin, and cyclophosphamide cycles (15,16). A meta-analysis of seven German prospective studies showed that response to the first two to four cycles of PST correlated strongly with both disease-free survival and OS, especially in TN breast cancer patients (17) (Figure 1). These data suggest that early response to PST increases the probability to attain pCR and improves prognosis.

Figure 1. Prognostic impact of early tumor response after two TAC cycles on overall survival in triple-negative breast cancer. Reproduced from von Minckwitz et al. (17). TAC = docetaxel, doxorubicin, and cyclophosphamide.

Figure 1. Prognostic impact of early tumor response after two TAC cycles on overall survival in triple-negative breast cancer. Reproduced from von Minckwitz et al. (17). TAC = docetaxel, doxorubicin, and cyclophosphamide.

Conclusion

Available data highlighted that prognosis of patients with highly aggressive tumor who attain pCR is comparable to that of patients with less aggressive tumor (8,17). By contrary, in patients with low-grade HR-positive tumor achieving pCR do not affect on survival (7,8,10).

Therefore, pCR could be a suitable intermediate endpoint for patients with TN, high-grade HR-positive, and HER2-positive breast tumors but not for low-grade HR-positive tumors.

The worries about risk/benefit ratio of new neoadjuvant drugs may be managed by addressing clinical trials for patients who have the greater possibility of benefit and the higher risk of recurrence. Moreover, early response after two to four cycles of PST may be considered a predictive marker for pCR and used for driving clinical trial design.

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