Carlos Castañeda

The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer

The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth, proliferation, and survival. The alteration of integrants of this pathway through mutation of its coding genes increases the activation status of the signaling and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in breast cancer (BC) and the mediation of this pathway in different processes characteristically implicated in tumorigenesis have attracted the interest of this pathway in BC; however, a more comprehensive understanding of the signaling intricacies is necessary to develop clinical applications of the modulation of this pathway in this pathology. We review a series of experiments examining the contribution of alteration of integrants of this signaling network to human BC and we make an update of the information about the effect of the modulation of this pathway in this cancer.

Pazopanib: an antiangiogenic drug in perspective

Pazopanib, a tyrosine kinase inhibitor targeted to angiogenesis, has been tested in preclinical and clinical trials and has shown promising activity against a variety of solid tumors, such as renal cancer, all of which are related to the angiogenic pathway. It has a safety profile related to this mechanism of action. Diarrhea, hypertension, hair depigmentation and nausea are the most common side effects. Pazopanib is currently under evaluation as monotherapy and in combination with some potentially synergistic agents of proven activity.

Implication of miRNA in the diagnosis and treatment of breast cancer

Breast cancer (BC) comprises a group of different diseases characterized by changes in tissue structure and gene expression. Recent advances in molecular biology have shed new light on the participation of genes and their products in the biology of BC. MicroRNAs (miRNAs) are small noncoding endogenous RNA molecules that appear to modulate the expression of more than a third of human genes, and their implications in cancer have grasped the attention of the scientific community. Recently, several studies have described the association between miRNA expression profiles and pathological and clinical BC features. Moreover, these molecules represent a new type of molecular marker that can identify prognosis and guide the management of BC patients. With the increasing understanding of miRNA networks and their impact in the biology of BC, as well as the development of viable strategies to modulate specific miRNAs, we could improve the treatment of this disease.

The present and future of gene profiling in breast cancer.

Gene signatures can provide prognostic and predictive information to help in the treatment of early-stage breast cancer. Although many of these signatures have been described, only a few have been properly validated. MammaPrint and OncoType offer prognostic information and identify low-risk patients who do not benefit from adjuvant chemotherapy. With regard to prediction of response, molecular subtypes of breast cancer differ in their sensitivity to chemotherapy, although further studies are needed in this field. Cost, small sample size, and the need to use central laboratories are common limitations to the widespread use of these tools.

Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies.

Targeted therapies: Combined lapatinib and paclitaxel in HER2-positive breast cancer.

A randomized phase III trial evaluated the effect of adding lapatinib to paclitaxel as first-line therapy for patients with metastatic breast cancer whose tumors were negative or untested for human epidermal growth factor receptor 2 (HER2) overexpression. Progression-free survival was prolonged significantly in patients with HER2-overexpressing tumors, which indicates that lapatinib exerts its main effects via the HER2 pathway.

Behaviour of breast cancer molecular subtypes through tumour progression

IntroductionBreast cancer (BC) becomes more aggressive throughout disease progression. Clinical stage is correlated with patient outcome. We hypothesised that BC molecular subtypes are associated with a poor prognosis in advanced clinical stages. We analysed the distribution and behaviour of molecular subtypes at different BC tumour size and variation of molecular subtype in recurrent lesions.Patients and methodsWe studied 1647 consecutive patients with non-metastatic invasive and microinvasive (Tmi) BC treated from January 1997 to December 2007. Patients were categorised by tumour size and molecular subtype. A chi-square method was used for multiple group comparisons. Kaplan-Meier product limit method was used to calculate overall survival and disease-free survival.ResultsMedian follow-up was 7.2 years. For patients with invasive BC the median age was 56 years. Four hundred and fifteen patients recurred and 225 died. Larger tumours were more frequently of triple-negative (TN) subtype than small ones or Tmi lesions. Any molecular subtype change from primary tumour to recurrent lesions is more likely to happen from a good prognosis to a subtype of worse prognosis than the opposite. Larger tumours of luminal A, luminal B and TN, but not HER2 subtype, are more likely to carry aggressive markers and to have worse outcomes than small ones.ConclusionWe found accumulation of TN subtype, migration to a poor prognosis subtype and increasing aggressiveness of luminal and TN subtypes throughout tumour progression. Tumours belonging to the HER2 subtype behave aggressively regardless of the primary size.

Prognostic effect of hormone receptor status in early HER2 positive breast cancer patients

BACKGROUND This study was conducted to determine the prognostic effect hormone receptor (HR) status in early HER2 positive (HER2+) breast cancer patients, since it has not yet been established whether HR status can be used in the prognosis of patients with (HER2+) breast cancer. PATIENTS AND METHODS We obtained data from 299 patients with early HER2+ breast cancer who underwent surgery and received standard adjuvant chemotherapy, hormonal therapy and/or radiation between 2000 and 2002 at the Instituto Nacional De Enfermedades Neoplasicas, Perú. Clinical and pathological features were compared. Endpoints analyzed were disease free survival (DFS) and overall survival (OS). RESULTS Overall, 155 patients were HR-positive (HR+) and 144 were negative (HR-). The two groups had similar characteristics except for histologic grade and extracapsular extension. With a median follow-up of 93 months, 5-year DFS was statistically different between the two groups: 65.0% for (HER2+/ HR-) and 74.6% for the (HER2+/ HR+) patients (p=.045). OS at 5 years was not statistically different between the two groups with 75.5% for (HER2+/ HR-) patients and 82.4% for the (HER2+/ HR+)(p=.140). CONCLUSIONS Patients with (HER2+/ HR-) breast cancers treated with surgery and standard adjuvant chemotherapy exhibited a statistically worse DFS compared to those with (HER2+/ HR+) tumors. However, OS was similar in both groups.

PIK3CA mutations in Peruvian patients with HER2-amplified and triple negative non-metastatic breast cancers.

PURPOSE To determine the frequency of PIK3CA mutations in a Peruvian cohort with HER2-amplified and triple negative breast cancers (TNBC). METHODS We analyzed two cohorts of 134 primary non-metastatic breast cancer patients from Peru. Cohorts consisted of 51 hormone receptors (+)/HER2-amplified breast tumor patients surgically resected as first treatment included in the ALTTO trial (ALTTO cohort) and 81 TNBC patients with residual disease after neoadjuvant treatment (neoadjuvant cohort). Genomic DNA was extracted from paraffin-embedded tumor samples. Samples from the ALTTO and neoadjuvant cohorts were taken at biopsies and from residual tumors, respectively. PIK3CA mutations were detected by sequencing DNA fragments obtained by PCR amplification of exons and their flanking introns. All of the detected PIK3CA mutations were confirmed in a second independent run of sample testing. RESULTS PIK3CA mutations were present in 21/134 cases (15.7%). Mutations in exon 9 and 20 were present in 10/134 (7.5%) and 11/134 (8.2%), respectively. No cases had mutations in both exons. Mutations in exon 9 consisted of E545A (seven cases), E545K (two cases) and E545Q (one case); while in exon 20, mutations consisted of H1047R (10 cases) and H1047L (one case). Compared to TNBC patients, HER2-amplified patients were more likely to have PIK3CA mutated (23% vs 9.6%; P=0.034). There were no associations between mutational status of PIK3CA with estrogen receptor status (P=0.731), progesterone receptor status (P=0.921), age (P=0.646), nodal status (P=0.240) or histological grade (P=1.00). No significant associations were found between PIK3CA mutational status and clinicopathological features. CONCLUSIONS We found a similar frequency of PIK3CA mutations to that reported in other series. Although we did not include HR+/HER2 patients, those with HER2-amplified tumors were more likely to present PIK3CA mutations compared to patients with triple negative tumors.

The implementation of the Plan Esperanza and response to the imPACT Review

Following the implementation of the National Cancer Prevention and Control Results-based Budget Programme (PpR Cancer-024) in 2011, the Peruvian Government approved the Plan Esperanza-a population-based national cancer control plan-in 2012. Legislation that ensured full government-supported funding for people who were otherwise unable to access or afford care and treatment accompanied the Plan. In 2013, the Ministry of Health requested an integrated mission of the Programme of Action for Cancer Therapy (imPACT) report to strengthen cancer control in Peru. The imPACT Review, which was executed in 2014, assessed Perus achievements in cancer control, and areas for improvement, including cancer control planning, further development of population-based cancer registration, increased prevention, early diagnosis, treatment and palliative care, and the engagement and participation of civil society in the health-care system. This Series paper gives a brief history of the development of the Plan Esperanza, describes the innovative funding model that supports it, and summarises how funds are disseminated on the basis of disease, geography, and demographics. An overview of the imPACT Review, and the governments response in the context of the Plan Esperanza, is provided. The development and execution of the Plan Esperanza and the execution of and response to the imPACT Review demonstrates the Peruvian Governments commitment to fighting cancer across the country, including in remote and urban areas.