How I treat metastatic triple-negative breast cancer

Triple-negative breast cancer (TNBC) is associated with a high risk of recurrence and generally a bad prognosis. More than one-third of patients with TNBC will present distant metastases during the course of their disease. Although chemotherapy has been the main treatment option for metastatic TNBC for a long time, this scenario has changed recently with the advent of the polyadenosine diphosphate-ribose polymerase inhibitors (PARPis) for patients harbouring a mutation in the BRCA genes (BRCAmut) and also with the results of immunotherapy in patients with PD-L1-positive tumours. The present manuscript proposes a treatment algorithm for patients with metastatic TNBC based on the currently available, most relevant literature on the topic. For patients with a BRCAmut and able to tolerate chemotherapy, we recommend initiating treatment with platins (carboplatin/cisplatin) and to start PARPis at disease progression. For patients with PD-L1-positive tumours (PD-L1 expression on tumour-infiltrating immune cells >= 1%), we recommend first-line treatment with nab-paclitaxel and atezolizumab, when available. In patients without a BRCA mutation and with PD-L1-negative tumours, we recommend single-agent chemotherapy with taxanes (paclitaxel or docetaxel) as a first-line treatment. In patients with a high disease burden or who are very symptomatic, combinations such as anthracyclines plus cyclophosphamide or platins with taxanes are valid options. Chemotherapy should be maintained until the occurrence of disease progression or limiting toxicities. After progression to first-line chemotherapy, anthracyclines are an option for patients who received taxanes and vice versa. For patients who progressed to taxanes and anthracyclines, or who present contraindications to these agents, fluorouracil/capecitabine, eribulin, gemcitabine, cisplatin/carboplatin, vinorelbine and ixabepilone are alternatives. The treatment of TNBC is constantly evolving, and the inclusion of patients in ongoing trials evaluating new targeted agents, immunotherapy and predictive biomarkers should be encouraged, in an attempt to improve metastatic TNBC treatment outcomes

FOLFIRI as second-line treatment of metastatic biliary tract cancer patients

The combination of cisplatin and gemcitabine is the standard first-line treatment of metastatic biliary tract cancer (BTC) patients. The benefit of second-line chemotherapy in these patients is controversial. This study aims to evaluate the activity of FOLFIRI (fluorouracil and irinotecan) after failure to the first-line platinum and gemcitabine-based chemotherapy in metastatic BTC patients. We present a single-institution, retrospective cohort study. Patients with locally advanced or metastatic BTC who progressed after at least one line of chemotherapy, consecutively treated at our Institution between 2007 and 2017 were included. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), clinical benefit rate (CBR) and safety profile of FOLFIRI. Twelve patients were included in the analysis, with a median follow up of 5 months (95% CI 2.77-7.20). The median number of cycles received was 3 (range 1 to 9). Four grade 3 toxicities were recorded; no grade 4 toxicities and no treatment-related deaths occurred. The median PFS was 1.7 months (95% CI; 0.66-2.67), and median OS was 5 months (95% CI; 2.77-7.20). Two patients presented stable disease, providing a CBR of 17%. We concluded that FOLFIRI presented a favorable toxicity profile and a modest activity in metastatic BTC patients who had progressed to platinum and gemcitabine and may be considered in patients who are able to tolerate additional lines of chemotherapy. Immunotherapy and targeted therapies selected according to the tumoral genomic profile are promising alternatives to improve the outcomes of second-line treatment in BTC

Pulmonary nodules: a challenging diagnosis during the follow up of cancer patients

Pulmonary nodules (PN), frequently found on imaging studies, represent a diagnostic challenge during the follow up of cancer patients. However, published data regarding investigation of PNs incidentally found on chest imaging is scarce. The PN may be present at the time of cancer diagnosis, or arise during the treatment or follow-up periods. In the context of the oncologic patient these lesions are quite invariably considered as metastases, what impacts directly on patients treatment and prognosis. The present study reports 2 cases of pulmonary nodules found in two patients already diagnosed with cancer. Case 1 referred to a woman with squamous cell carcinoma and two pulmonary nodules, and in case 2 the patient was diagnosed with duodenal adenocarcinoma. Both patients were submitted to pulmonary biopsies before the oncologic treatment. In both cases the nodules were of infectious origin, what changed significantly the neoplasia staging and the oncologic treatment intention. The authors performed a literature review as well as a discussion about the management of PN in cancer patients

Stress, adrenergic activation and breast cancer

Stress is defined as a group of psychological and neuro-humoral reactions occurring in the human body to maintain homeostasis in adaptation to potentially hazardous conditions. The sympathetic autonomic nervous system is one of the first and main effectors activated in response to stress, acting via catecholamines and adrenergic stimulation to mediate key aspects of the neuro-humoral stress response. Besides its physiologic effects, stress may also impact the development and progression of breast cancer, as several preclinical studies show adrenergic activation occurring in response to stress may facilitate proliferation, stimulate invasiveness, and induce treatment resistance in breast cancer cells, whereas ß-blockers can inhibit these deleterious effects of stress. Conversely, other preclinical studies suggest that adrenergic activation may inhibit breast cancer proliferation via the modulation of the tumor immune microenvironment. In this context, the effects of stress and adrenergic activation on breast cancer cells and how these impact the outcomes of patients with breast cancer need to be further studied. The main purposes of the studies presented in this thesis are to investigate if adrenergic activation – a key mediator of stress neuro-humoral response – has an impact on the outcomes of patients with breast cancer, and to depict the mechanisms by which stress and adrenergic activation exert their effects on breast cancer cells and the tumor immune microenvironment. In Section 3.1, we investigated the impact of adrenergic activation – assessed via the expression of the ß2-adrenergic receptor gene (ADRB2) – on the prognosis of patients with breast cancer from 2 publicly available datasets and explored potential mechanisms by which ADRB2 interacts with breast cancer, by correlating ADRB2 expression with gene signatures associated with key oncogenic processes, such as angiogenesis, proliferation, invasiveness, and immune activation. The median value of ADRB2 expression in each dataset was defined as a cutoff to classify patients as having “ADRB2-high” or “ADRB2-low” tumors. Initially, in a dataset of 175 patients with HER2-positive early-stage breast cancer, we observed that a high expression of ADRB2 was associated with a longer DFS. Conversely, in another dataset of 202 patients with HER2-positive early-stage breast cancer enrolled in the FinHer trial, the high ADRB2 expression had no prognostic impact. The expression of ADRB2 was negatively correlated with angiogenesis- and proliferation-related signatures, whereas it was significantly correlated with immune-signatures associated with pro-inflammatory cytokines, interferon and STAT1 pathways, immune effector-cell activation, and differentiation, suggesting that the potential effects of ADRB2 on breast cancer may occur via modulation of the tumor immune microenvironment. To further study the effects of adrenergic activation on patients with HER2-positive breast cancer, in Section 3.2 we investigated the role of ADRB2 expression as a prognostic and predictive biomarker in 1,282 patients enrolled in the phase III NCCTG-N9831 trial. The ideal cutoff for ADRB2 expression assessed as a continuous variable for the outcome survival was established based on our own dataset, with levels above cutoff defined as “high” and levels below cutoff defined as “low”. In line with findings from one of the cohorts analyzed in Section 3.1, a high expression of ADRB2 was associated with a longer DFS in this post-hoc analysis of the NCCTG-N9831 trial. Additionally, ADRB2 expression was predictive of trastuzumab benefit, since the DFS improvement yielded by the addition of trastuzumab to adjuvant chemotherapy was restricted to the subset of patients whose tumors had a high ADRB2 expression. ADRB2 expression was significantly correlated with TIL levels, and high TIL levels positively impacted the prognosis of patients whose tumors had a high ADRB2 expression, reinforcing the role of ADRB2 as a potential modulator of the tumor immune microenvironment in patients with HER2-positive breast cancer.To further study the effects of stress and adrenergic activation on breast cancer, we investigated if the use of ß-blockers (antagonists of adrenergic activation) had an impact on the outcomes of patients with early-stage breast cancer. To meet this purpose, in Section 3.3 we performed a systematic literature review and meta-analysis that included a total of 13 publications and 103,065 patients. We showed that the likelihood of presenting a RFS event was significantly lower in patients who received ß-blockers, and a trend for a beneficial effect of ß-blockers was also observed in terms of breast cancer recurrence and breast cancer-specific mortality. Interestingly, the RFS benefit of ß-blockers was more robust in patients with TNBC, which is considered the most ‘immunogenic’ breast cancer subtype, with the worse prognosis and for which new therapeutic options are most needed. No effect of ß-blockers on pCR or OS was observed. These results suggest the use of ß-blockers prevents breast cancer recurrence and can potentially benefit these patients. In conclusion, the studies presented in this thesis highlighted the compelling potential of ADRB2 to be further explored as a biomarker in patients with HER2-positive early-stage breast cancer. In a landscape where immunotherapy is gaining relevance for the treatment of patients with breast cancer, adrenergic activation arises as an interesting potential therapeutic target, based on the correlation between ADRB2, immune-related signatures and tumor-infiltrating lymphocytes observed in our studies. Finally, by demonstrating that ß-blocker use was a favorable prognostic factor in patients with early-stage breast cancer, our meta-analysis provided updated evidence to address the important question on whether ß-blockers have a protective effect on this population. We hope these findings will support prospective studies investigating the therapeutic role of ß-blockers, which are unexpensive and safe alternatives to improve the outcomes of patients with breast cancer.Doctorat en Sciences médicales (Médecine)info:eu-repo/semantics/nonPublishe

CDK4/6 inhibition in HR-positive early breast cancer: Are we putting all eggs in one basket?

SCOPUS: re.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Systemic treatment of patients with early breast cancer: recent updates and state of the art

This review is focused on trials generating results that potentially impacted clinical practice since the 2017 St. Gallen Consensus; the most impactful trial was KATHERINE, which revealed a 11.3% absolute iDFS improvement with T-DM1 (compared to trastuzumab) in HER2-positive breast cancer patients who presented invasive residual disease following neoadjuvant treatment. These results, if reinforced by a subsequent overall survival benefit, will consolidate neoadjuvant treatment as the standard-of-care for most HER2-positive breast cancer patients. The addition of pertuzumab to adjuvant trastuzumab (APHINITY) or extending anti-HER2 therapy with 1 year of neratinib (ExteNET) also improved outcomes, but in a more modest way. In triple-negative early breast cancer patients presenting invasive residual disease after neoadjuvant chemotherapy, the CREATE-X trial demonstrated the benefit of post-neoadjuvant capecitabine. In patients with luminal tumours, updated results of the SOFT/TEXT trials confirmed the benefit of aromatase inhibitors plus ovarian suppression in high-risk premenopausal patients, and the 12-year results of the BIG1–98 trial demonstrated a sustained trend in favour of letrozole compared to tamoxifen in the adjuvant treatment of postmenopausal patients. The TAILOR-X study showed that, overall, patients with an intermediate recurrence risk score (11–25) in the OncotypeDX 21-gene assay did not benefit from adjuvant chemotherapy. A meta-analysis performed by the EBCTCG demonstrated that extended adjuvant aromatase inhibitors modestly reduced breast cancer recurrence risks, with a more pronounced benefit in patients previously treated with tamoxifen. Finally, an EBCTCG meta-analysis including patients with all breast cancer subtypes showed that dose-dense chemotherapy improved survival when compared to conventionally-timed chemotherapy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors

In this review, we discuss biomarkers of response and resistance to PI3K inhibitors (PI3Ki) in estrogen receptor-positive breast cancer, both in the early and advanced settings. We analyse data regarding PIK3CA mutations, PI3K pathway activation, PTEN expression loss, Akt signalling, insulin levels, 18FFDG-PET/CT imaging, FGFR1/2 amplification, KRAS and TP53 mutations. Most of the discussed data comprise retrospective and exploratory studies, hence many results are not conclusive. Therefore, among all of these biomarkers, only PIK3CA mutations have proved to have a predictive value for treatment with the α-selective PI3Ki alpelisib (SOLAR-1 trial) and the β-sparing PI3Ki taselisib (SANDPIPER trial) in the advanced setting. Since the accuracy of current individual biomarkers is not optimal, a composite biomarker, including DNA, RNA and protein expression data, to more precisely assess the PI3K/AKT/mTOR pathway activation status, may arise as a promising approach. Finally, we describe the rational for new combination therapies involving PI3Ki and anti-HER2 agents, chemotherapy, CDK4/6 inhibitors, mTOR inhibitors or new endocrine treatments and discuss the ongoing trials in this field.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Post-neoadjuvant treatment and the management of residual disease in breast cancer: state of the art and perspectives

Achieving a pathologic complete response after neoadjuvant treatment is associated with improved prognosis in breast cancer. The CREATE-X trial demonstrated a significant survival improvement with capecitabine in patients with residual invasive disease after neoadjuvant chemotherapy, and the KATHERINE trial showed a significant benefit of trastuzumab-emtansine (TDM1) in human epidermal growth factor receptor 2 (HER2)-positive patients who did not achieve a pathologic complete response after neoadjuvant treatment, creating interesting alternatives of post-neoadjuvant treatments for high-risk patients. New agents are arising as therapeutic options for metastatic breast cancer such as the cyclin-dependent kinase inhibitors and the immune-checkpoint inhibitors, but none has been incorporated into the post-neoadjuvant setting so far. Evolving techniques such as next-generation sequencing and gene expression profiles have improved our knowledge regarding the biology of residual disease, and also on the mechanisms involved in treatment resistance. The present manuscript reviews the current available strategies, the ongoing trials, the potential biomarker-guided approaches and the perspectives for the post-neoadjuvant treatment and the management of residual disease after neoadjuvant treatment in breast cancer

Anthracycline and taxane-based chemotherapy versus docetaxel and cyclophosphamide in the adjuvant treatment of HER2-negative breast cancer patients: a systematic review and meta-analysis of randomized controlled trials

Purpose: Standard adjuvant chemotherapy for HER2-negative breast cancer consists generally in an anthracycline and taxane-based regimen (A+T). The TC (docetaxel and cyclophosphamide) regimen arises as a potential alternative, although individual randomized controlled trials (RCTs) could not demonstrate the non-inferiority of TC over A+T. This is a systematic review and meta-analysis of RCTs comparing 6 cycles of TC versus sequential A+T in the adjuvant treatment of HER2-negative breast cancer. Methods: A systematic literature search was performed to identify RCTs comparing TC versus A+T. Disease-free survival (DFS) and overall survival (OS) were assessed. Subgroup analyses of DFS according to hormone receptor status, lymph node involvement, and menopausal status were performed. Hazard ratios (HRs) and 95% confidence intervals (CI) for DFS and OS were extracted from each trial, and a pooled analysis was conducted using the random-effect model. The Higgins\u2019 I-Squared Test was used to quantify heterogeneity. Results: Seven RCTs were included (12,741 patients). Overall, no difference was observed between TC and A+T in DFS (HR 1.08, 95% CI 0.96\u20131.20) and OS (HR 1.05; 95% CI 0.90\u20131.22). A trend favoring A+T was observed in hormone receptor-negative (HR 1.12, 95% CI 0.93\u20131.34) and N2 patients (HR 1.25; 95% CI 0.82\u20131.90). Emesis/vomiting, mucositis, thrombocytopenia and sensory neuropathy were significantly more frequent with A+T. Conclusion: As adjuvant treatment of HER2-negative breast cancer, sequential A+T regimen was associated with increased risk of toxicities and no clear survival benefit as compared to 6 cycles of TC. Higher-risk patients may benefit the most from A+T, whilst TC may be an efficacious and less toxic alternative for lower-risk patients