Implications of constructed biologic subtype and its relationship to locoregional recurrence following mastectomy

Introduction

We examined the prognostic value of biologic subtype on locoregional recurrence (LRR) after mastectomy in a cohort of low risk women who did not receive adjuvant radiation therapy.

Methods

A total of 819 patients with invasive breast cancer underwent mastectomy from January 2000 through December 2005. No patient received preoperative chemotherapy. Estrogen receptor (ER) receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status were used to construct the following 4 subtypes: i) ER+ or PR+ and HER2- (HR+/HER2-), ii) ER+ or PR+ and HER2+ (HR+/HER2+), iii) ER- and PR- and HER2+ (HR-/HER2+)and iv) ER- and PR- and HER2- (HR-/HER2-). LRR-free survival was estimated by the Kaplan-Meier method. Cox proportional hazard models were used to evaluate the association between time-to-event outcomes and patient prognostic factors.

Results

At a median follow-up of 58 months, five-year cumulative incidence of LRR for the entire cohort was 2.5%. Subtype specific LRR rates were 1% for HR+/HER2-, 6.5% in HR+/HER2+, 2% for HR-/HER2+ and 10.9% for HR-/HER2- (P < 0.01). In HER-2+ patients (irrespective of ER/PR status), trastuzumab therapy was not associated with LRR-free survival. On multivariate analysis, one to three positive lymph nodes (HR 4.75 (confidence interval (CI) 1.75 to 12.88, P < 0.01), ?? 4 positive lymph nodes (HR23.4 (CI 4.64 to 117.94, P < 0.01), HR+/HER2+ (HR 4.26 (CI 1.05 to 17.33), P = 0.04), and HR-/HER2- phenotype (HR 13.87 (CI 4.96 to 38.80), P < 0.01) were associated with shorter LRR-free survival whereas age > 50 at diagnosis (HR 0.31 (CI 0.12 to 0.80), P = 0.02) was associated with improved LRR-free survival. Among the HR-/HER2- subtypes, five-year LRR incidence was 23.4% in patients with positive lymph nodes compared to 7.8% for lymph node negative patients (P = 0.01), although this association did not reach significance when the analysis was limited to HR-/HER2- women with only one to three positive lymph nodes (15.6% versus 7.8%, P = 0.11).

Conclusions

Constructed subtype is a prognostic factor for LRR after mastectomy among low risk women not receiving adjuvant radiation therapy, although rates of LRR remain low across subtypes. Patients with node positive, HR-/HER2- type tumors were more likely to experience LRR following mastectomy alone. Prospective studies to further investigate the potential benefit of adjuvant radiation therapy in these women are warranted.     

Local-regional control according to surrogate markers of breast cancer subtypes and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast conserving therapy

Introduction

Breast cancers of different molecular subtypes have different survival rates. The goal of this study was to identify patients at high risk for local-regional recurrence according to response to neoadjuvant chemotherapy and surrogate markers of molecular subtypes in patients undergoing breast conserving therapy (BCT).

Methods

Clinicopathologic data from 595 breast cancer patients who received neoadjuvant chemotherapy and BCT from 1997 to 2005 were identified. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression determined by immunohistochemistry were used to construct the following subtypes: ER+ or PR+ and HER2- (hormone receptor (HR)+/HER2-; 52%), ER+ or PR+ and HER2+ (HR+/HER2+; 9%), ER- and PR- and HER2+ (HR-/HER2+; 7%) and ER- and PR- and HER2- (HR-/HER2-; 32%). Actuarial rates were calculated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards models were used for multivariate analysis (MVA).

Results

After a median follow-up of 64 months, the five-year local-regional recurrence (LRR)-free survival rate for all patients was 93.8%. The five-year LRR-free survival rates varied by subtype: HR+/HER2- 97.0%, HR+/HER2+ 95.9%, HR-/HER2+ 86.5% and HR-/HER2- 89.5% (P = 0.001). In addition to subtype, clinical stage III disease (90% vs. 95% for I/II, P = 0.05), high nuclear grade (92% vs. 97% with low/intermediate grade, P = 0.03), presence of lymphovascular invasion (LVI) (89% vs. 95% in those without LVI, P = 0.02) and four or more positive lymph nodes on pathologic examination (87% vs. 95% with zero to three positive lymph nodes, P = 0.03) were associated with lower five-year LRR-free survival on univariate analysis. On MVA, HR-/HER2+ and HR-/HER2- subtypes and disease in four or more lymph nodes were associated with decreased LRR-free survival. A pathologic complete response (pCR) was associated with improved LRR-free survival.

Conclusions

Patients with HR+/HER2- and HR+/HER2+ subtypes had excellent LRR-free survival regardless of tumor response to neoadjuvant chemotherapy. Patients with HR-/HER2+ and HR-/HER2- subtypes with poor response to neoadjuvant chemotherapy had worse LRR-free survival after BCT. Additional study is needed to determine the impact of trastuzumab on local-regional control in HER2+ tumors. Our data suggest that patients with HR-/HER2- subtype tumors not achieving pCR may benefit from novel strategies to improve local-regional control.     

Pre-treatment hormonal receptor status and Ki67 index predict pathologic complete response to neoadjuvant trastuzumab/taxanes but not disease-free survival in HER2-positive breast cancer patients

Trastuzumab-containing neoadjuvant chemotherapy achieves a pathologic complete response (pCR) rate of about 40?% in HER2-positive breast cancers, and pCR predicts better survival. A cohort of 102 consecutive Chinese HER2-positive stage II/III patients with neoadjuvant trastuzumab/taxanes were retrospectively analyzed, to evaluate the role of hormonal receptor (HR) status and Ki67 index, along with other parameters, in pCR and survival prediction. pCR rate of the cohort was 44.1?% (45/102). Fifty-three patients were HR-positive and 49 were HR-negative. Median Ki67 index was 40?%, and 49 patients had a high Ki67 index (>40?%) whereas 53 had a low Ki67 index (??40?%). HR status and Ki67 index were confirmed as the only two parameters associated with pCR in multivariate analysis (hazard ratio?=?2.952; 95?% CI, 1.227?C7.105; P?=?0.016 for HR status and hazard ratio?=?2.583, 95?% CI 1.107?C6.026, P?=?0.028 for Ki67 index). Patients with coexisting HR-negative and high Ki67 index had higher pCR rate (69.2?%), compared to those with either HR-negative alone or high Ki67 alone (hazard ratio?=?3.038; 95?% CI, 1.102?C8.372; P?=?0.029), and to those with coexisting HR-positive and low Ki67 index as well (hazard ratio?=?7.071; 95?% CI, 2.150?C23.253; P?=?0.001). In a median follow-up duration of 25.9?months, 11 disease-free survival events (DFS) were recorded. pCR predicted better DFS (log rank P?=?0.018) and was the only significant factor in Cox regression analysis (hazard ratio?=?0.184; 95?% CI, 0.038?C0.893; P?=?0.036). Our study indicates that HR status and Ki67 index are predictors for pCR but not for DFS in HER2-positive patients with neoadjuvant trastuzumab/taxanes, which deserves further investigations.     

Prognosis of patients with advanced gastric cancer by HER2 status and trastuzumab treatment

Background

The purpose of this study was to evaluate the impact of human epidermal growth factor receptor 2 (HER2) status and trastuzumab treatment on the prognosis of patients with advanced gastric cancer (AGC).

Methods

We retrospectively analyzed 364 AGC patients who received systemic chemotherapy. To evaluate the impact of trastuzumab exposure during any type of chemotherapy, our analysis used time-varying covariates to avoid a possible lead-time bias.

Results

Among the 364 patients, 58 (15.9 %) were HER2-positive. The median overall survival of the HER2-positive patients treated with trastuzumab (n = 43) was significantly longer than that of the HER2-negative patients [n = 306; 24.7 vs. 13.9 months, with an adjusted hazard ratio (HR) of 0.58; 95 % confidence interval (CI), 0.36–0.95; P = 0.03]. Notably, 22 patients continued with trastuzumab beyond the date of progression. By contrast, the HER2-positive patients not treated with trastuzumab (n = 15) showed survival similar to that of the HER2-negative patients (13.5 vs. 13.9 months, with an adjusted HR of 1.04; 95 % CI, 0.52–2.11; P = 0.91). According to the multivariate analysis, exposure to trastuzumab was independently associated with a better prognosis (HR 0.56; 95 % CI; 0.33–0.93; P = 0.026).

Conclusions

Recent HER2-positive AGC patients have a better prognosis than HER2-negative patients, particularly when treated with trastuzumab.     

Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial

Introduction

The PACS01 trial has demonstrated that a docetaxel addition to adjuvant anthracycline-based chemotherapy improves disease-free survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel's benefit.

Methods

Tumor samples from 1,099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested.

Results

Progesterone receptor-negativity (HR = 0.66; 95% CI 0.47 to 0.92, P = 0.013), and Ki67-positivity (HR = 1.53; 95% CI 1.12 to 2.08, P = 0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67-positivity was associated with DFS improvement with docetaxel addition (adjusted HR = 0.51, 95% CI 0.33 to 0.79 for Ki67-positive versus HR = 1.10, 95% CI 0.75 to 1.61 for Ki67-negative tumors, P for interaction = 0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR = 1.16, 95% CI 0.73 to 1.84); the reduction in the relapse risk was 53% (HR = 0.47, 95% CI 0.22 to 1.01), 34% (HR = 0.66, 95% CI 0.37 to 1.19), and 12% (HR = 0.88, 95% CI 0.49 to 1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively.

Conclusions

In patients with node-positive EBC receiving adjuvant anthracycline-based chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity.     

Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy

Introduction

Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described.

Methods

Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy.

Results

Disease-free survival (DFS) was 75% after 5 and 61% after 10 years, respectively. Patients with HER2+ hormone receptor-positive (HR+ (hormone receptor-positive); ER+ (estrogen receptor-positive) or PR+ (progesterone receptor-positive)) disease had a significantly better DFS than patients with HER2+ HR- (ER-/PR-) disease (hazard ratio 0.72, P = 0.02). This difference was explainable by a significantly higher hazard of recurrence in years 1 to 5 in HER2+ HR- compared to HER2+ HR+ patients, with a mean risk of recurrence of 9%/year for HR- versus 5%/year in HR+ patients (hazard ratio 0.59, P = 0.002 for years 1 to 5). The high early risk of recurrence of HER2+ HR- patients declined sharply over time, so that it was similar to that seen in HER2+ HR+ patients in years 6 to 10 (hazard ratio 0.97, P = 0.92 for years 6 to 10).

Conclusions

Our results show that outcomes in HER2+ patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression. The very high early risk of relapse seen in HER2+ HR- patients is particularly relevant in health care settings with limited access to adjuvant anti-HER2 treatment. The event rates shown for subpopulations of HER2+ BC patients suggest that in resource-constrained environments patients with HER2+ HR- early BC should be prioritized for consideration of adjuvant anti-HER2 therapy.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-015-0568-1) contains supplementary material, which is available to authorized users.     

Do type 1 receptor tyrosine kinases inform treatment choice? A prospectively planned analysis of the TEAM trial

Background:

Epidermal growth factor receptors contribute to breast cancer relapse during endocrine therapy. Substitution of aromatase inhibitors (AIs) may improve outcomes in HER-positive cancers.

Methods:

Tissue microarrays were constructed. Quantitative analysis of HER1, HER2, and HER3 was performed. Data were analysed relative to disease-free survival and treatment using outcomes at 2.75 and 6.5 years.

Results:

Among 4541 eligible samples, 4225 (93%) had complete HER1–3 data. Overall, 5% were HER1-positive, 13% HER2-positive, and 21% HER3-positive; 32% (n=1351) overexpressed at least one HER receptor. In the HER1–3-negative subgroup, the hazard ratio (HR) for upfront exemestane vs tamoxifen at 2.75 years was 0.67 (95% confidence interval (CI), 0.52–0.87), in the HER1–3-positive subgroup, the HR was 1.15 (95% CI, 0.85–1.56). A prospectively planned treatment-by-marker analysis demonstrated a significant interaction between HER1–3 and treatment at 2.75 years (HR=0.58; 95% CI, 0.39–0.87; P=0.008), as confirmed by multivariate regression analysis adjusting for prognostic factors (HR=0.55; 95% CI, 0.36–0.85; P=0.005). This effect was time dependent.

Conclusion:

In the 2.75 years prior to switching patients initially treated with tamoxifen to exemestane, a significant treatment-by-marker effect exists between AI/tamoxifen treatment and HER1-3 expression, suggesting HER expression could be used to select appropriate endocrine treatment at diagnosis to prevent or delay early relapses.     

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.     

Effect Modification of Hormonal Therapy by p53 Status in Invasive Breast Cancer

Purpose

We aimed to confirm the prognostic and predictive value of p53 expression, particularly in invasive breast cancer patients, according to immunohistochemical hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status.

Methods

Immunohistochemical data for p53, estrogen receptor, progesterone receptor, and HER2 expression from a total of 15,598 patients were retrospectively retrieved from the web-based database of the Korean Breast Cancer Society. Overall survival (OS) and breast cancer-specific survival (BCSS) were calculated and compared using the Kaplan-Meier method and log-rank test, respectively. Multivariate analyses were performed using a stratified Cox proportional hazard regression model. A model evaluating interactions between p53 expression and both hormonal therapy and chemotherapy was used to determine the treatment benefit from both modalities.

Results

The prognostic value of p53 for OS and BCSS was most significant in the HR+/HER2- subgroup, with hazard ratios of 1.44 (95% confidence interval [CI], 1.08-1.93) and 1.47 (95% CI, 1.09-1.99), respectively. The p53 overexpression hazard ratios were of borderline significance for the HR+/HER2+ subgroup and were not significant for the HR-/HER2+ and HR-/HER2- subgroups. The model with interaction terms revealed that hormonal therapy significantly interacts with p53 status (p=0.002 and p=0.007 for OS and BCSS, respectively), suggesting an insignificant prognostic value for p53 status (p=0.268 and p=0.296 for OS and BCSS, respectively). An interaction between chemotherapy and p53 status was not found in this model.

Conclusion

p53 overexpression has independent prognostic value, particularly in cases of HR+/HER2- invasive breast cancer, which may be due to effect modification of hormonal therapy dependent on p53 status.     

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.

     

Impact of breast cancer subtypes on 3-year survival among adolescent and young adult women

Introduction

Young women have poorer survival after breast cancer than do older women. It is unclear whether this survival difference relates to the unique distribution of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2)-defined molecular breast cancer subtypes among adolescent and young adult (AYA) women aged 15 to 39 years. The purpose of our study was to examine associations between breast cancer subtypes and short-term survival in AYA women, as well as to determine whether the distinct molecular subtype distribution among AYA women explains the unfavorable overall breast cancer survival statistics reported for AYA women compared with older women.

Methods

Data for 5,331 AYA breast cancers diagnosed between 2005 and 2009 were obtained from the California Cancer Registry. Survival by subtype (triple-negative; HR+/HER2-; HR+/HER2+; HR-/HER2+) and age-group (AYA versus 40- to 64-year-olds) was analyzed with Cox proportional hazards regression with follow-up through 2010.

Results

With up to 6 years of follow-up and a mean survival time of 3.1 years (SD = 1.5 years), AYA women diagnosed with HR-/HER + and triple-negative breast cancer experienced a 1.6-fold and 2.7-fold increased risk of death, respectively, from all causes (HR-/HER + hazard ratio: 1.55; 95% confidence interval (CI): 1.10 to 2.18; triple-negative HR: 2.75; 95% CI, 2.06 to 3.66) and breast cancer (HR-/HER + hazard ratio: 1.63; 95% CI, 1.12 to 2.36; triple-negative hazard ratio: 2.71; 95% CI, 1.98 to 3.71) than AYA women with HR+/HER2- breast cancer. AYA women who resided in lower socioeconomic status neighborhoods, had public health insurance, and were of Black, compared with White, race/ethnicity experienced worse survival. This race/ethnicity association was attenuated somewhat after adjusting for breast cancer subtypes (hazard ratio, 1.33; 95% CI, 0.98 to 1.82). AYA women had similar all-cause and breast cancer-specific short-term survival as older women for all breast cancer subtypes and across all stages of disease.

Conclusions

Among AYA women with breast cancer, short-term survival varied by breast cancer subtypes, with the distribution of breast cancer subtypes explaining some of the poorer survival observed among Black, compared with White, AYA women. Future studies should consider whether distribution of breast cancer subtypes and other factors, including differential receipt of treatment regimens, influences long-term survival in young compared with older women.     

Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab

Background: The aim of this study was to compare the extent of pathologic response in patients with HER2-positive (HER2+) breast cancer treated with standard neoadjuvant chemotherapy, with or without trastuzumab (H), according to hormone receptor (HR) status.Patients and methods: We included 199 patients with HER2+ breast cancer from three successive cohorts of neo-adjuvant chemotherapy on the basis of paclitaxel (Taxol) (P) administered weekly (w) or three weekly (3-w), followed by 5-fluorouracil (F), doxorubicin (A) or epirubicin (E), and cyclophosphamide (C). Residual cancer burden (RCB) was determined from pathologic review of the primary tumor and lymph nodes and was classified as pathologic complete response (pCR) or minimal (RCB-I), moderate (RCB-II), or extensive (RCB-III) residual disease.Results: In HR-positive (HR+) cancers, a higher rate of pathologic response (pCR/RCB-I) was observed with concurrent H + 3-wP/FEC (73%) than with 3-wP/FEC (34%, P = 0.002) or wP/FAC (47%; P = 0.02) chemotherapy alone. In HR-negative (HR-) cancers, there were no significant differences in the rate of pathologic response (pCR/RCB-I) from 3-wP/FAC (50%), wP/FAC (68%), or concurrent H + 3-wP/FEC (72%).Conclusions: Patients with HR+/HER2+ breast cancer obtained significant benefit from addition of trastuzumab to P/FEC chemotherapy; pathologic response rate was similar to that seen in HR-/HER2+ breast cancers.     

First‐Line Treatment Patterns and Clinical Outcomes in Patients With HER2‐Positive and Hormone Receptor‐Positive Metastatic Breast Cancer From registHER

Background.

Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting.

Methods.

registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors.

Results.

HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22–0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27–1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42–0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36–0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54–1.21; adjusted OS HR: 0.48, 95% CI: 0.26–0.89).

Conclusions.

These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times.     

An independent survival prognostic role for human epidermal growth factor receptor 2 in gastric cancer: evidence from a meta-analysis

Background

Some studies have suggested that human epidermal growth factor receptor 2 (HER2) positive is associated with poor outcomes in gastric cancer (GC), whereas another inconsistent studies make the situation confused. This meta-analysis was performed to determine whether HER2 played an independent prognostic role in clinicopathological characteristics and survival outcomes of GC.

Patients and methods

Combination of GC and human epidermal growth factor 2 or HER2 or HER2/neu or erbB-2 or cerbB-2 or c-erbB2 or CD340 or p185 were used as key words. Data were compared according to the HER2 status. Time-to-event outcomes of overall survival (OS) were analyzed using Hazard Ratios (HRs) with fixed effect, while 5-year survival rate and clinicopathological factors were performed using odd ratios (OR) with random effect.

Results

Nighteen trials, from 1986 to October 2013, were identified by two independent authors. A total of 6344 GC patients were included in this meta-analysis, with 1148 HER2 protein overexpression or gene amplification. Comparison of 5-year survival of patients with HER2-positive status versus HER2-negative status showed that OR was 0.58 [95% confidence interval (CI), 0.37–0.91], and the result was significant (P = 0.02). The survival outcome of HER2 protein overexpression or gene amplification patients was worse than those with normal HER2 (HR 1.15; 95% CI 1.12–1.18; P < 0.00001). However, the difference of III–IV stage ratio between HER2-positive and HER2-negative patients was not significant (OR 1.44; 95% CI 0.95–2.18; P = 0.09) even in the subgroup analysis of Asia (P = 0.12 and Europe (P = 0.51).

Conclusion

HER2 protein overexpression or gene amplification in GC patients is associated with a poor survival outcome, and may play a role in GC tumorigenesis.

     

Defining prognosis for women with breast cancer and CNS metastases by HER2 status

BackgroundThe purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and central nervous system (CNS) metastases, the effect of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive disease and to compare this with that of patients with HER2-negative disease.MethodsFive hundred and ninety-eight patients with invasive breast cancer, CNS metastases and known HER2 status were identified. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan–Meier method, and Cox models were fitted to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics.ResultsIn the multivariable model, patients with HER2-negative disease [Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15–1.95, P = 0.003] and patients with HER2-positive disease who did not receive trastuzumab (HR 2.13, 95% CI 1.51–3.00, P < 0.0001) had shorter times to CNS metastases compared with patients with HER2-positive disease who had received trastuzumab as first-line therapy for metastases. Furthermore, patients with HER2-negative disease (HR 1.66, 95% CI 1.31–2.12, P < 0.0001) and patients with HER2-positive disease who had never received trastuzumab (HR 1.34, 95% CI 0.78–2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis.ConclusionIn our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.     

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study)

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85–90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36–5.21, P = 0.004 for cN2–3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15–2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22–3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43–4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16–4.20, P = 0.017 for cT3–4 vs. cT1–2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48–6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53–13.14, P = 0.005 for cN2–3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12–4.94, P = 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31–5.97, P = 0.006 and HR 3.86, 95 % CI 1.13–24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.     

MRI predicts pathologic complete response in HER2-positive breast cancer after neoadjuvant chemotherapy

Background

Neoadjuvant treatment of HER2-positive breast cancer frequently leads to a pathologic complete response (pCR), which is associated with favourable long-term outcome. Treatment regimens typically consist of 6–9 cycles of trastuzumab-based chemotherapy, although many patients achieve early radiologic complete response (rCR). If rCR accurately predicts pCR, the number of chemotherapy cycles can possibly be reduced.

Methods

We performed a diagnostic accuracy study to determine the association between rCR and pCR in patients with stage II–III HER2-positive breast cancer treated with neoadjuvant trastuzumab-based chemotherapy at the Netherlands Cancer Institute. RCR was defined as the disappearance of pathologic contrast enhancement in the original tumour region on repeated magnetic resonance imaging (MRI). PCR was defined as the absence of invasive tumour cells in the resected breast specimen (ypT0/is). Diagnostic accuracy was estimated in the overall population and in subgroups based on hormone receptor (HR) status. The prognostic value of rCR for recurrence-free interval was evaluated as an exploratory analysis.

Results

We identified 296 eligible patients with 297 HER2-positive tumours (154 HR-negative and 143 HR-positive) treated with neoadjuvant trastuzumab-based chemotherapy between 2004 and 2016. Overall, the rCR rate was 69% (206/297) and the pCR rate was 61% (181/297). Among 206 patients with rCR, 150 also had pCR (negative predictive value [NPV] = 150/206 = 73%). Among 91 patients without rCR, 60 had residual tumour at pathology (positive predictive value [PPV] = 60/91 = 66%). The NPV was better in HR-negative compared to HR-positive tumours (88 vs. 57%), while the PPV was better in HR-positive tumours (50 vs. 78%). Achieving rCR was associated with a 5-year recurrence-free interval of 88% compared to 68% without rCR (hazard ratio 0.34, 95% confidence interval 0.17–0.65, P = 0.001).

Conclusion

Achieving rCR corresponds well with pCR in HER2-positive breast cancer, particularly in the HR-negative subgroup. RCR is also associated with improved long-term outcome.

     

Combined Estrogen Receptor and Progesterone Receptor Level Can Predict Survival Outcome in Human Epidermal Growth Factor Receptor 2-positive Early Breast Cancer

BackgroundIn human epidermal growth factor receptor 2 (HER2)-positive breast cancer, emerging evidence imply that clinical behaviors differ according to hormone receptor (HR) status. However, there is no conclusion about the relevance between estrogen receptor (ER) or progesterone receptor (PR) expression and clinical outcome of HER2+ breast cancer. Our study aimed to determine the influence of different ER/PR levels on survival outcome of HER2+ early breast cancer.Patients and MethodsNine hundred and nineteen early HER2+ breast cancer patients treated between 2009 and 2016 were retrospectively reviewed and HR+/HER2+ patients were further divided based on ER level (Low/L: 1%-9%; Median/M: 10%-79%; High/H: 80%-100%) and PR level (Low/L: 0%-19%; High/H: 20%-100%) according to restricted cubic spline (RCS) smoothing curve. Disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan–Meier method and log rank test.ResultsFour hundred and forty two HR+/HER2+ and 477 HR-/HER2+ breast cancer patients were included in our study and 73.2% received target therapy (HR+ 69.7%, HR- 76.5%). While HR+/HER2+ breast cancer showed better survival than HR-/HER2+ subtype in 5-year disease free survival (DFS, 93.0% vs. 86.8%, P < .001), no significant difference was observed between DFS in ER+/PR+ and ER+/PR- subgroup (94.4% vs. 90.4%, P = .22). However, a potential correlation was found between ER/PR levels and DFS in HR+/HER2+ (P = .074) tumors. In HR+/HER2+ breast cancer, all subgroups showed DFS improvement trend versus M-ER/L-PR. In all HER2+ patients, hazard ratio of H-ER/H-PR compared with HR- subtype was 0.10 (95%CI 0.01-0.74, P = .024) in all patients and 0.14 (95%CI, 0.02-1.02, P = .053) in patients receiving anti-HER2 therapy.ConclusionER/PR expression may become a predictor of survival benefit in HER2+ early breast cancer and a higher ER/PR level might be associated with better DFS.     

Reproductive behaviors and risk of developing breast cancer according to tumor subtype: A systematic review and meta-analysis of epidemiological studies

BackgroundBreast cancer is composed of distinct subtypes defined mainly based on the expression of hormone receptors (HR) and HER2. For years, reproductive factors were shown to impact breast cancer risk but it is unclear whether this differs according to tumor subtype. In this meta-analysis we evaluated the association between parity, age at first birth, breastfeeding and the risk of developing breast cancer according to tumor subtype.MethodsPubMed and Embase were searched to identify epidemiological studies that evaluated the impact of parity and/or age at first birth and/or breastfeeding on breast cancer risk with available information on HR and HER2. Tumor subtypes were defined as: luminal (HR-positive, HER2-negative or HER2-positive), HER2 (HR-negative, HER2-positive) and triple-negative (HR-negative, HER2-negative). Summary risk estimates (pooled OR [pOR]) and 95% confidence intervals (CI) were calculated using random effects models. The MOOSE guidelines were applied.ResultsThis meta-analysis evaluated 15 studies, including 21,941 breast cancer patients and 864,177 controls. Parity was associated with a 25% reduced risk of developing luminal subtype (pOR 0.75; 95% CI, 0.70–0.81; p < 0.0001). Advanced age at first birth was associated with an increased risk of developing luminal subtype (pOR 1.15; 95% CI, 1.00–1.32; p = 0.05). Ever breastfeeding was associated with a reduced risk of developing both luminal (pOR 0.77; 95% CI, 0.66–0.88; p = 0.003) and triple-negative (pOR 0.79, 95% CI, 0.66–0.94; p = 0.01) subtypes.ConclusionsThe reproductive behaviors impact the risk of developing breast cancer but this varies according to subtype.     

Association between the HER2 Ile655Val polymorphism and response to trastuzumab in women with operable primary breast cancer

BackgroundHuman epidermal growth factor receptor 2 (HER2) Ile655Val polymorphism may affect the efficacy of trastuzumab treatment of breast cancer.Patients and methodsHER2 Ile655Val polymorphism was determined in 4167 patients with primary breast cancer using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay. We investigated the associations between the HER2 Ile655Val polymorphism and clinical outcomes in women with HER2-negative breast cancer and with HER2-positive breast cancer who received trastuzumab or who did not.ResultsAt a median follow-up of 44 months, HER2 Ile655Val polymorphism was not significantly associated with survival either in the entire study population of 4167 patients or in 2976 HER2-negative breast cancer patients. Among 816 HER2-positive patients who received adjuvant chemotherapy and/or endocrine therapy without trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly worse disease-free survival (DFS) and distant DFS (DDFS) than those with the Ile/Ile genotype (DFS, adjusted hazard ratio [HR] 1.5; 95% confidence interval [CI] 1.0–2.3; P = 0.037; DDFS, adjusted HR 1.9; 95% CI 1.2–2.9 P = 0.005). In contrast, among 212 HER2-positive patients who received chemotherapy in combination with trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly better DFS and DDFS than those with the Ile/Ile genotype (5-year DFS, 100% versus 83%; P = 0.008; 5-year DDFS, 100% versus 89%; P = 0.031).ConclusionsHER2 Ile655Val polymorphism affects the function of HER2 gene only restricted in HER2-positive breast cancers. HER2-positive breast cancer patients with the Val variant have an aggressive phenotype, but are sensitive to trastuzumab treatment.