Nab-paclitaxel for the management of triple-negative metastatic breast cancer: a case study

The optimal sequence of systemic chemotherapy in metastatic breast cancer (MBC) is unknown. We report the case of a woman who was successfully treated with nanoparticle albumin-bound (nab)-paclitaxel for triple negative MBC in our institution. In November 2008, a 48-year-old woman underwent surgical treatment for a triple negative invasive ductal breast cancer and subsequently received adjuvant chemotherapy with fluorouracil/epirubicin/cyclophosphamide and radiotherapy. Sixteen months after surgery, she presented with a left chest wall metastatasis. The patient received combination therapy with conventional paclitaxel (90 mg/m² weekly for 3 out of 4 weeks [QW 3/4]) and bevacizumab (10 mg/kg every 2 weeks [Q2W]) as first-line treatment for MBC (six cycles; March to September 2010) and achieved a partial response at the metastatic site. Bevacizumab monotherapy was continued until disease progression (April 2011) with the development of a single infraclavicular lymph node metastasis and an increase in the dimensions of the left chest wall lesion. From May to December 2011, the patient received nab-paclitaxel 260 mg/m² every 3 weeks (Q3W) as second-line treatment (11 cycles). After three cycles, the left chest wall lesion and the infraclavicular lymph node metastasis were undetectable and the patient was considered to have achieved a complete response. Treatment was well tolerated with no significant toxicity or need for dose reduction. Given our case, here we review the clinical evidence and discuss the potential role of nab-paclitaxel for the treatment of triple negative MBC, a subgroup typically characterized as having aggressive disease and limited treatment options

Features of aggressive breast cancer

Aggressive breast cancer is a term commonly used in literature to describe breast cancer with a poor prognosis. Identifying and understanding the factors associated with aggressiveness could be helpful to the management of patients with breast cancer. Breast cancer is a heterogeneous disease, both clinically and biologically, which may be responsible for the wide range of survival durations for patients with metastatic disease

Nab-paclitaxel for the treatment of triple-negative breast cancer: Rationale, clinical data and future perspectives

Triple-negative breast cancer (TNBC) accounts for ∼10-20% of breast cancers and is associated with relatively poor prognosis, earlier disease recurrence and higher number of visceral metastases. Despite an increasing understanding of the molecular heterogeneity of TNBC, clinical trials of targeted agents have thus far been disappointing; chemotherapy, in particular with anthracycline and taxanes, remains the backbone medical management for both early and metastatic TNBC. Nab-paclitaxel is a solvent-free, albumin-bound, nanoparticle formulation of paclitaxel and represents a novel formulation of an established, effective chemotherapeutic agent. Nab-paclitaxel has been specifically designed to overcome the limitations of conventional taxane formulations, including the barriers to effective drug delivery of highly lipophilic agents. It has shown significant efficacy and better tolerability than conventional taxanes in metastatic breast cancer and is approved for use in this setting. Increasing evidence suggests that nab-paclitaxel is effective in patients with more aggressive tumours, as seen in TNBC. Indeed, results of Phase II/III studies indicate that nab-paclitaxel may be effective as neoadjuvant treatment of TNBC. This article reviews the rationale and evidence supporting a role for nab-paclitaxel in the treatment of TNBC, including ongoing studies such as ADAPT-TN and tnAcity. In addition, the article reviews ongoing research into targeted therapies and immuno-oncology for the treatment of TNBC, and explores the potential role, current evidence and ongoing studies of nab-paclitaxel as the chemotherapy partner in combination with immunotherapy, where the unique properties of this taxane, including the lack of requirement for steroid pre-medication, may present an advantage

Combination of Cytotoxic Drugs for Patients with HER2-Negative Metastatic Breast Cancer

In the last few decades the approach to metastatic breast cancer (MBC) treatment using chemotherapy, either as single or combination agents, has been largely studied and a wide spectrum of therapeutic options is now available. Anthracyclines and taxanes remain the cornerstone of treatment in this setting. The choice of combination chemotherapy versus monochemotherapy is still open to debate since results from clinical trials are, unfortunately, conflicting. Despite improvements in response and disease-free survival rates, there has been no overall survival benefit reported although toxicity is increased. Therefore, based on available data, clinical decision-making for a busy practitioner should consider not only patient/tumor characteristics and the potential benefits of treatments, but also their toxicity profiles and patient preferences. Novel cytotoxic compounds have been approved for clinical use and combination regimens incorporating these agents may bring new treatment opportunities for MBC patients. In this review, we summarize the main achievements and the currently available and future combinations of cytotoxic drugs for patients with HER2-negative MBC

Hormone Receptor/Human Epidermal Growth Factor Receptor 2-positive breast cancer: Where we are now and where we are going

AbstractNear 75% of all breast cancers (BC) express estrogen receptors (ER) and/or progesterone receptors (PgR), while up to 20% of BC show an overexpression/amplification of Human Epidermal Growth Factor Receptor 2 (HER2). Around 50% of all HER2-overexpressing BC show the coexistence of both HER2 overexpression/amplification and ER and/or PgR overexpression. Numerous in vitro and in vivo studies suggest the existence of a cross-talk between their downstream pathways, which seem to affect the natural history, response to therapy and outcome of patients affected by this subset of BC. Meta-analyses or subgroup analysis of numerous neo-/adjuvant trials demonstrated significant clinical implications deriving from ER/HER2 co-existence, consisting in a different pattern of relapse and dissimilar outcome in response to anti-HER2 therapy. However, only two randomized trials in early disease and three in advanced disease specifically addressed the issue whether a combined approach with both hormonal and anti-HER2 therapy would have a better therapeutic impact in this subset of BC compared to the lone anti-HER2 or hormonal therapies (HT). None of these trials demonstrated improvements in overall survival, even though several efficacy end-points such as progression free survival, in advanced setting, or pCR rates in neoadjuvant setting, often favored the combined hormonal and anti-HER2 therapeutic approach. In the next few years, a certain number of ongoing randomized trials, both in neoadjuvant and advanced setting, will evaluate the efficacy of new anti-HER2 drugs, T-DM1 and pertuzumab, in combination with HT, helping to improve the therapeutic strategy for this specific subtype of breast tumors

Continuing trastuzumab beyond disease progression: outcomes analysis in patients with metastatic breast cancer

INTRODUCTION: We performed a retrospective analysis of HER2-overexpressing metastatic breast cancer patients to describe clinical outcomes of those who, despite progression of the disease (PD), maintained trastuzumab for multiple chemotherapy lines. We also compared survival of these patients with that of those who halted trastuzumab at first PD. METHODS: We identified 101 patients treated between July 2000 and January 2007. Nineteen were still receiving the first-line trastuzumab-based treatment without evidence of PD and were not included in this analysis. Of the remaining 82 patients, 59 retained trastuzumab for one or more additional lines of chemotherapy after PD, according to our institution policy. Twenty-three patients who changed treating institution and stopped trastuzumab at first progression were used as a control group. RESULTS: For patients retaining trastuzumab, the median follow-up was 39.6 months. Clinical outcomes showed the typical degradation between first and second lines of therapy which we would expect by halting trastuzumab at first progression. Response rates were 35\% and 16\% and median times to progression were 7.25 and 5.25 months for the first and second lines of trastuzumab therapy, respectively. The median overall survival (OS) rates were 70 months for patients who retained trastuzumab and 56 months for patients who halted the drug (hazard ratio [HR] 0.87, 95\% confidence interval [CI] 0.51 to 1.18; P = 0.52). If we consider OS from the start of trastuzumab therapy, the figures are 53.9 and 34.8 months, respectively (HR 0.78, 95\% CI 0.58 to 1.32; P = 0.2). CONCLUSION: A nonstatistically significant trend of improved survival for patients retaining trastuzumab is observed. This is in line with most retrospective analyses and recent randomized data. Retaining trastuzumab after progression is a reasonable option, but further randomized data are warranted to better define its role in comparison with other available options.

CDK 4/6 inhibitors as single agent in advanced solid tumors

Cyclin-dependent kinases (CDK) 4/6 inhibitors, namely abemaciclib, palbociclib, and ribociclib, interfere with cell cycle progression, induce cell senescence and might promote cancer cell disruption by a cytotoxic T cells-mediated effect. Phase III randomized clinical trials have proven that CDK4/6 inhibitors (CDK4/6i) in combination with several endocrine agents improve treatment efficacy over endocrine agents alone for hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (MBC). Based on such results, these combinations have been approved for clinical use. Preclinical studies in cell cultures and mouse models proved that CDK4/6i are active against a broad spectrum of solid tumors other than breast cancer, including liposarcoma, rhabdomyosarcoma, non-small cell lung cancer, glioblastoma multiforme, esophageal cancer, and melanoma. The role of CDK4/6i in monotherapy in several solid tumors is currently under evaluation in phase I, II, and III trials. Nowadays, abemaciclib is the only of the three inhibitors that has received approval as single agent therapy for pretreated HR+ HER2- MBC. Here we review biological, preclinical and clinical data on the role of CDK4/6 inhibitors as single agents in advanced solid tumors

Bladder‐sparing, combined‐modality approach for muscle‐invasive bladder cancer

AbstractBACKGROUND.The authors evaluated their long‐term experience with combined‐modality, conservative treatment in patients with muscle‐invasive bladder cancer.METHODS.In total, 121 patients with T2, T3, or T4 bladder cancer (mean age, 63 years; ratio of men to women, 3:1) underwent induction by transurethral resection (TUR) of the tumor and received 2 cycles of neoadjuvant chemotherapy followed by radiotherapy (RT) (n = 43 patients) or radiochemotherapy (RCT) (n = 78 patients). Six weeks after RT or RCT, responses were evaluated by restaging TUR. Patients who achieved a complete response (CR) were observed at regular intervals. In patients who had persistent or recurrent invasive tumor, further treatment was recommended.RESULTS.Local response evaluation by restaging TUR was possible in 119 patients, and 102 of those patients (85.7%) achieved a CR. After a median follow‐up of 66 months (range, 6–182 months), no local or distant disease recurrences were observed in 67 of 102 complete responders (65.7%), 17 of 102 complete responders (16.7%) experienced superficial local disease recurrence, and 18 of 102 complete responders (17.6%) had a muscle‐invasive relapse. The 5‐year tumor‐specific, overall, and bladder‐intact survival rates were 73.5%, 67.7%, and 51.2%, respectively. Treatment modality, tumor classification, and resection status after initial TUR had an impact on survival rates (P = .04, P = .02, and P = .02, respectively).CONCLUSIONS.The current results indicated that conservative combined treatment is a reasonable alternative to radical cystectomy in selected patients with muscle‐invasive bladder cancer. Cancer 2008. © 2007 American Cancer Society

Unexpected ovarian activity in premenopausal breast cancer survivors treated with exemestane and GnRH analogues

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Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer

Background: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation. Methods: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets. Results: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database. Conclusions: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC