Giuseppa Ferraro

A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy. The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with.

The Risk of Toxicities from Trastuzumab, Alone or in Combination, in an Elderly Breast Cancer Population

Background: Breast cancer in the elderly is associated with high recurrence and death rates, due mostly to undertreatment. Human epidermal growth factor receptor type 2 (HER2) overexpression is infrequent in older patients. Trastuzumab-based chemotherapy is often withheld from elderly patients because of its cardiotoxicity. Patients and Methods: Medical records of consecutive HER2-positive breast cancer patients aged ≥70 years old treated between 2005 and 2010 in the participating centers were retrospectively reviewed. All patients underwent multidimensional geriatric assessment (MGA). Results: Among 59 patients identified, 51 patients were evaluable (median age 76 years). The rate of any adverse event was 20% (10/51). The most relevant cardiac adverse event consisted of symptomatic congestive heart failure (CHF; n = 1, 2%) followed by asymptomatic decreases of left ventricular ejection fraction (LVEF; n = 6, 12%). Other toxicities included moderate hypersensitivity reactions during trastuzumab infusions (n = 3, 6%). Hypertension, obesity, prior anthracyclines exposure and concurrent chemotherapy were associated with a higher incidence of toxic events. Previous radiotherapy, concurrent endocrine therapy and different trastuzumab-based regimens did not seem to influence toxicity. Conclusions: Our data suggest that trastuzumab has a good safety profile in nonfrail women aged 70 years and older. These favorable findings may be related to a limited number of anthracycline pretreatments, patient selection and a close cardiologic monitoring.

Current knowledge and future directions on bisphosphonate-related osteonecrosis of the jaw in cancer patients

Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe adverse event of long-term use of bisphosphonates that heavily affects the quality of life of cancer patients. Objective: To review epidemiologic data, pathobiology, risk factors, diagnosis and management of BRONJ. Methods: Articles were identified by searching the PubMed and MEDLINE databases and recent meetings abstracts. Results/conclusion: BRONJ pathobiology is thought to be related to bisphosphonate-induced suppression of normal bone remodeling and impairment of bone blood flow. Dental extractions, daily masticatory traumas, oral infections, chemotherapy and antiangiogenic drugs can also play an active role. Collaboration between oncologists and dentists is essential to prevent BRONJ. A conservative approach based on pain control, oral rinses, antibiotics and limited debridement represents the current management. Optimization of therapy based on reduction of bisphosphonate doses or exposure time, newer bisphosphonates and biomolecular agents could favorably impact on BRONJ incidence.

Androgen Receptor (AR), E-Cadherin, and Ki-67 as Emerging Targets and Novel Prognostic Markers in Triple-Negative Breast Cancer (TNBC) Patients

Background TNBC is an aggressive subset of breast cancer (BC) without specific target therapy. Methods This observational, retrospective study included 45 cases of TNBC. The aim of this study was to evaluate the expression of the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival (OS). Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients defined TNBC. Results The AR was positive (IHC >10%) in 26.6%. E-cadherin (CDH1) expression was considered positive if the score was ≥ 2. This expression was negative in 53.3% cases. The Ki-67 index was ≥ 20% in 37.7%. Univariate analyses showed that AR, CDH1 and Ki-67 are significantly associated with OS. Multivariate analysis showed that AR and Ki-67 expression are independent variables associated with OS. The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with poor outcome. Conclusions Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC. Hence, these molecular determinants could play an interesting role to classify subgroups of TNBC.

NSCLC and HER2: Between Lights and Shadows

The therapeutic landscape of non–small-cell lung cancer (NSCLC) has dramatically changed in the last few years with the introduction of molecularly targeted agents, leading to unprecedented results in lung tumors with a paradigmatic shift from a “one size fits all” approach to an histologic and molecular-based approach. The discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC in 2004 and the marked response to the EGFR tyrosine kinase inhibitor gefitinib, in a small subset of patients harboring these genetic abnormalities, stimulated the study of other kinase mutants involvement in NSCLC. The incredible story of ALK rearranged tumors, with the rapid Food and Drug Administration approval of Crizotinib after only 4 years from the discovery of EML4-ALK translocation in NSCLC, has profoundly influenced the concept of drug development in NSCLC, paving the way to a novel series of molecularly selected studies with specific inhibitors. The identification of these oncogenic drivers has dramatically changed the genetic landscape of NSCLC moving away from the old concept of a large indistinct histological entity to a combination of rare clinically relevant molecular subsets. Recently, a renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time to be associated in NSCLC with different sensitivity to the EGFR tyrosine kinase inhibitors, to have a possible prognostic role and more recently HER2 amplification has been emerged as a possible mechanism in EGFR-mutated tumors of acquired resistance to the EGFR tyrosine kinase inhibitors. In addition, dysregulation of the HER2 pathway, in particular HER2 mutations (mostly, in-frame exon 20 insertions), may represent a possible novel therapeutic target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC patients with HER2 mutations, several targeted agents have been evaluated in HER2-mutated patients, generating a growing interest upon this oncogenic driver, leading to the design of molecularly selected trials with anti-HER2 compounds and the rediscover of hastily thrown out drugs, such as neratinib. The aim of this article is to provide an overview of the role of HER2 dysregulation in NSCLCs, trying to throw a light not only on the strengths but also the weaknesses of the studies conducted so far. It is a long way to the clinical implementation of these biomarkers and probably the increasing use of next generation sequencing techniques, the creation of large multi-institutional molecular testing platforms and the design of rationally based trials can get closer personalized medicine in NSCLC.

Central nervous system involvement in ALK-rearranged NSCLC : promising strategies to overcome crizotinib resistance

ABSTRACT Introduction: ALK rearranged Non Small Cell Lung Cancers (NSCLCs) represent a distinct subgroup of patients with peculiar clinic-pathological features. These patients exhibit dramatic responses when treated with the ALK tyrosine kinase inhibitor Crizotinib, albeit Central Nervous System (CNS) activity is much less impressive than that observed against extracranial lesions. CNS involvement has become increasingly observed in these patients, given their prolonged survival. Several novel generation ALK inhibitors have been developing to increase CNS penetration and to provide more complete ALK inhibition.. Areas covered: The CNS activity of Crizotinib and novel generation ALK inhibitors will be summarized in this review, evaluating the strengths and weaknesses of the therapeutic strategies developed to date in this specific subgroup of NSCLCs with a look towards the future. Expert commentary: In the next few years, the results of ongoing comparative head-to-head trials will provide the definitive conclusions on the optimal treatment sequence in ALK-rearranged NSCLCs. Moreover, ongoing clinical trials with novel-generation ALK inhibitors will produce more evidences on the best approach in the growing number of ALK-positive NSCLCs with CNS involvement.

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients

Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and <10 cigarettes/day. This study clearly showed lack of any correlation between cigarette smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.

Efficacy of nab-paclitaxel plus trastuzumab in a long-surviving heavily pretreated HER2-positive breast cancer patient with brain metastases

Brain metastases (BMs) represent a major issue in clinical practice and are associated with a significant worsening of patient’s quality of life and, often, a dismal prognosis. Breast cancer (BC) is the second most common solid malignancy that metastasizes to the central nervous system. Incidence of BM varies according to the tumor subtype, with higher rates in patients with epidermal growth factor receptor 2 (HER2) overexpression and in triple negative breast cancers. The incidence of BM in HER2-positive BC patients has increased as a consequence of the success of trastuzumab-based therapy. BM represents an emerging unmet medical need and no specific treatment options exist because, until recently, nearly all randomized clinical trials in metastatic breast cancer (MBC) excluded such patients. Therefore, novel approaches in this setting are eagerly awaited. Herein, we report a lengthy progression-free survival with the combination trastuzumab/nanoparticle albumin-bound (nab)-paclitaxel in a heavily pretreated HER2-positive BC patient with BM. The long-term disease stabilization reported in the present case (>13 months) is of note for several reasons. First, the nab-paclitaxel plus trastuzumab combination, despite several previous lines of treatment, some of which were associated with known activity on BM, was the first systemic therapy not associated with central nervous system recurrence, avoiding recourse to additional locoregional treatments. Moreover, this combination was associated with long extracranial stabilization with minimal toxicity. The remarkably lengthy progression-free survival reported in our case with the nab-paclitaxel plus trastuzumab combination further confirms the efficacy and the favorable toxicity profile of this promising schedule that showed intriguing results in two phase II studies in first-line MBC and suggests a possible activity on BM. In conclusion, weekly nab-paclitaxel plus trastuzumab may represent a valuable option in the treatment of HER2-positive MBC with BM after radiotherapy and is effective and associated with a good toxicity profile, even in heavily pretreated patients.

Effectiveness of the combination therapy with lisinopril, ivabradine and multivitamin supplementation in anthracycline-induced severe cardiotoxicity

Introduction:Leftventricular(LV)dysfunctionmimickingcongestiveheart failure represents the most dramatic feature of anthracycline-induced cardiotoxicity (AIC) [1–4]. Over the last decade, a growinginterest arose about less cardiotoxic compounds and more valuablecardioprotective strategies [5]. Doxorubicin and epirubicin are potentcancer-fightingmedicationsbelongingtothegroupofasantineoplastics,in particular to the family of anthracyclines, habitually used in breastcancer patients. The risk of developing cardiac dysfunction is muchlower by using nonpegylated liposomal doxorubicin hydrochloride thanstandard doxorubicin, at least for a lifetime cumulative dose not over-coming 600 mg/m

Uncommon breast metastatic site and eribulin responsiveness in a heavily pretreated patient

During the last decades, the introduction of new cytotoxics and targeted therapies resulted in a prolongation of survival and a minimization of toxicity in the treatment of metastatic breast cancer. However, to date, there was no standard of care following second-line therapy in this setting. In Phase III EMBRACE study, eribulin obtained a statistically significant improvement in the overall survival of pretreated metastatic breast cancer patients. This case report describes a heavily chemo-pretreated woman with important bone, nodal, hepatic and choroidal involvement from breast cancer who had a remarkable, unexpected and lasting disease response after treatment with eribulin. This case underlines how this well-tolerated monochemotherapy may be able to obtain a prolonged disease control and a good clinical outcome.