Imaging and Clinicopathologic Features Associated With Pathologic Complete Response in HER2-positive Breast Cancer Receiving Neoadjuvant Chemotherapy With Dual HER2 Blockade

BackgroundIn human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer, the incorporation of a dual HER2 blockade into neoadjuvant chemotherapy (NAC) has been shown to induce a higher rate of pathologic complete response (pCR). The purpose of this study was to investigate whether pretreatment imaging and clinicopathologic features show any association with pCR in HER2⁺ breast cancer receiving NAC plus dual blockade.Materials and MethodsThis retrospective study evaluated 94 consecutive patients (mean age, 49.8 ± 9.9 years) with HER2⁺ breast cancer who underwent NAC plus dual blockade with trastuzumab and pertuzumab between April 2016 and June 2018. All patients underwent mammography, ultrasound, and magnetic resonance imaging prior to NAC. Clinicopathologic and imaging features acquired before NAC were evaluated for their ability to predict the pathologic response after surgery. Multivariate analysis was used to identify independent predictors of pCR.ResultsFifty patients (53.2%) showed pCR and 44 (46.8%) did not. According to a univariate analysis, fine pleomorphic/fine linear or linear-branching calcification morphology on mammography, parallel orientation on ultrasound, intratumoral high signal intensity on T2-weighted magnetic resonance imaging, progesterone receptor negativity, and high levels of tumor-infiltrating lymphocytes were associated with pCR. On multivariate analysis, fine pleomorphic/fine linear or linear-branching calcification morphology on mammography (odds ratio [OR], 7.23), progesterone receptor negativity (OR, 6.76), and a high tumor-infiltrating lymphocyte level (OR, 5.92) remained significant independent factors associated with pCR.ConclusionSeveral pretreatment imaging and clinicopathologic features were shown to be independent variables predicting pCR in patients with HER2⁺ breast cancer receiving NAC with dual blockade.     

曲妥珠单抗联合新辅助化疗对HER-2阳性乳腺癌患者近远期疗效的影响

目的 探讨曲妥珠单抗联合新辅助化疗对表皮生长因子受体-2(HER-2)阳性乳腺癌患者的疗效.方法 选取HER-2阳性乳腺癌患者58例,随机分为观察组和对照组,各29例.对照组给予表柔比星联合多西他赛的方案进行新辅助化疗,观察组在对照组的基础上给予曲妥珠单抗治疗.比较两组患者的近期、远期疗效.结果 观察组有效率(RR)及病理完全缓解(pCR)率明显优于对照组,5年总生存率(OS)及5年无病生存率(DFS)明显高于对照组.结论 曲妥珠单抗联合新辅助化疗治疗HER-2阳性乳腺癌近期疗效显著,并可有效改善患者预后,值得临床推广应用.     

Treatment Strategies for Residual Disease following Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer

Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy.     

Immune Effective Score as a Predictor of Response to Neoadjuvant Trastuzumab Therapy and a Prognostic Indicator for HER2-Positive Breast Cancer

Background: HER2-positive breast cancer (BC) is a highly aggressive phenotype. The role of the host immune features in predictive response to anti-HER2 therapies and prognosis in BC has already been suggested. We aimed to develop a predictive and prognostic model and examine its relevance to the clinical outcomes of patients with HER2-positive BC. Methods: Immune effective score (IES) was constructed using principal component analysis algorithms. A bioinformatic analysis using four independent cohorts ({"type":"entrez-geo","attrs":{"text":"GSE66305","term_id":"66305"}}GSE66305, n = 88; {"type":"entrez-geo","attrs":{"text":"GSE130786","term_id":"130786"}}GSE130786, n = 110; TCGA, n = 123; METABRIC, n = 236) established associations between IES and clinical outcomes. Results: Genes associated with neoadjuvant trastuzumab therapy response were enriched in pathways related to antitumor immune activities. IES was demonstrated to be a predictive biomarker to neoadjuvant trastuzumab therapy benefits ({"type":"entrez-geo","attrs":{"text":"GSE66305","term_id":"66305"}}GSE66305: area under the curve (AUC) = 0.804; {"type":"entrez-geo","attrs":{"text":"GSE130786","term_id":"130786"}}GSE130786: AUC = 0.704). In addition, IES was identified as an independent prognostic factor for overall survival (OS) in the TCGA cohort (p = 0.036, hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.449–0.97) and METABRIC cohort (p = 0.037, HR: 0.9, 95% CI: 0.81–0.99). Conclusion: IES has a predictive value for response to neoadjuvant trastuzumab therapy and independent prognostic value for HER2-positive breast cancer.     

TCH方案术前新辅助化疗对HER-2阳性乳腺癌的疗效观察

目的 观察TCH方案术前新辅助化疗对HER-2阳性乳腺癌的近期疗效及毒副反应.方法 37例女性HER-2阳性乳腺癌患者给予TCH方案术前新辅助化疗,治疗3～4周期后进行疗效和毒副反应评价.结果 37例患者中CR 5例,PR 28例,NC 4例,PD 0例,有效率为89.2％.主要毒副反应:中性粒细胞减少22例(59.5％),恶心呕吐15例(40.5％),肝功能异常8例(21.6％).结论 TCH方案用于HER-2阳性乳腺癌患者术前辅助化疗疗效较好,毒副反应可耐受.     

Efficacy of Neoadjuvant Endocrine Therapy Versus Neoadjuvant Chemotherapy in ER-positive Breast Cancer: Results From a Prospective Institutional Database

BackgroundAlthough neoadjuvant chemotherapy (NACT) has been established as a standard for medically fit patients with locally advanced breast cancer, there has been renewed interest in utilizing neoadjuvant endocrine therapy (NET) for women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Rates of pathologic complete response (pCR) are known to be low, but data regarding down-staging and long-term outcomes are inconsistent.Patients and MethodsA prospective institutional database of patients with breast cancer treated with neoadjuvant therapy from 2012 to 2017 was analyzed to identify patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Patients who received NET were compared with those who received NACT. A matched analysis (age, stage, grade) was performed to compare rates of down-staging, pCR, breast conserving surgery, and CPS+EG scores.ResultsA total of 176 patients met eligibility criteria. Of these, 111 (63%) patients received NACT, 51 (29%) received NET, and 14 (8%) received both sequentially. Women prescribed NET were older (65.5 vs. 51.2 years; P < .0001) and presented with lower clinical stage (P < .0001). The median duration of NET was 90 days. When matched, clinical down-staging was more frequent with NACT (20/51; 39%) compared with NET (11/51; 22%) (P = .032). Of these, 2% achieved pCR in each cohort. Conversion rates to breast conserving surgery eligibility were low (8% and 13% with NET and NACT; P = .70). No significant differences in CPS+EG scores were identified.ConclusionsSignificantly higher rates of down-staging were achieved with NACT compared with NET when patients were matched. This study highlights the importance of establishing tumor biology and the need for biomarkers that can be used as predictive tools to inform treatment.     

Prevalence of HER-2-Positive Invasive Breast Cancer: A Systematic Review from Iran

Background: The HER-2/neu gene is altered in 15-20% of breast cancer patients. Immunohistochemistry (IHC)is considered to be the most cost-effective method for HER-2 detection in many countries. Approximately 8,000new cases of breast cancer are observed annually in Iran. The aims of this study were to conduct a systematicreview of the literature on the rate of HER-2-positive breast cancer diagnosed by IHC in Iran. Methods: Asystematic search of the medical literature using the Medline/PubMed, ISI and SID databases revealed articlespublished in the English and Persian languages evaluating HER-2-positive breast cancer in Iran. Results: From22 studies, 3,033 patients were evaluated, of whom 1,350 were diagnosed as HER-2-positive by IHC HER-2testing. The mean percentage of HER-2-positive patients was 44.5%, which is higher than that recorded ininternational statistics. Results of this meta-analysis showed a significant heterogeneity between ratios. There wasa statistically significant difference between the results of pre- and post implementation of 2007 American Societyof Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline. IHC HER-2 testing has beenperformed in Iran for over 10 years. Similar to many other countries, before establishment of an infrastructurefor IHC diagnostic tests, HER-2 testing was routinely performed in Iran. Our study showed that the statisticsreported from Iran varied widely; for instance, the rate of HER-2-positive cases varied from 23.3% to 81.0%.Conclusions: Our results demonstrate that the lack of standardization and harmonization of this test have ledto marked variations in breast cancer diagnosis in Iran.     

Neoadjuvant Pertuzumab-containing Regimens Improve Pathologic Complete Response Rates in Stage II to III HER-2/neu-positive Breast Cancer: A Retrospective,Single Institution Experience

Introduction

Several human epidermal growth factor 2 (HER2)-targeted regimens are used to treat HER2-positive (HER2⁺) breast cancer (BC). The goal of this study was to retrospectively determine the pathologic complete response (pCR) rate for trastuzumab and pertuzumab (HP)-containing regimens compared with trastuzumab (H)-containing regimens for stage II to III HER2⁺ BC.

Single-Agent Gemcitabine vs. Carboplatin-Gemcitabine in Advanced Breast Cancer: A Retrospective Comparison of Efficacy and Safety Profiles

Background

Single-agent gemcitabine is a moderately effective compound in metastatic breast cancer (mBC) treatment. Carboplatin is frequently used in addition to gemcitabine to improve tumor responses, but with an unclear effect on survival outcomes. In this study we evaluated the antitumor efficacy and safety profiles of gemcitabine and carboplatin-gemcitabine in mBC patients.

Predictors of Pathological Complete Response to Neoadjuvant Chemotherapy in Iranian Breast Cancer Patients

Background: Achievement of pathologic complete response (pCR) in breast cancer patients receiving neoadjuvant chemotherapy (NAC) is associated with both overall survival and disease-free survival. The aim of present study was to identify clinical and pathological factors associated with achieving pCR in Iranian breast cancer patients receiving NAC. Methods: A retrospective review of all breast cancer patients treated with neoadjuvant chemotherapy between April 2012 and September 2016 at our institution was performed; 207 cases were evaluable for analysis. pCR was defined as having no residual invasive tumor in the breast surgical specimen removed following neoadjuvant therapy. Results: In univariate analysis, factors associated with pCR were age less than 35 years (p = 0.03), absence of Lymphovascular invasion (LVI) (p = 0.002) and negative hormone receptor status (p = 0.003). Hormone receptor status (P = 0.01; OR, 2.45; CI, 1.20 - 4.99) and LVI (P = 0.001; OR, 0.22; CI, 0.10 - 0.46) remained predictive variables in multivariate analysis after correction for the other variables. Conclusions: In conclusion, the results of this study suggests that presence of Lymphovascular invasion and positive hormone receptor status are associated with poorer response to neoadjuvant chemotherapy in breast cancer patients.     

Evolving Role of Risk Tailored Therapy in Early Stage HER2-Positive Breast Cancer: A Canadian Perspective

The advent of HER2-targeted therapies has led to an important shift in the management of HER2-positive early breast cancer. However, initial treatment approaches apply uniform treatment regimens to all patients, with significant treatment-related and financial toxicities for both the patient and the health care system. Recent data demonstrates that for many patients, the chemotherapy backbone, duration and nature (mono- versus dual-targeted therapy) of the HER2 blockade can be better targeted to an individual patient’s risk of recurrence. We will provide a review of current data supporting risk tailored therapy in early stage HER2-positive breast cancer along with key completed and ongoing Canadian and international risk tailored trials. Neoadjuvant systemic therapy should now be considered for patients with clinical stage 2 disease, with greater use of non-anthracycline based chemotherapy regimens. Patients with residual disease following neoadjuvant therapy should be considered for escalated treatment with adjuvant T-DM1. Patients with stage I disease can often be managed with upfront surgery and evidence-based de-escalated adjuvant chemotherapy regimens. The modest benefit of 12- versus 6 months of adjuvant HER2 therapy and/or dual adjuvant HER2 therapy should be carefully weighed against the toxicities. All patients with HER2-positive breast cancer should be enrolled in ongoing risk tailored treatment trials whenever possible. Increasing data supports risk tailored therapy in early stage HER2-positive breast cancer in place of the routine application of aggressive and toxic systemic therapy regimens to all patients. While much progress has been made towards treatment de-escalation in appropriate patients, more is needed, as we highlight in this review. Indeed, Canadian-led clinical trials are helping to lead these efforts.     

曲妥珠单抗和帕妥珠单抗联合化疗对HER2阳性乳腺癌新辅助治疗的真实世界研究

目的 分析曲妥珠单抗(H)和帕妥珠单抗(P)联合化疗对HER2阳性乳腺癌新辅助治疗的疗效和安全性.方法 回顾性分析行HP联合化疗新辅助治疗并完成手术的HER2阳性乳腺癌患者的临床资料,主要研究终点为总体病理完全缓解(tpCR)(ypT0/isypN0),次要研究终点为乳腺病理完全缓解(bpCR)(ypT0/is)和腋窝...     

Clinical Implications of HER-2 and P53 in Taxane-Based and Anthracycline-Based Neoadjuvant Chemotherapy in Breast Cancer

Objective  To evaluate the predictive value of human epidermal growth factor receptor-2 (HER-2) and P53 in taxanebased and anthracycline-based neoadjuvant chemotherapy (NAC) in breast cancer. Methods  Sixty-two patients with breast cancer were included in this study. Twenty-two patients were treated with taxane-based (taxane group) and 40 with anthracycline-based (anthracycline group). ER, PR, c-erbB2 and P53 were detected by immunohistochemistry staining before NAC, and Fluorescence In Situ Hybridization(FISH) was used to detect the HER-2 gene amplification for the cases with the expression of c-erbB2 protein as (++) or (+++). The efficacy of the regimens was evaluated a er NAC. Results  In the anthracycline group, objective response (OR) was observed in 30 out of 40 patients (75%), whereas no response (NR) was observed in 10 patients (25%). In the taxane group, OR was observed in 15 patients out of 22 patients (68.2%), whereas NR was observed in 7 patients (31.8%). HER-2-negative status was correlated with a high OR in both taxane-based and anthracycline-based NAC (P = 0.023 and P = 0.029), whereas P53-negative status was correlated with high OR rate in anthracycline-based NAC (P = 0.041). The significant difference of the CR rates was observed between the patients took < 4 cycles and ≥ 4 cycles NAC (4.65% vs. 21.05%, P < 0.05). Conclusion  The patients with HER-2 gene non-amplication may be sensitive to both taxane-based and anthracycline-based chemotherapy; the patients without P53 overexpression may suitable to select anthracycline-based chemotherapy; and proper increased NAC cycles may increase CR rates. This work was supported by a grant from the Ministry of Public Health Scientific Research Foundation of China (No.WKJ2007-3-001).     

Retrospective Analysis of Neoadjuvant Chemotherapy for Breast Cancer in Turkish Patients

Background: Neoadjuvant systemic chemotherapy is the accepted approach for women with locally advancedbreast cancer. Anthracycline- and taxane-based regimens have been extensively studied in clinical trials andconsequently are widely used. In this study aimed to research the complete response (pCR) rates in differentregimens for neoadjuvant setting and determine associated clinical and biological factors. Methods: This studyincluded 63 patients diagnosed with breast carcinoma among 95 patients that had been treated with neoadjuvantchemotherapy between 2007 and 2010. TNM staging system was used for staging. The histologic response toneoadjuvant chemotherapy was characterized as a pCR when there was no evidence of residual invasive tumorin the breast or axillary lymph nodes. Biologic subclassification using estrogen receptor (ER), progesteronereceptor (PR), HER2 were performed. Luminal A was defined as ER+, PR+, HER2-; Luminal B tumor wasdefined as ER+, PR-, HER2-; ER+, PR-, HER2+; ER-, PR+, HER2-; ER+, PR+, HER2+; HER2 like tumorER-, PR+, HER2+; and triple negative tumor ER, PR, HER2 negative. Results: Patients median age was 54.14(min-max: 30-75). Thirty-two patients (50.8%) were premenapousal and 31 (49.2%) were postmenapousal.Staging was performed postoperatively based on the pathology report and appropriated imaging modalitiesThe TNM (tumor, lymph node, metastasis) system was used for clinical and pathological staging. Fifty-seven(90.5%) were invasive ductal carcinomas, 6 (9.5%) were other subtypes. Thirty nine (61.9%) were grade IIand 24 (38.1%) were grade III. Seven (11.1%) patients were stage II and 56 (88.9) patients were stage III. Thepatients were classified for ER, PR receptor and HER2 positivity. Seventeen patients had complete response tochemotherapy. Forty patients (63.5%) were treated with dose dense regimen (cyclophosphamide 600 mg/m2 anddoxorubicine 60 mg/m every two weeks than paclitaxel 175 mg/m2 every two weeks with filgrastim support) 40patients (48%) were treated anthracycline and taxane containing regimens. Thirteen patients (76%) from 17patients with pCR were treated with the dose dense regimen but without statistical significance (p=0.06). pCRwas higher in HER2(-), ER(-), grade III, premenopausal patients. Conclusion: pCR rate was higher in the groupthat treated with dose dense regimen, which should thus be the selected regimen in neoadjuvant setting. Someother factors can predict pCR in Turkish patients, like grade, menopausal status, triple negativity, percentageof ER positivity, and HER2 expression.     

Contrast-Enhanced Spectral Mammography Assessment of Patients Treated with Neoadjuvant Chemotherapy for Breast Cancer

Background: Evaluating the tumor response to neoadjuvant chemotherapy is key to planning further therapy of breast cancer. Our study aimed to evaluate the effectiveness of low-energy and subtraction contrast-enhanced spectral mammography (CESM) images in the detection of complete response (CR) for neoadjuvant chemotherapy (NAC) in breast cancer. Methods: A total of 63 female patients were qualified for our retrospective analysis. Low-energy and subtraction CESM images just before the beginning of NAC and as a follow-up examination 2 weeks before the end of chemotherapy were compared with one another and assessed for compliance with the postoperative histopathological examination (HP). The response to preoperative chemotherapy was evaluated based on the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Results: Low-energy images tend to overestimate residual lesions (6.28 mm) and subtraction images tend to underestimate them (2.75 mm). The sensitivity of low-energy images in forecasting CR amounted to 33.33%, while the specificity was 92.86%. In the case of subtraction CESM, the sensitivity amounted to 85.71% and the specificity to 71.42%. Conclusions: CESM is characterized by high sensitivity in the assessment of CR after NAC. The use of only morphological assessment is insufficient. CESM correlates well with the size of residual lesions on histopathological examination but tends to underestimate the dimensions.     

The Neutrophil to Lymphocyte Ratio has a High Negative Predictive Value for Pathologic Complete Response in Locally Advanced Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

Background: The neutrophil-to-lymphocyte ratio (NLR) is a strong predictor of mortality in patients withpancreatic, colorectal, lung, gastric cancer and renal cell carcinoma. The aim of this study was to determine therelationship between pathological complete response (pCR) and pretreatment NLR values in locally advancedbreast cancer (BC) patients receiving neoadjuvant chemotherapy (NACT). Materials and Methods: Datawerecollected retrospectively from the Akdeniz University School of Medicine Database for locally advanced BCpatients treated with NACT between January 2000- December 2013. Results: A total of 78 patients were analyzed.Sixteen (20%) patients achieved pCR. Estrogen receptor (ER) positivity was lower in pCR+ than pCR- cases(p=0.011). The median NLR values were similar in both arms. The optimum NLR cut-off point for BC patientswith PCR+ was 2.33 (AUC:0.544, 95%CI [0.401- 0.688], p=0.586) with sensitivity, specificity, positive predictivevalue and negative predictive value (NPV) of 50%, 51,6%, 21,1%, and 80%, respectively. Conclusions: This studyshowed no relationship between the pCR and pretreatment NLR values. Because of a considerable high NPV,in the patients with higher NLR who had luminal type BC in which pCR is lower after NACT, such treatmentmay not be recommended.     

HER-2 阳性晚期乳腺癌治疗策略

HER-2 阳性晚期乳腺癌患者预后差,以抗HER-2 靶向治疗为基础的综合治疗显著延长了患者的生存期、改善了预后。目前多种抗HER-2 靶向药物已应用于临床,抑制HER-2 通路是HER-2 阳性晚期乳腺癌患者一线治疗及一线治疗进展后的基础治疗。本文简要介绍HER-2 阳性晚期乳腺癌治疗相关的关键临床研究、指南推荐及今后的研究方向,以指导临床实践。     

Influence of Biologic Subtype of Inflammatory Breast Cancer on Response to Neoadjuvant Therapy and Cancer Outcomes

Background

Few data exist on the influence of tumor biologic subtype on treatment response and outcomes for inflammatory breast cancer (IBC). We examined a contemporary cohort of IBC patients treated with current targeted systemic therapies, selected on the basis of tumor biologic subtype, to evaluate pathologic treatment response and cancer outcomes across biologic subtypes.