Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer

BackgroundA trial-level surrogate end point for a randomized clinical trial may allow assessment of the relative benefits of the treatment to be performed at an earlier time point and potentially with a smaller sample size. However, determining whether an end point is a reliable trial-level surrogate based on results of previous trials is not straightforward. The question of trial-level surrogacy is easily confused with the question of individual-level surrogacy, and this confusion can lead to controversy. A recent example concerns the evaluation of pathologic complete response (pCR) as a surrogate for event-free survival (EFS) and overall survival (OS) in early-stage breast cancer.Materials and methodsThe differences between individual-level surrogacy (i.e. for patients receiving a specific treatment, the surrogate end point predicts the definitive end point) and trial-level surrogacy (the results of the trial for the surrogate end point predict the results of the trial for the definitive end point) are discussed. Trial-level data used in two previous meta-analyses evaluating pCR as a trial-level surrogate for EFS and OS were re-analyzed using methods that appropriately account for the variability in pCR rates as well as the variability in the hazard ratios for EFS and OS.ResultsThere is no evidence that pCR is a trial-level surrogate for EFS or OS, nor is there evidence that pCR could be used reliably to screen out nonpromising agents from further drug development.ConclusionsAt present, neoadjuvant RCTs should continue to follow patients to observe EFS and OS to assess clinical benefit, and they should be designed with sufficient sample size to reliably assess EFS. However, one cannot rule out the possibility that future meta-analyses involving more trials and in which the patient population or class of treatments is restricted could suggest the validity of pCR as a trial-level surrogate for EFS or OS in some focused settings.     

Surrogate endpoints for overall survival in lung cancer trials: a review

Introduction: Intermediate endpoints are often used as primary endpoints instead of overall survival (OS) in lung cancer trials but they are not systematically validated as surrogate endpoints for OS.

Areas covered: The aim of the study was to review the studies which assessed potential surrogate endpoints for OS in lung cancer trials.

Expert commentary: Twenty studies were identified. In operable non-small cell lung cancer (NSCLC) (adjuvant trials) and locally advanced NSCLC (radiotherapy trials), one individual-patient data meta-analysis found a high correlation of disease-free survival (DFS) and progression-free survival (PFS) with OS at patient and trial level. In trials of adjuvant chemotherapy, correlation between disease-free survival DFS and OS were 0.83 at the individual level (95% CI 0.83–0.83) and 0.92 at trial level (95% CI 0.88–0.95). In locally advanced disease, correlation between PFS and OS was 0.77 to 0.85 at the individual level, and 0.89 to 0.97 at trial level. This study provides a ‘proof’ of the surrogacy of PFS and DFS on OS according to the IQWiG framework and the surrogacy of PFS and DFS on OS was classified level 2 according to Fleming hierarchy. In all the other setting, no endpoint was judged to be valid surrogate for OS.     

Down-staging depth score could be a survival predictor for locally advanced gastric cancer patients after preoperative chemoradiotherapy

ObjectiveThe predictive effect of preoperative chemoradiotherapy (CRT) is low and difficult in guiding individualized treatment. We examined a surrogate endpoint for long-term outcomes in locally advanced gastric cancer patients after preoperative CRT.MethodsFrom April 2012 to April 2019, 95 patients with locally advanced gastric cancer who received preoperative concurrent CRT and who were enrolled in three prospective studies were included. All patients were stage T_3/4N₊. Local control, distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were evaluated. Clinicopathological factors related to long-term prognosis were analyzed using univariate and multivariate analyses. The down-staging depth score (DDS), which is a novel method of evaluating CRT response, was used to predict long-term outcomes. ResultsThe median follow-up period for survivors was 30 months. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve predicted by the DDS was 0.728, which was better than the pathological complete response (pCR), histological response and ypN0. Decision curve analysis further affirmed that DDS had the largest net benefit. The DDS cut-off value was 4. pCR and ypN0 were associated with OS (P=0.026 and 0.049). Surgery and DDS are correlated with DMFS, DFS and OS (surgery: P=0.001, <0.001 and <0.001, respectively; and DDS: P=0.009, 0.013 and 0.032, respectively). Multivariate analysis showed that DDS was an independent prognostic factor of DFS (P=0.021).ConclusionsDDS is a simple, short-term indicator that was a better surrogate endpoint than pCR, histological response and ypN0 for DFS.     

Clinical endpoints in oncology - a primer

Clinical endpoints are essential for assessing the safety and efficacy of new cancer therapies. They are used by oncologists to help guide clinical decision making. While overall survival (OS) has frequently been regarded as the “gold standard” primary clinical endpoint, it’s utility is constrained by several disadvantages. The time-consuming nature of trials using OS has led to a recent push to explore surrogate clinical endpoints and their potential to serve as primary clinical endpoints in lieu of OS. Additionally, it is becoming evident that other endpoints add valuable information about quality of life and treatment failure as their use is becoming increasingly prevalent in oncology clinical trials. Without a doubt, the use of clinical endpoints will continue to expand and evolve as new cancer therapies are developed and novel treatments, including immunotherapy, draw interest. This review explores the roles of primary and surrogate clinical endpoints as well as the benefits and drawbacks of each specific endpoint. In addition, it directly compares the unique features of each suggesting some of the specific uses each one fulfills.     

Operable Breast Cancer of the Inner Hemisphere Is Associated with Poor Survival

Purpose

This study investigated the clinicopathological features of operable breast cancer lesions located in different hemispheres of the breast and determined related survival outcomes.

Methods

Data from 5,330 patients with invasive ductal carcinoma were retrospectively analyzed based on tumor location.

Results

The median follow-up time was 68 months (range, 18-176 months). Patients with breast cancer located in the outer hemisphere of the breast had lesions with more advanced nodal stages and more frequently received adjuvant chemotherapy than patients with breast cancer in the inner hemisphere. The 5-year disease-free survival (DFS) rates of patients with tumors located in outer versus inner hemispheres were 81.5% and 77.0%, respectively (p=0.004); the overall survival (OS) rates were 90.7% and 88.8%, respectively (p<0.001). The association between tumor location and the 5-year DFS rate was most apparent in node-positive patients (73.1% vs. 65.8% for outer vs. inner hemisphere lesions, p<0.001) and in patients with primary tumors greater than 2 cm in diameter (78.2% vs. 72.3%, p=0.002). Multivariate analysis showed that tumor location was an independent predictor of DFS (hazard ratio [HR], 1.23; p=0.002) and OS (HR, 1.28; p=0.006). There were no significant differences in 5-year DFS or OS rates between patients with outer versus inner hemisphere tumors when internal mammary node irradiation was performed.

Conclusion

This study demonstrated that tumor location was an independent prognostic factor for operable breast cancer. Internal mammary node irradiation is recommended for patients with breast cancer of the inner hemisphere and positive axillary lymph nodes or large primary tumors.     

Long-term outcome of the REMAGUS 02 trial,a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status

BackgroundThe REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS).Patients and methodsFrom 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106).ResultsMedian follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021).ConclusionCelecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.     

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Background:

Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment.

Methods:

We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed.

Results:

pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P<0.0001). DFS also differed significantly between patients receiving adjuvant trastuzumab or not (hazard ratio=4.84, 95% CI (2.52; 9.31), P<0.001). We analysed 199 patients given neoadjuvant and adjuvant trastuzumab. Multivariate analysis identified older age and hormone receptor-negative tumours as independent predictors of pCR. T stage (hazard ratio=2.55, 95% CI (1.01; 6.48), P=0.05) and strict pCR (hazard ratio=9.15, 95% CI (1.22; 68.83), P=0.03) were independent predictors of DFS. The latter association was significant in the HR-negative subgroup (P=0.02) but not in the HR-positive subgroup (P=0.12).

Conclusions:

Major pCR and DFS gains in HER2-positive BC were observed since ‘trastuzumab'' era. Further improvements rely on the enrollment of accurately selected patients into clinical trials.     

Association between Pathological Complete Response and Outcome Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients

Purpose

We aimed to determine the rate of pathological complete response (pCR), clinicopathological factors associated with pCR, and clinical outcomes following neoadjuvant chemotherapy in locally advanced breast cancer.

Methods

Medical records of patients who had undergone neoadjuvant chemotherapy for breast cancer between January 2007 and September 2011 were retrospectively reviewed, and the pCR rates were calculated according to three sets of criteria: the National Surgical Adjuvant Breast and Bowel Project (NSABP), the MD Anderson Cancer Center (MDACC), and the German Breast Group (GBG). Tumors were classified as luminal A like, luminal B like, human epidermal growth factor receptor 2 (HER2), or triple-negative. pCR and clinical outcome, including overall survival (OS) and disease-free survival (DFS) rates were analyzed at the median follow-up of 54.2 months.

Results

Of a total of 179 patients who had received neoadjuvant chemotherapy, 167 patients (93.3%) had locally advanced breast cancer and 12 patients (6.7%) had early-stage breast cancer. The majority of patients (152 patients, 89.4%) received anthracycline-based neoadjuvant chemotherapy. The objective clinical response rate was 61.5%, comprising clinical partial response in 5.5% and clinical complete response in 3.9% of patients. Twenty-one (11.7%), 20 (11.2%), and 17 patients (9.5%) achieved pCR according to NSABP, MDACC, and GBG definitions, respectively. pCR rates, as defined by NSABP, according to breast cancer subtype were 4.4%, 9.7%, 24.2%, and 19.2% in luminal A like, luminal B like, HER2, and triple-negative subtypes, respectively. Patients who achieved pCR had significantly better DFS (5-year DFS rates, 80% vs. 53%, p=0.030) and OS (5-year OS rates, 86% vs. 54%, p=0.042) than those who did not.

Conclusion

The pCR rate following neoadjuvant chemotherapy for breast cancer in Thai women attending our institution was 11.7%; pCR was more frequently observed in HER2 and triple-negative breast tumor subtypes. Patients who achieved pCR had significantly improved survival.     

Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study

Background:

Progesterone receptor (PR) expression assessment in early invasive breast cancer remains controversial. This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer; particularly in oestrogen receptor (ER)-positive, lymph node (LN)-negative disease.

Methods:

A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years (2000–2004) underwent surgery for primary invasive breast cancer with curative intent. Prospective data collection included patient demographics, pathology, ER and PR expression, HER2 status, adjuvant chemotherapy and endocrine therapy. Progesterone receptor expression was compared with (all causes) overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS).

Results:

Overall survival was 71.0% and BCSS was 83.0% at median follow-up of 8.34 years. Absent PR expression was significantly associated with poorer prognosis for OS, BCSS and DFS (P<0.0001, log-rank), even within the ER-positive, LN-negative group (hazard ratio for BCSS 3.17, 95% CI 1.43–7.01) and was not influenced by endocrine therapy. Cox''s regression analysis demonstrated that PR expression was an independent prognostic variable.

Conclusion:

Absence of PR expression is a powerful, independent prognostic variable in operable, primary breast cancer even in ER-positive, LN-negative patients receiving endocrine therapy. Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy.     

Identification and analysis of <Emphasis Type="Italic">CHEK2</Emphasis> germline mutations in Chinese <Emphasis Type="Italic">BRCA1/2</Emphasis>-negative breast cancer patients

Purpose

The estrogen receptor (ER) is involved in control of progesterone receptor (PgR) expression and lack of PgR may be also a surrogate of altered growth factor signaling. The aim of this study was therefore to investigate PgR expression as predictive factor for response to neoadjuvant therapy and long-term outcome.

Methods

Five thousand and six hundred and thirteen patients with primary breast cancer and positive ER expression from ten German neoadjuvant trials of anthracycline and taxane-based chemotherapy were included. Pathologic complete response (pCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and local recurrence-free survival (LRFS) were compared according to PgR expression.

Results

The lack of PgR expression (1172 patients) was associated with grade 3 (38.4 vs. 26.3%; p < 0.001), nodal involvement (>cN2) (6.8% vs. 4.7%; p = 0.004), and HER2 positivity (36.2 vs. 22.3%; p < 0.001). pCR rates of PgR-negative tumors were higher in the entire cohort (13.8 vs. 7.5%; p < 0.001) and in the HER2-negative subgroup (11.2 vs. 5.8%; p < 0.001). In multivariable logistic regression, PgR negativity was an independent predictive factor for pCR overall (OR 1.76; p < 0.001) and in the HER2-negative patients (OR 1.99; p < 0.001). Patients with PgR-negative disease had significantly worse outcome (p < 0.001, respectively). Multivariable Cox regression analysis revealed that PgR was an independent prognostic factor for DFS, OS, DDFS, and LRFS.

Conclusion

ER-positive/PgR-negative breast carcinomas are associated with higher response but also worse long-term outcome after neoadjuvant therapy. PgR negativity is an independent predictive factor for pCR after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer.

     

Evaluation of the Predictive and Prognostic Values of Stromal Tumor-Infiltrating Lymphocytes in HER2-Positive Breast Cancers treated with neoadjuvant chemotherapy

Background

Stromal tumor-infiltrating lymphocytes (sTILs) have been identified as a predictive biomarker for response to neoadjuvant chemotherapy (NAC) and prognosis in human epidermal growth factor receptor 2 (HER2)-positive breast cancers. However, standardized scoring methods for use in clinical practice need to be established, and the optimal threshold of sTILs to predict pathological complete response (pCR) and prognosis in HER2+ breast cancers has not yet been defined.

Objective

The predictive and prognostic values of sTILs in patients with HER2-positive breast cancer treated with NAC were evaluated, with the aim to explore the optimal thresholds of sTILs and to investigate the feasibility of scoring methods in clinical practice.

Patients and Methods

A total of 143 core needle biopsy specimens of HER2-positive invasive breast cancers obtained from Chinese patients who had been treated with trastuzumab-based NAC followed by surgery between 2009 and 2015 were extracted from the pathology database of Fudan University Shanghai Cancer Center. sTIL levels in the pre-NAC core needle biopsy specimens were scored using methods recommended by the International TILs Working Group 2014. The associations between sTILs and pCR, disease-free survival (DFS), and overall survival (OS) were evaluated, and the optimal thresholds for predictive and prognostic values of sTILs were analyzed.

Results

First, sTILs were associated with a higher pCR rate in HER2-positive breast cancers. Univariate (per 10% sTILs: odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.08, p?=?0.001) and multivariate regression analyses (per 10% sTILs: OR 1.04, 95% CI 1.00–1.07, p?=?0.034) indicated that sTILs as a continuous variable were a significant predictor of pCR in HER2-positive breast cancers. Receiver operating characteristics (ROC) curve analysis showed that a 20% threshold best distinguished the pCR subgroup from the non-pCR subgroup. The dichotomized sTILs with a threshold set at 20% was a strong predictor of pCR in the univariate (OR 0.25, 95% CI 0.12–0.52, p?<?0.001) and multivariate analyses (OR 0.35, 95% CI 0.14–0.87, p?=?0.024). Second, sTILs were associated with better prognosis in HER2-positive breast cancers. Univariate (DFS: hazard ratio [HR] 0.91, 95% CI 0.88–0.95, p?<?0.001; OS: HR 0.88, 95% CI 0.83–0.94, p?<?0.001), and multivariate analyses (DFS: HR 0.93, 95% CI 0.90–0.97, p?<?0.001; OS: HR 0.92, 95% CI 0.86–0.98, p?=?0.009) suggested that sTILs as a continuous variable had a strong predictive value for improved DFS and OS. As a binary variable with a threshold of 20%, univariate (DFS: HR 6.60, 95% CI 2.91–14.95, p?<?0.001; OS: HR 10.29, 95% CI 2.37–44.66, p?=?0.002) and multivariate analyses (DFS: HR 3.87, 95% CI 1.65–9.12, p?=?0.002; OS: HR 4.74, 95% CI 1.02–22.01, p?=?0.047) indicated that patients with ≥ 20% sTILs had a significantly better prognosis than the patients with < 20% sTILs.

Conclusions

Our study indicates that baseline sTILs scored by methods recommended by the International TILs Working Group in pre-NAC core needle biopsy specimens are significantly correlated with pCR and prognosis in HER2-positive breast cancers. A 20% threshold for sTILs may be a feasible diagnostic marker to predict pCR to NAC and prognosis in patients with HER2-positive breast cancers.

     

Identification of biology-based breast cancer types with distinct predictive and prognostic features: role of steroid hormone and HER2 receptor expression in patients treated with neoadjuvant anthracycline/taxane-based chemotherapy

Introduction

Reliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable breast cancer to test for associations with pathological complete response (pCR) and disease-free survival (DFS). Particularly, we evaluated if interactions between hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression might lead to a different clinical behavior of HR+/HER2+ co-expressing and HR+/HER2- tumors and whether subgroups of triple negative tumors might be identified by the help of Ki67 labeling index, cytokeratin 5/6 (CK5/6), as well as cyclooxygenase-2 (COX-2), and Y-box binding protein 1 (YB-1) expression.

Methods

Expression analysis was performed using immunohistochemistry and silver-enhanced in situ hybridization on tissue microarrays (TMAs) of pretherapeutic core biopsies.

Results

pCR rates were significantly different between the biology-based tumor types (P = 0.044) with HR+/HER2+ and HR-/HER2- tumors having higher pCR rates than HR+/HER2- tumors. Ki67 labeling index, confirmed as significant predictor of pCR in the whole cohort (P = 0.001), identified HR-/HER- (triple negative) carcinomas with a higher chance for a pCR (P = 0.006). Biology-based tumor type (P = 0.046 for HR+/HER2+ vs. HR+/HER2-), Ki67 labeling index (P = 0.028), and treatment arm (P = 0.036) were independent predictors of pCR in a multivariate model. DFS was different in the biology-based tumor types (P < 0.0001) with HR+/HER2- and HR+/HER2+ tumors having the best prognosis and HR-/HER2+ tumors showing the worst outcome. Biology-based tumor type was an independent prognostic factor for DFS in multivariate analysis (P < 0.001).

Conclusions

Our data demonstrate that a biology-based breast cancer classification using estrogen receptor (ER), progesterone receptor (PgR), and HER2 bears independent predictive and prognostic potential. The HR+/HER2+ co-expressing carcinomas emerged as a group of tumors with a good response rate to neoadjuvant chemotherapy and a favorable prognosis. HR+/HER2- tumors had a good prognosis irrespective of a pCR, whereas patients with HR-/HER- and HR-/HER+ tumors, especially if they had not achieved a pCR, had an unfavorable prognosis and are in need of additional treatment options.

Trial registration

ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00793377","term_id":"NCT00793377"}}NCT00793377     

Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results

Objective.

To compare the pathologic complete response (pCR) rate of patients treated with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting and to compare the delivered dose intensity, disease-free survival (DFS) and overall survival (OS) times, and toxicity between treatment arms in patients with breast cancer.

Methods.

Patients were randomized to receive preoperative FAC (5-FU, 500 mg/m²; doxorubicin, 50 mg/m²; cyclophosphamide, 500 mg/m²) every 21 days for four cycles or dose-intense FAC (5-FU, 600 mg/m²; doxorubicin, 60 mg/m²; cyclophosphamide, 1,000 mg/m²) plus G-CSF every 18 days for four cycles.

Results.

Two hundred two patients were randomly assigned. The median follow-up was 7.5 years. Patients randomized to FAC plus G-CSF had a higher pCR rate as well as clinical complete response rate; however, these differences were not statistically different from those with the FAC arm. Patients in the FAC + G-CSF arm had a higher delivered dose intensity of doxorubicin in the neoadjuvant and adjuvant settings than those in the standard FAC arm. DFS and OS times were not significantly different between the two groups. However, the OS and DFS rates were significantly higher for patients who achieved a pCR than for those who did not. Thrombocytopenia, febrile neutropenia, and infection rates were higher in the FAC + G-CSF arm.

Conclusions.

A higher delivered dose intensity of doxorubicin with the FAC + G-CSF regimen did not result in a statistically significant higher pCR rate. However, patients who achieved a pCR experienced longer DFS and OS times.     

Achieving higher pathological complete response rates in HER-2-positive patients with induction chemotherapy without trastuzumab in operable breast cancer

Recent trials of induction chemotherapy in bulky operable breast cancer have shown much higher pathological complete response (pCR) rates with trastuzumab-driven combinations. However, it is useful to take into account the specific chemosensitivity of HER-2-positive tumors. The aim of this study was to assess the pCR rate according to HER-2 status in response to chemotherapy, without an anti-HER-2 specific biological agent, in 710 operable breast cancer patients. Since 1982, these patients have been treated with several different neoadjuvant chemotherapy combinations. During this period, HER-2 overexpression was most often not assessed. Subsequently, we assessed HER-2 expression using archival paraffin-embedded tissue. A technically usable specimen was available for 413 of the 710 patients. Before treatment, 51 patients were HER-2 positive, 287 patients were HER-2 negative, and the results were inconclusive for 75 patients. Of these patients, a pCR in breast and nodes was obtained in 94 patients (14.3%), but this event was threefold more frequent for HER-2-positive patients (23.5%) than for HER-2-negative patients (7%). The overall survival (OS) and disease-free survival (DFS) rates at 10 years were 66.6% and 57.4%, respectively. The DFS rate was, as expected, better for HER-2-negative patients, with HER-2 status assessed before as well as after chemotherapy. A significant difference was found for OS in favor of HER-2-negative patients only with postchemotherapy assessment of HER-2, a fact similar to our previous findings. Finally, there was a tendency toward a higher DFS rate for HER-2-positive patients who achieved a pCR compared with HER-2-positive patients who did not.     

Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

Background  

Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL).     

Prognostic Value of the Nodal Ratio and Ki-67 Expression in Breast Cancer Patients Treated with Postmastectomy Radiotherapy

Purpose

This pilot study aimed to evaluate prognostic factors of postmastectomy radiotherapy (PMRT) for breast cancer patients undergoing systemic therapy in either preoperative or postoperative setting.

Methods

Between 2003 and 2009, 113 patients received PMRT: 61 underwent preoperative systemic therapy (PST subgroup) and 52 received postoperative systemic therapy (non-PST subgroup).

Results

The median follow-up time was 72.3 months (range, 34.0-109.4 months) for surviving patients. In univariate analysis of all patients, disease-free survival (DFS) was associated with age, nodal ratio (NR), and Ki-67 expression; overall survival (OS) was associated with NR and Ki-67 expression. Pathologic N stage and HER2 expression were marginally associated with DFS and OS. In the non-PST subgroup, DFS was associated with age, NR, venous invasion, and Ki-67 expression; OS was associated with age. In the PST subgroup, DFS was associated with ypN stage and NR; OS was associated with ypN, histologic grade, HER2 expression, and p53 expression. In multivariate analysis of all patients, DFS and OS were significantly associated with NR (p=0.003 and p=0.019, respectively) and Ki-67 expression (p=0.002 and p=0.015, respectively). Patients were classified into low-risk (NR ≤0.2 and Ki-67 ≤20%; n=34), intermediate-risk (NR >0.2 or Ki-67 >20%; n=63), and high-risk (NR >0.2 and Ki-67 >20%; n=16) subgroups. All low-risk patients were alive at the time of analysis. High-risk (p<0.001 and p=0.001, respectively) and intermediate-risk (p=0.022 and p=0.008, respectively) patients had significantly shorter DFS and OS than low-risk patients. This prognostic model was statistically significant for DFS when applied to the PST (p=0.001) and non-PST (p=0.016) subgroups separately.

Conclusion

For breast cancer patients undergoing PMRT, NR and Ki-67 are potential prognostic factors. A model using these factors might help predict a poor prognosis. Whether NR and Ki-67 are also prognostic for different setting of systemic therapy, preoperative or postoperative, warrants further study.     

Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2‐positive breast cancer

BACKGROUND:

The axillary pathologic complete response rate (pCR) and the effect of axillary pCR on disease‐free survival (DFS) was determined in patients with HER2‐positive breast cancer and biopsy‐proven axillary lymph node metastases who were receiving concurrent trastuzumab and neoadjuvant chemotherapy. The use of neoadjuvant chemotherapy is reported to result in pCR in the breast and axilla in up to 25% of patients. Patients achieving a pCR have improved DFS and overall survival. To the authors' knowledge, the rate of eradication of biopsy‐proven axillary lymph node metastases with trastuzumab‐containing neoadjuvant chemotherapy regimens has not been previously reported.

METHODS:

Records were reviewed of 109 consecutive patients with HER2‐positive breast cancer and axillary metastases confirmed by ultrasound‐guided fine‐needle aspiration biopsy who received trastuzumab‐containing neoadjuvant chemotherapy followed by breast surgery with complete axillary lymph node dissection. Survival was evaluated by the Kaplan‐Meier method. Clinicopathologic factors and DFS were compared between patients with and without axillary pCR.

RESULTS:

Eighty‐one patients (74%) achieved a pCR in the axilla. Axillary pCR was not associated with age, estrogen receptor status, grade, tumor size, initial N classification, or median number of lymph nodes removed. More patients with an axillary pCR also achieved a pCR in the breast (78% vs 25%; P < .001). At a median follow‐up of 29.1 months, DFS was significantly greater in the axillary pCR group (P = .02).

CONCLUSIONS:

Trastuzumab‐containing neoadjuvant chemotherapy appears to be effective in eradicating axillary lymph node metastases in the majority of patients treated. Patients who achieve an axillary pCR are reported to have improved DFS. The success of pCR with concurrent trastuzumab and chemotherapy in eradicating lymph node metastases has implications for surgical management of the axilla in these patients. Cancer 2010. © 2010 American Cancer Society.     

Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer

The aim of this study was to ascertain if oestrogen receptor (ER) status predicts for pathological complete response (pCR) to neoadjuvant chemotherapy in operable breast cancer, and the effects of pCR on survival. Using a single-institution database, 435 patients were identified, who received neoadjuvant chemotherapy for operable breast cancer and were eligible for the analysis. Patients whose tumours were ER negative were more likely to achieve a pCR than patients who were ER positive (21.6 vs 8.1%, P<0.001). Owing to a strong correlation between ER status and grade, these variables were not shown to be independent predictors of pCR. Overall survival (OS) was better in those patients who achieved a pCR compared to those who did not (5-year OS 91 vs 73%; P=0.02). This was still the case when only patients with ER-negative tumours were examined (5-year OS 90 vs 52%, P=0.005), but not in the subset of patients with ER-positive tumours (5-year OS 93 vs 79%; P=0.3). Therefore, patients with ER-negative tumours were found to be more likely to achieve a pCR to neoadjuvant chemotherapy than those with ER-positive tumours, and pathological response did not have prognostic significance in patients with ER-positive tumours.     

Moderate Immunohistochemical Expression of HER‐2 (2+) Without HER‐2 Gene Amplification Is a Negative Prognostic Factor in Early Breast Cancer

Background.

Human epidermal growth factor receptor (HER)-2 testing in patients with operable breast cancer is aimed at identifying candidates for adjuvant anti–HER-2 treatment. However, commonly defined “HER-2⁻” tumors express variable levels of the HER-2 protein, which can influence prognosis. We compared the clinical outcomes of operable breast cancer patients stratified according to a common HER-2 testing algorithm.

Methods.

We studied 1,150 women (median age, 58 years; range, 22–94 years) undergoing surgery for early breast cancer at our institution. HER-2 status was determined using the HercepTest™ (Dako, Glostrup, Denmark) and, when needed, by fluorescence in situ hybridization (FISH). Patients receiving adjuvant trastuzumab were excluded. The impact of HER-2 status on the disease-free survival (DFS) time was studied using multivariate Cox proportional regression analysis.

Results.

Four hundred-fifty seven (40%), 454 (39%), 116 (10%), and 123 (11%) patients were considered HER-2 0+, HER-2 1+, HER-2 2+/HER-2⁻ by FISH, and HER-2⁺ (3+ or HER-2⁺ by FISH), respectively. Compared with a HER-2 0 or 1+ status, a HER-2 2+/HER-2⁻ by FISH status was associated with a worse DFS outcome on multivariate analysis. Compared with a HER-2⁺ status, a HER-2 2+/HER-2⁻ status showed a time-dependent effect on the DFS probability, with an initial advantage that worsened every year by a factor of 1.649.

Conclusion.

A HER-2 2+/HER-2⁻ status is an adverse prognostic factor in patients with operable breast cancer. Because of suggestions from randomized trials that the benefits of adjuvant trastuzumab may not be limited to patients with HER-2⁺ tumors, patients with a HER-2 2+/HER-2⁻ status are ideal candidates for studies testing this hypothesis.