Introduction Of Targeted Therapies Research Articles

Pharmacological Basis of Breast Cancer Resistance to Therapies - An Overview.

Breast Cancer (BC) is a molecular heterogeneous disease and patients with similar clinico-pathological characteristics often display different response to treatment. Cellular processes, including uncontrolled cell-cycle, constitutive activation of signalling pathways and alterations in DNA-repair mechanisms are the main altered features in breast cancer. These cellular processes play significant roles in the emergence of resistance to therapies. The introduction of target therapies and immunotherapy significantly improved the survival of breast cancer patients. The incorporation of novel biomarkers together with the introduction of new therapeutic options may help to overcome treatment resistance. Molecular profiling promises to help in refine personalized treatment decisions and catalyse the development of further strategies when resistances inevitably occurs. This review provides a summary of genetic and molecular aspects of resistance mechanisms to available treatments for BC patients, and its clinical implications.

Treatment of patients with acute lymphoblastic leukemia who are not suitable for high-dose chemotherapy and hematopoietic stem cell transplantation

Introduction. Acute lymphoblastic leukemia is a malignant disease characterized by the proliferation of precursor B-cells, Tcells or less often, precursors of NK-cells. B-cell acute lymphoblastic leukemia is more common in patients >60 years of age compared to patients <60 years of age (89% vs. 66%), and cytogenetic abnormalities such as t(9;22) (Ph+) are more common in older than younger patients (36% against 19%). Elderly patients often have a poor status and comorbidities, so poor disease outcome is more common. Clinical and biological features. B cell acute lymphoblastic leukemia is more common in patients >60 years of age compared to patients <60 years of age (89% vs 66%) and cytogenetic abnormalities such as t(9;22) are more common in older vs. younger (36% vs. 19%). Therapy. The elderly and patients with comorbidities require less intensive therapy, based on corticosteroids, vincristine and asparaginase, while avoiding anthracyclines and alkylating agents, due to the high mortality associated with treatment. For ?unfit? patients with Ph-positive acute lymphoblastic leukemia, tyrosine kinase inhibitors with reduced-intensity chemotherapy or corticosteroids alone are recommended. For t(9;22) negative patients, low-dose corticosteroid chemotherapy with or without immunotherapy is recommended. For patients with T-cell acute lymphoblastic leukemia, chemotherapy with venetoclax may be an option. Conclusion. The introduction of targeted therapy has changed treatment options in acute lymphoblastic leukemia. For elderly patients, targeted therapy is a necessary modality since standard chemotherapy leads to a poor outcome due to its toxicity and ineffectiveness.

Dermatological adverse drug reactions of anticancer drugs: International data of pharmacovigilance: VigiBase®

In the 2000s, newer generations of drugs appeared on the market called drugs of targeted therapy (TT) drugs. The introduction of TT in oncology has profoundly changed the prognosis of many cancers but also introduced a wide variety of adverse drugs reactions (ADR), including in particular dermatological adverse drug reactions (DADRs). We investigated the evolutions of the notifications of DADRs of anticancer drugs since 2000s in international pharmacovigilance data. For this purpose, we separated non-targeted therapy and targeted therapy. During the period from 01/01/2000 to 31/12/2017, 1,226,252 ICSRs (8.7%) were related to anticancer drugs, among them concerning anticancer drugs, 192,108 cases (15.6%) contained at least one MedDRA term for "skin and subcutaneous tissue disorders" system organ classes. The DADRs of anticancer drugs are in constant increase on the period 2000 to 2017, from 0.91% to 1.90% of the total ADR of Vigibase®. The number of DADRs drugs in the non-targeted therapies class remained stable during this period, while the DADRs of targeted therapy drugs increased and exceeded those of non-targeted therapy in recent years. Using a disproportionality analysis, we found that targeted therapy drugs are associated with a higher risk of reporting DADRs of the type: dermatitis acneiform, hair color changes, acne, and hyperkeratosis and skin toxicity. While, non-targeted therapy drugs are associated with a higher risk of reporting DADRs of the type: skin hyperpigmentation, nail discoloration, dermatitis exfoliative, Hyperhidrosis and alopecia. TT drugs are used more and more for cancer indications and even beyond. This problematic of DADR will become more and more common and should benefit from specialized support with the organization of a coordinated network of professionals.

Ovarian Cancer Treatments Strategy: Focus on PARP Inhibitors and Immune Check Point Inhibitors.

Simple SummaryOvarian cancer treatment is the deadliest of gynecological cancers but the introduction of target therapies in its therapeutic algorithm has significantly improved outcomes. The aim of this article was to provide a review of completed and ongoing clinical trials involving the use of PARP inhibitors and/or immune checkpoint inhibitors for the treatment of ovarian cancer in front line and relapse settings. We confirmed the role of bevacizumab and PARP inhibitors which have transformed OC into a chronic disease while almost all trials involving immunotherapy were disappointing. Ovarian cancer treatment strategy is mainly based on three pillars: cytoreductive surgery, platinum-based chemotherapy, and targeted therapies. The latter in the last decade has provided a remarkable improvement in progression free patients and, hopefully, in overall survival. In particular, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit BRCA 1/2 mutations and DNA damage response deficiencies, which are believed to concern up to 50% of high grade epithelial ovarian cancer cases. While these agents have an established role in ovarian cancer treatment strategy in BRCA mutated and homologous recombination deficient patients, an appropriate predictive molecular test to select patients is lacking in clinical practice. At the same time, the impressive results of immunotherapy in other malignancies, have opened the space for the introduction of immune-stimulatory drugs in ovarian cancer. Despite immune checkpoint inhibitors as a monotherapy bringing only modest efficacy when assessed in pretreated ovarian cancer patients, the combination with chemotherapy, anti-angiogenetics, PARP inhibitors, and radiotherapy is believed to warrant further investigation. We reviewed literature evidence on PARP inhibitors and immunotherapy in ovarian cancer treatment.

Clinical and pathological characteristics of patients with overexpressed her 2 breast cancer in the national cohort study – Amazona III

Introduction: HER2 overexpressed breast cancer (+) is observed at around 15-20%. The introduction of target therapies in this subtype changed the prognosis of these patients, improving mortality and reducing surgical morbidity when neoadjuvant therapy allows downstaging of breast and axillary surgery. A recent publication with 1,310 samples from Brazilian patients described 20% of HER-2 + tumors. There are few epidemiological studies evaluating patients in our population. The Amazona III study evaluated the epidemiology of breast cancer in a sample of the Brazilian population including 2,950 patients from 23 Brazilian hospitals, completed in 2018. Objective: To characterize the frequency of positive HER-2 breast cancer in patients in the Amazona III study and its clinical characteristics. Method: Prospective, multicenter cohort study. All female patients with invasive breast cancer over 18 years of age included in the Amazona III Project were considered eligible. Immunohistochemical determination was made according to the pathology laboratory of each center. Results: Of the 2,950 study participants, 643 (21%) were HER2 +, 71% from the Unified Health System (SUS) and 28.9% from the complementary system. Most had grade 2 (52.6%) or 3 (36.4%), were post-menopausal (53%), positive estrogen receptor (71.9%), and did not undergo neoadjuvant therapy (52%). As for the number of lymph nodes, 45% were positive lymph nodes, with cN1 (27%), cN2 (12%), and cN3 (5%). 49% had positive lymph nodes in SUS and 37% in the private system. The rate of conservative breast surgery was similar in both groups, being around 46%. Conclusion: The prevalence of HER-2 + in patients included in the Amazona Study III (current epidemiological study of breast cancer in Brazil) is compatible with data from the literature. The prevalence of positive lymph node at diagnosis is high, especially in SUS (49%), therefore the impact of access to therapies that increase the chance of increasing overall survival, decreasing invasive recurrence, and decreasing surgical morbidity must be evaluated.

ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin.

In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy.

Is there a role for adjuvant pertuzumab in HER2-positive breast cancer?

The outcomes of human epidermal growth factor receptor 2 (HER2)-positive breast cancer was dramatically changed by the introduction of targeted therapies against the HER2 receptor (1).The monoclonal antibody trastuzumab was the first HER2-directed treatment that demonstrated, together with chemotherapy, a significant improvement in treatment outcomes of this subgroup of patients, both in the metastatic (2) and neo-/adjuvant (3-7) settings, thus becoming the mainstay of treatment in HER2 positive breast cancer. The remarkable results achieved led to the development of additional HER2-targeted drugs, raising the hypothesis of a double-HER2 blockade against breast cancer.

Overall survival (OS) in renal cell carcinoma (RCC) before and after the introduction of targeted therapies (TTs): A Norwegian population-based study (2000–2011).

443 Background: The Renal Comparison study in Norway (RECON) is a retrospective non-interventional study of OS in all patients diagnosed with RCC and metastatic (m)RCC before and after the introduction of TTs. Methods: Using data from two national health registries, Cancer Registry of Norway (diagnosis and cause of death) and Norwegian Prescription Database (all dispensed drugs), we assessed OS in RCC and mRCC patients diagnosed during two periods after (2009–2011 and 2006–2008) and one period before (2000–2005 [RCC]; 2002–2005 [mRCC]) the introduction of TTs and factors influencing OS in mRCC. Multivariate analysis was performed using a Cox proportional hazards model, including estimation of adjusted HR. The regression model included the covariates age, gender, geographic region, nephrectomy status, diagnostic period and TT prescription. Results: In total, 2,176, 1,887, and 3,233 RCC patients were identified in 2009–2011, 2006–2008 and 2000–2005, respectively, of whom 2,160 (30%) had mRCC. From 2006 to 2011, TT use in mRCC patients significantly increased from 21% to 56% (p<0.01); sunitinib was the most frequent first-line treatment (93%). RCC patients diagnosed in 2009–2011 and 2006–2008 had a significant improvement in OS compared with patients diagnosed in 2000–2005 (median OS: not reached and 76 vs. 49 months, respectively; both p<0.001 [log-rank]). Similarly, a significant OS improvement was shown in mRCC patients diagnosed in 2009–2011 and 2006–2008 compared with 2002–2005 (median OS: 11.0 and 8.0 vs. 6.0 months, respectively; both p<0.001 [log-rank]; with adjusted HR [95% CI] of 0.77 [0.68–0.87] and 0.87 [0.78–0.98], respectively). Factors significantly associated with longer OS in mRCC were (HR, 95% CI): younger age (0.98, 0.98–0.99), female gender (0.88, 0.79–0.97), prior nephrectomy (0.49, 0.43–0.55) and TT prescription (0.58, 0.51–0.65). Significant regional variation was also shown. Conclusions: A significant OS improvement was shown in RCC and mRCC patients following the introduction of TTs. This advance has continued into the later TT era and, although multifactorial in origin, the contribution of TTs in mRCC is highly likely.

Abstract 337: A NSCLC PDX with EML4-ALK fusion mutation responds to crizotinib.

Abstract Non-small cell lung cancer (NSCLC) has the highest mortality among all malignances while with limited treatment options. Among the most significant treatment advancement in recent years are the introduction of target therapies of EGFR-TKIs (Erlotinib and Gefitinib) for adenocarcinoma with EGFR activating mutations, and Crizotinib for NSCLC with ALK activation (EML4-ALK fusion)1. ALK activation are associated with a subset of NSCLC patients (3∼5%).Crizotinib is considered not a particularly potent ALK inhibitor, with IC50 at range of tens of nanomoles. It may not be an ideal agent for treating NSCLC with activating ALK. Therefore, a new ALK inhibitor with better potency and specificity could be of particularly medical importance. Currently, the industry is actively searching for such new agents. A relevant experimental model could also greatly facilitate evaluating and validating these new drug candidates. Patient derived xenografts (PDX) (including NSCLC PDX) mirror patients’ histopathology and genetic profiles2, thus known as “patient avatar”. It has improved predictive power as preclinical cancer models, and enables discovery of predictive biomarkers for targeted therapeutics. We have established a large collection of NSCLC PDX models (NSCLC-HuPrime®) by engrafting naïve patient tumor tissues into immune-compromised mice2. Among these models, we have identified one model, LU1656, of NSCL carcinosarcoma histology and with EML4-ALK fusion mutation. This mutation apparently causes over-expression of ALK as measured at mRNA level. This model has wild-type KRAS, c-MET and EGFR genes. Treatment of LU1656 with Crizotinib caused significant but not complete tumor response, suggesting ALK activation is one of the oncogenic drivers of this model. In addition, LU1656 also responded to Cetuximab, but respond poorly to Erlotinib. It would be interesting to examine the combination of these treatments. This model is, to our knowledge, the first reported PDX model with EML4-ALK fusion mutation. We believe that LU1656 would be a useful model to evaluate investigational ALK inhibitors, and new combination treatment regimens of Crizotinib and standard of care chemotherapies. Citation Format: Jie Cai, Mengmeng Yang, Jianyun Deng, Xiaoming Song, Xuesong Huang, Taiping Chen, Jean Pierre Wery, Yiyou Chen, Henry QX Li. A NSCLC PDX with EML4-ALK fusion mutation responds to crizotinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 337. doi:10.1158/1538-7445.AM2013-337

Dramatic complete response in patient with lung adenocarcinoma

The poor prognosis of non-small-cell lung cancer (NSCLC) is changing thanks to the constant development of new treatments and the introduction of target therapies, even in stage IV disease. This patient had bone metastases when he was diagnosed. Maintenance treatment, a much discussed topic nowadays, achieved a dramatic complete response.

Effect of hematologic improvement (HI) on survival in patients (pts) given targeted therapy (TT) as initial treatment of acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS)

7059 Background: Recent years have seen the introduction of TT for pts with AML and HR- MDS (> 10% marrow blasts). New criteria, less stringent than those for CR, for response to these agents have been promulgated, giving rise to the response category HI. However, the effect of achieving HI on survival is uncertain. Methods: 180 pts, median age 73, with AML or HR-MDS received TT, most commonly decitabine (69 pts), from 2000–2006. Treatment-related death occurred in 11%, CR in 28%, CRp in 6%, and 55% (99 pts) were resistant. We examined survival in these 99 according to whether TT produced HI, blood count criteria for which were as defined by the International Working Group (IWG) for MDS. Initially, we, unlike the IWG, did not require any duration of HI, however; in subsequent analyses, we required durations of = 4 weeks (HI-4) and, like the IWG, = 8 weeks (HI-8). Results: Survival time dated from start of TT was similar in the 32 pts who achieved HI and the 67 who did not. However, the 13 pts with HI-8 lived longer than those with shorter or no HI (48% vs. 11% at 2 years, p=0.01) as did the 14 with HI-4 (p=0.01). Because HI-4 and HI-8 pts had to live long enough to achieve and maintain HI, we re-did the analysis including only the 84 pts who lived = 67 days from start of TT, the median time needed to observe HI-4. This analysis, which included HI-4, age, and cytogenetics as predictors of survival, indicated that HI-4 was the strongest predictor of longer survival (HR 0.34, 95% CI 0.13–0.86, p=0.02). Results were analogous when we limited the analysis to the 68 pts who lived at least 138 days, by which time 75% of HI-4 pts had achieved HI (p=0.06). Conclusions: Our results suggest that HI-4 (or HI-8 as defined by the IWG) following TT confers a survival benefit in AML or HR-MDS. No significant financial relationships to disclose.