SerpinB3, a new prognostic tool in breast cancer patients treated with neoadjuvant chemotherapy

It is unclear which patients with breast cancer benefit from anthracycline-based neoadjuvant chemotherapy and whether taxanes increase survival. Hsp70 and serpinB3 inhibit a lysosomal cell death pathway induced in anthracycline and taxane treated cells, which may be critical for breast cancer cell survival. Thus we evaluated serpinB3 and Hsp70 as putative prognostic biomarkers in breast cancer patients treated with neoadjuvant chemotherapy. SerpinB3 and Hsp70 were measured by immunohistochemistry in residual breast tumours of patients without a complete pathological response [pCR] (n = 250), from a retrospective cohort of 296 patients treated with anthracycline-based chemotherapy with or without sequential docetaxel prior to surgical resection. SerpinB3 (P = 0.02) and Hsp70 (P = 0.008) positivity in residual tumour were associated with a poor pathological response and serpinB3 was an independent prognostic biomarker (HR 2.1 (95% CI 1.2–3.8), P = 0.02). Docetaxel significantly improved overall survival of breast cancer patients treated with neoadjuvant chemotherapy. Furthermore, serpinB3 positivity predicted poor survival in patients treated with anthracycline-based chemotherapy alone (P = 0.02), but those with serpinB3 negative tumours had as equally good survival as those also treated with docetaxel (P = 0.7). Survival was independent of serpinB3 expression in patients who received sequential docetaxel. The Nottingham prognostic index (NPI), calculated at surgical resection, predicted overall survival in these neoadjuvantly treated patients (P < 0.001) and serpinB3 status segregated patients with a moderate NPI into distinct prognostic subgroups. The use of clinical (NPI) and molecular (serpinB3) biomarkers measured at surgical resection to provide accurate prognostication in patients who do not achieve a pCR following neoadjuvant chemotherapy could facilitate optimal post-operative clinical management of these patients and is of significant clinical value. Furthermore, serpinB3 status in residual tumour is a biomarker of neoadjuvant docetaxel benefit in patients not achieving a pCR and use of serpinB3 molecular subtyping for adjuvant docetaxel treatment planning warrants further investigation.     

DNA methylation of circulating DNA: a marker for monitoring efficacy of neoadjuvant chemotherapy in breast cancer patients

Identification of biomarkers for monitoring efficacy of neoadjuvant chemotherapy in breast cancer patients is of utmost importance in individual tailoring of treatment and save from toxicity due to non-effective drugs. We hypothesized that methylation of circulating tumor-specific DNA may reflect changes in tumor burden in response to chemotherapy and help stratify responders from non-responders. The aim of this study was to evaluate the potential of methylation changes in circulating DNA to monitor treatment response of breast cancer patients. Six consecutive sera samples collected from 30 breast cancer patients undergoing neoadjuvant chemotherapy were analyzed for methylation status of a panel of five genes namely, BRCA1, MGMT, GSTP1, Stratifin, and MDR1. Among these five genes, BRCA1 methylation frequency was different among responders and non-responders groups. The correlation coefficients between total gene methylation with initial chemotherapy and tumor volume reduction were R ²?=?0.8 and R ²?=?0.05 in the responders and non-responders groups, respectively. Our findings warrant further development of this approach for monitoring response in patients undergoing neoadjuvant chemotherapy.     

Post-neoadjuvant strategies in breast cancer: From risk assessment to treatment escalation

The post-neoadjuvant setting in early breast cancer represents an attractive scenario for adjuvant clinical trials, offering the opportunity to test new drugs or combinations in high-risk patients who did not achieve pathologic complete response after primary treatment. No standard therapies are routinely proposed to patients with residual disease after neoadjuvant chemotherapy and few trials have explored this setting. To date, only one randomized phase III study showed the benefit of additional capecitabine after neoadjuvant chemotherapy, and international guidelines recommend at least to consider its use, particularly for triple negative breast cancer. Therefore, the management of these patients is still a clinical challenge, with limited data supporting the use of an additional adjuvant non-cross-resistant chemotherapy. Escalation strategies are currently under evaluation, with new agents proposed as supplementary post-neoadjuvant treatment (e.g. platinum salts, capecitabine, poly ADP-ribose polymerase inhibitors, immune checkpoint inhibitors, cyclin-dependent kinase 4/6 inhibitors). Based on these premises, selection criteria are critical to identify patients who may benefit from post-neoadjuvant therapies, through the validation of prognostic and predictive biomarkers for a reliable risk assessment and estimation of benefit.The present review summarizes the efforts in introducing new therapeutic options for patients with breast cancer and residual disease after neoadjuvant treatment, with a particular focus on the ongoing clinical trials and useful biomarkers for risk stratification.     

Role of Positron Emission Tomography for the Monitoring of Response to Therapy in Breast Cancer

This review considers the potential utility of positron emission tomography (PET) tracers in the setting of response monitoring in breast cancer, with a special emphasis on glucose metabolic changes assessed with ¹⁸F‐fluorodeoxyglucose (FDG). In the neoadjuvant setting of breast cancer, the metabolic response can predict the final complete pathologic response after the first cycles of chemotherapy. Because tumor metabolic behavior highly depends on cancer subtype, studies are ongoing to define the optimal metabolic criteria of tumor response in each subtype. The recent multicentric randomized AVATAXHER trial has suggested, in the human epidermal growth factor 2‐positive subtype, a clinical benefit of early tailoring the neoadjuvant treatment in women with poor metabolic response after the first course of treatment. In the bone‐dominant metastatic setting, there is increasing clinical evidence that FDG‐PET/computed tomography (CT) is the most accurate imaging modality for assessment of the tumor response to treatment when both metabolic information and morphologic information are considered. Nevertheless, there is a need to define standardized metabolic criteria of response, including the heterogeneity of response among metastases, and to evaluate the costs and health outcome of FDG‐PET/CT compared with conventional imaging. New non‐FDG radiotracers highlighting specific molecular hallmarks of breast cancer cells have recently emerged in preclinical and clinical studies. These biomarkers can take into account the heterogeneity of tumor biology in metastatic lesions. They may provide valuable clinical information for physicians to select and monitor the effectiveness of novel therapeutics targeting the same molecular pathways of breast tumor.     

PD‐L1 expression of the residual tumor serves as a prognostic marker in local advanced breast cancer after neoadjuvant chemotherapy

This study sought to investigate the prevalence of programmed death ligand 1 (PD‐L1) and its prognostic value in patients with residual tumors after neoadjuvant chemotherapy (NCT) for locally advanced breast cancer. A total of 309 patients considered as non‐pathological complete responders (non‐pCR) after NCT followed by mastectomy were selected. The expression of PD‐L1 and tumor‐infiltrating lymphocytes (TILs) in residual breast cancer cells was assessed by immunohistochemistry in surgical specimens. The median density was used to classify PD‐L1 expression from low to high. The prognostic value of various clinicopathological factors was evaluated. The expression of PD‐L1 was more commonly observed in patients with low levels of total TILs (p < 0.001), high levels of FOXP3+ TILs (p < 0.001) and low levels of CD8+ TILs (p < 0.001). This served as an independent prognostic factor for both relapse‐free survival (Hazard ratio = 1.824, p = 0.013) and overall survival (OS) (Hazard ratio = 2.585, p = 0.001). High expression of PD‐L1 was correlated to worse survival, which is most significantly observed in triple‐negative patients. Patients classified as PD‐L1‐high/CD8‐low exhibited relatively unfavorable survival, whereas patients with either low expression of PD‐L1 or high expression of CD8 had similar outcomes. PD‐L1 expression in residual tumor can be used as a prognostic marker in non‐pCR patients after receiving NCT for breast cancer, which highlights the importance of immune evasion in the therapeutic vulnerability of chemoresistant cancer cells as well as the potential of anti‐PD‐L1 treatments in non‐pCR responders.     

Neoadjuvant taxanes in the treatment of non-metastatic breast cancer: a systematic review

In recent years the role of neoadjuvant (primary, preoperative) chemotherapy has undergone rapid progress. Initially, neoadjuvant chemotherapy use was limited to those patients with inoperable locally advanced breast cancer in an attempt to try to down-size the tumour to make effective surgery possible. The advent of more effective chemotherapy regimens has led to an increased use of neoadjuvant therapy to shrink potentially operable tumours to allow for breast conservation when a mastectomy would have been required previously. While neoadjuvant treatment for operable tumours has indeed allowed increased rates of breast conserving surgery, it has not yet demonstrated any survival benefit over standard postoperative anthracycline-based chemotherapy. Echoing the evolution of taxane based chemotherapy from the metastatic setting through to the adjuvant situation, there has been increased interest in the role of taxanes in neoadjuvant regimens. The use of taxane-based therapies in this setting has so far shown improvements over more standard regimens in terms of clinical response rates, breast conservation, pathologic response rates, disease free survival, and overall survival. The aim of this review is to systematically summarize and interpret the results of published randomized controlled trials of neoadjuvant taxane chemotherapy for women with non-metastatic breast cancer.     

Neoadjuvant therapy for breast cancer: Assessing treatment progress and managing poor responders

There is no clear consensus regarding the most effective management of poor responders to neoadjuvant chemotherapy. Intensifying or changing primary systemic treatment has not been shown to offer any benefit. There is a paucity of trials testing the utility of adjuvant chemotherapy in this setting. Adjuvant hormonal treatment significantly decreases relapse rates in patients with estrogen receptor-positive breast cancer, regardless of initial response to chemotherapy. Neoadjuvant hormonal therapy is usually reserved for patients who are not candidates for chemotherapy or surgery. In patients with HER-2-overexpressing tumors who are candidates for chemotherapy, trastuzumab improves outcomes when administered in the preoperative or postoperative setting. This article examines issues related to the assessment of response to preoperative therapy and the clinical use of these assessments. It reviews important clinical evidence related to the utility of further treatment in patients with breast cancer that has responded poorly to neoadjuvant treatment.     

Neoadjuvant therapy for breast cancer: Assessing treatment progress and managing poor responders

There is no clear consensus regarding the most effective management of poor responders to neoadjuvant chemotherapy. Intensifying or changing primary systemic treatment has not been shown to offer any benefit. There is a paucity of trials testing the utility of adjuvant chemotherapy in this setting. Adjuvant hormonal treatment significantly decreases relapse rates in patients with estrogen receptor-positive breast cancer, regardless of initial response to chemotherapy. Neoadjuvant hormonal therapy is usually reserved for patients who are not candidates for chemotherapy or surgery. In patients with HER2-overexpressing tumors who are candidates for chemotherapy, trastuzumab improves outcomes when administered in the preoperative or postoperative setting. This article examines issues related to the assessment of response to preoperative therapy and the clinical use of these assessments. It reviews important clinical evidence related to the utility of further treatment in patients with breast cancer that has responded poorly to neoadjuvant treatment.     

Growth fraction as a predictor of response to chemotherapy in node‐negative breast cancer

Accurate predictive markers of chemotherapeutic response in early breast cancer are still lacking. The role of tumour growth fraction as a predictor of response to chemotherapy was assessed in early breast cancer. In this study, immunohistochemical expression of MIB1 was studied in a well‐characterised series of early (Stages I and II) node‐negative breast carcinoma cases (n = 100) with long‐term follow‐up that have received adjuvant chemotherapy (cyclophosphamide/methotrexate/5‐fluorouracil regimen). In addition, 728 cases who did not receive adjuvant chemotherapy were used as a control group. Increased tumour growth fraction was associated with a better response to adjuvant chemotherapy in terms of longer breast cancer specific survival and disease‐free interval [hazard ratio (HR) = 0.354, 95% CI = 0.177–0.688, p = 0.003 and HR = 0.396, 95% CI = 0.205–0.768, p = 0.006, respectively]. In contrast to the control group, patients with high growth fraction tumour (>70%) showed an excellent outcome with infrequently reported events during the period of follow‐up. Importantly, patients with a low growth fraction (≤10%) showed frequent recurrences and shorter survival time with outcome comparable to those of high growth fraction who did not receive chemotherapy. Therefore, tumour growth fraction can be used to assign patients into distinct groups showing differential response to adjuvant chemotherapy. Patients with a high growth fraction appear to be ideal candidates for adjuvant chemotherapy while those with low growth fraction are less likely to benefit and are prone to the potential serious side effects of adjuvant chemotherapy.     

Quantification of the response of circulating epithelial cells to neodadjuvant treatment for breast cancer: a new tool for therapy monitoring

Introduction

In adjuvant treatment for breast cancer there is no tool available with which to measure the efficacy of the therapy. In contrast, in neoadjuvant therapy reduction in tumour size is used as an indicator of the sensitivity of tumour cells to the agents applied. If circulating epithelial (tumour) cells can be shown to react to therapy in the same way as the primary tumour, then this response may be exploited to monitor the effect of therapy in the adjuvant setting.

Method

We used MAINTRAC^® analysis to monitor the reduction in circulating epithelial cells during the first three to four cycles of neoadjuvant therapy in 30 breast cancer patients.

Results

MAINTRAC^® analysis revealed a patient-specific response. Comparison of this response with the decline in size of the primary tumour showed that the reduction in number of circulating epithelial cells accurately predicted final tumour reduction at surgery if the entire neoadjuvant regimen consisted of chemotherapy. However, the response of the circulating tumour cells was unable to predict the response to additional antibody therapy.

Conclusion

The response of circulating epithelial cells faithfully reflects the response of the whole tumour to adjuvant therapy, indicating that these cells may be considered part of the tumour and can be used for therapy monitoring.     

miRNAs as therapeutic predictors and prognostic biomarkers of neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis

Breast Cancer Research and Treatment - Accumulating evidence has shown that microRNAs (miRNAs) are promising biomarkers of neoadjuvant chemotherapy (NAC) response in breast cancer (BC). However,...     

Application of neoadjuvant chemoendocrine therapy for operable breast carcinomas

The use of neoadjuvant chemotherapy in primary breast cancer is based on sound theoretical, experimental and clinical principles. Higher objective response rates have been seen in patients with locally advanced breast carcinoma. Furthermore, when used in patients with operable breast carcinomas, sufficient downstaging has been achieved to allow for breast conservation surgery in patients who would otherwise require a mastectomy. This has been achieved without an increase in local recurrence. The anthracenedione mitoxantrone was used as part of the 3M/2M regimen in the neoadjuvant trial at the Royal Marsden Hospital, which was the first to establish within the setting of a clinical trial, the reduction in mastectomy requirements. This regimen combined high objective response rate with low symptomatic toxicity. An important benefit of neoadjuvant therapy is the opportunity to study in vivo the effects of treatment in primary breast carcinomas. The use of the primary tumour as a marker of response prior to surgery may, in the future, allow for the optimization of therapy for individual patients.     

Neoadjuvant treatment for early-stage breast cancer: opportunities to assess tumour response

Primary, preoperative, or neoadjuvant chemotherapy was introduced in the early 1970s as part of an integrated therapeutic approach to treat inoperable locally advanced breast cancer. The approach resulted in high responses, and sufficient downstaging to allow mastectomy in some patients. In addition, a small number of pathological complete responders were reported. Gradually, the idea of preoperative chemotherapy was extended to include patients with large but operable early-stage breast cancer, with the possibility in some cases of downstaging the primary tumour to avoid mastectomy, and to allow breast-conserving surgery to be done. This approach allows the tumour to be used as a measure of treatment response in vivo. More recently, the possibility has opened up for neoadjuvant chemotherapy to provide information on the use of clinical, pathological, and molecular endpoints, which can be used as surrogate markers to predict long-term outcome in the adjuvant setting. In addition, the anatomical accessibility of the breast provides the potential for serial biopsies to investigate molecular changes during treatment.     

Alteration of immunohistochemical biomarkers between pre- and post-chemotherapy: hormone receptors,HER2 and Ki-67

The immunohistochemical (IHC) biomarkers of breast cancer, especially hormone receptors and HER2, are very important because the pharmacological therapeutic strategy is generally decided by biomarker expression patterns. Biomarkers are examined on pre-chemotherapeutic biopsy materials from patients in whom neoadjuvant chemotherapy is planned. Statistically significant changes between pre- and post-chemotherapeutic markers have been reported; however, the alterations in biomarkers are poorly understood. Fluctuation of the Ki-67 labeling index (LI) between pre- and post-neoadjuvant therapy is associated with chemotherapeutic effects and with the prognosis of patients. It has been shown that IHC evaluation of Ki-67 LI is useful as a predictive and a prognostic factor. There are issues to be considered surrounding the use of the IHC Ki-67 LI in routine practice, including the standardization of staining procedures and a cutoff point for Ki-67 LI detection. The current understanding of IHC evaluation of biomarkers for breast cancer under neoadjuvant chemotherapy is reviewed based on the literature.     

Molecular biomarkers to predict response to neoadjuvant chemotherapy for bladder cancer

Cystectomy is the gold standard for treatment of localized muscle-invasive bladder cancer. However, about 50% of patients develop metastases within 2 years after cystectomy and subsequently die for the disease. Neoadjuvant cisplatin-based chemotherapy before cystectomy improves the overall survival in patients with muscle-invasive bladder cancer, and pathological response to neoadjuvant treatment (downstaging to ⩽pT1 at cystectomy) is a strong predictor of better disease-specific survival. Nevertheless, some patients do not benefit from neoadjuvant therapy. The identification of reliable biomarkers that could enable the clinicians to identify patients who will really benefit from neoadjuvant chemotherapy is a major issue. This approach could lead to individualized therapy, in order to optimize the chance of response, avoiding the impact of neoadjuvant treatment on quality of life and the delay of cystectomy in non-responder patients. However, no molecular predictive biomarkers have shown clinical utility.This paper aims to review currently available data about biomarkers predictive of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.     

Neoadjuvant Therapy for Breast Cancer: State of the Science and Future Directions

Systemic neoadjuvant chemotherapy has long been known to confer clinical benefits for breast cancer patients by downstaging inoperable disease or providing those with operable disease the opportunity for breast conservation, without compromising risk of recurrence. In recent years, its benefits have broadened as it has become a pivotal platform for clinical research, providing new prognostic and predictive insights into in vivo response to therapy and long-term outcomes. The use of neoadjuvant chemotherapy in the research setting has expanded our knowledge of heterogeneity in tumor biology and chemosensitivity and provided insights into the relationships between molecular signatures of tumors, pathologic complete response (pCR), and long-term outcomes. This has provided opportunities to specifically select patients who might benefit from novel therapies and test these in a more efficient manner. Despite these major advancements, however, the majority of patients do not attain a pathologic complete response with systemic neoadjuvant chemotherapy. This review describes the standard of care for systemic neoadjuvant therapy for breast cancer and discusses current management controversies and ongoing clinical trials designed to increase the proportion of patients who currently achieve a pCR.     

乳腺癌辅助化疗的新进展

辅助化疗、内分泌治疗对乳腺癌远期无瘤生存率和总生存率有明显提高。目前乳腺癌辅助化疗应用最多的仍是蒽环类及紫杉类药物。已证明,单用紫杉类比单用蒽环类药物疗效更好。由于具有不同的抗癌机制,紫杉类与蒽环类联用可取得更好疗效。对于乳腺癌的辅助治疗,如何选择给药方式、给药密度,以达到最佳的远期疗效是目前关注的焦点之一。此外,利用生物标志物对临床早期乳腺癌预后的指导作用,在化疗及内分泌治疗中进行合理取舍,提高疗效、降低复发及治疗风险,也是目前的研究方向。     

Neoadjuvant epirubicin,gemcitabine and docetaxel for primary breast cancer: Long‐term survival data and major prognostic factors based on two consecutive neoadjuvant phase I/II trials

We previously reported primary endpoints of two consecutive phase I/II trials, evaluating different schedules of neoadjuvant epirubicin (E), gemcitabine (G) and docetaxel (Doc) for primary breast cancer (PBC). Here, we report mature survival data and prognostic factors. One hundred fifty‐one patients were recruited into two consecutive phase I/II trials of neoadjuvant chemotherapy for T2–4 N0–2 M0 PBC. Patients received six cycles of G/E/Doc every 3 weeks with G repeated on d8 (GEDoc, n = 84) or five cycles of G/E followed by four cycles of Doc all given every two weeks (GEsDoc, n = 67). Prognostic factors were investigated using univariate and multivariate analyses. No survival differences by treatment were found. Among reported predictive factors for pathologic complete response (pCR), oestrogen receptor (ER) status was the only relevant factor in the multivariate analysis. Unexpectedly, pCR resulted in poorer survival (univariate HR for overall survival [OS] 3.11, p = 0.007). Multivariate analyses identified molecular subtype and tumour size as the most relevant prognostic factors for OS. HER2‐receptor status and the CPS‐EG score (Mittendorf et al., J Clin Oncol 2011;29:1956–62), based on clinical and pathological stage, ER‐status and tumour grade, were particularly relevant in disease‐free survival. Our findings cast doubt on the reliability of pCR as single marker for prognosis of this unselected breast cancer cohort, with an abundance of luminal subtypes. These results underline the significance of additional molecular characteristics for breast cancer survival.     

Magnetic resonance imaging in patients with newly diagnosed breast cancer: A review of the literature

The use of magnetic resonance imaging (MRI) in patients with newly diagnosed breast cancer remains controversial. Here we review the current use of breast MRI and the impact of MRI on short‐term surgical outcomes and rates of local recurrence. In addition, we address the use of MRI in specific patient populations, such as those with ductal carcinoma in situ, invasive lobular carcinoma, and occult primary breast cancer, and discuss the potential role of MRI for assessing response to neoadjuvant chemotherapy. Although MRI has improved sensitivity compared with conventional imaging, this has not translated into improved short‐term surgical outcomes or long‐term patient benefit, such as improved local control or survival, in any patient population. MRI is an important diagnostic test in the evaluation of patients presenting with occult primary breast cancer and has shown promise in monitoring response to neoadjuvant chemotherapy; however, the data do not support the routine use of perioperative MRI in patients with newly diagnosed breast cancer. Cancer 2014;120:120:2080–2089. © 2014 American Cancer Society.