Muaiad Kittaneh

Molecular Profiling for Breast Cancer: A Comprehensive Review

In recent years advances in molecular biology have launched disruptive innovations in breast cancer diagnostics and therapeutics. The advent of genomics has revolutionized our understanding of breast cancer as several different biologically and molecularly distinct diseases. This research has led to commercially available polymerase chain reaction (PCR) and microarray tests that have begun to fundamentally change the way medical oncologists quantify recurrence risk in early stage breast cancer patients. The Genomics era has altered the clinicopathologic paradigm of selecting patients for adjuvant cytotoxic chemotherapy. Sufficiently powered prospective studies are underway that may establish these molecular assays as elements of standard clinical practice in breast cancer treatment. In this article, we review the strengths and limitations of currently available breast cancer-specific molecular tests.

Exemestane in the Adjuvant Treatment of Breast Cancer in Postmenopausal Women

Exemestane is an irreversible inhibitor of the aromatase enzyme, which is a key component in the production of estrogen. The majority of breast cancers are sensitive to the proliferative effects of estrogen. Exemestane is approved for the adjuvant treatment of postmenopausal women with breast cancer after 2 to 3 years of tamoxifen therapy, based on a 32% improvement in disease-free survival compared with 5 years of tamoxifen alone (P < 0.001). Exemestane has also shown clinical benefits as an upfront therapy. The safety profile of exemestane shares some side effects with tamoxifen (hot flashes and arthralgia), but is not associated with an increased risk of endometrial cancer or thromboembolic events. This review will discuss in detail the efficacy and safety of exemestane in early breast cancer.

1086OPHASE IB/II STUDY OF LEE011 (CDK4/6 INHIBITOR) AND LGX818 (BRAF INHIBITOR) IN BRAF-MUTANT MELANOMA

ABSTRACT Aim: Despite improvements in BRAF-mutant melanoma therapy, resistance is problematic. The cyclin D–CDK4/6–INK4A–Rb pathway is frequently dysregulated in melanoma and is associated with reduced BRAF inhibitor (BRAFi) response. LGX818 and LEE011 selectively inhibit BRAF and CDK4/6, respectively. In preclinical models, adding LEE011 to LGX818 delayed BRAFi resistance. This study investigates safety and efficacy of LEE011 and LGX818 in pts with BRAF-mutant locally advanced or metastatic, BRAFi-naive or BRAFi-pretreated melanoma. Methods: Pts receive once-daily LEE011 (3-weeks-on/1-week-off) and LGX818 (continuously). Dose escalation is guided by Bayesian Logistic Regression Model with overdose control principle and real-time PK. Primary objective: MTD and/or RP2D determination. Secondary objectives: safety, PK, and efficacy. Results: As of April 8, 2014, 18 pts received LEE011 and LGX818: 6 at 200/300; 7 at 300/200; 3 at 400/100; 2 at 400u2003mg LEE011/200u2003mg LGX818. Median age: 64 (23–81) yrs; median 3 prior regimens: 78% prior BRAFi therapy; 44% prior MEKi therapy (all of whom received prior BRAFi). Two DLTs reported, both at the 200/300 dose (G3 myalgia and G3 conjugated hyperbilirubinemia). Study-drug related (SDR) all-grade AEs (>25%; N = 11): palmar–plantar hyperkeratosis (PPH; 46%); flushing (36%); pruritus (36%); rash (36%); alopecia, dry skin, dysgeusia, fatigue, myalgia, and nausea (27% each). SDR G3/4 AEs observed in 1 pt: PPH, rash, myalgia, and blood bilirubin increase. At steady-state, exposure of LGX818 was increased 1.5-fold and 2- to 3-fold at the 200/300 and 300/200 doses, respectively, compared with single agent (SA). Exposure of LEE011 was unaltered at the 200/300 dose and decreased 0.5-fold compared with SA at the 300/200 dose. Of 9 pts evaluable for response, 2 had PRs (1 BRAFi naive and 1 BRAFi pretreated) and 6 had SD (4 ongoing ≥ 4 cycles, 2 BRAFi naive, 2 BRAFi pretreated). 9 pts remain on treatment. Conclusions: At the 200/300 dose DLTs were observed. At the 300/200 dose, a 2- to 3-fold increase in blood levels of LGX818 compared with historic levels was observed. In latter cohorts, reduced LGX818 and increased LEE011 doses are being tested and appear better tolerated. Clinical signs of activity were observed even in BRAFi-pretreated pts. Dose escalation continues. Disclosure: M. Taylor: has served on a paid advisory board for Onyx. No other conflicts; M.S. Carlino: has received honoraria from Novartis; W. Miller: has worked in a consultancy capacity or on advisory boards for Novartis, Roche, GSK, and BMS; A. Marino: is an employee of Novartis Pharma AG; V. Zhang: is an employee of and holds shares in Novartis Pharma AG; S.G. Bhansali: is an employee of and holds shares in Novartis Pharmaceuticals Corporation; S. Parasuraman: is an employee of and holds shares in Novartis Pharma AG.All other authors have declared no conflicts of interest.

Use of cyclin-dependent kinase (CDK) 4/6 inhibitors for hormone receptor-positive, human epidermal growth factor receptor 2-negative, metastatic breast cancer: a roundtable discussion by The Breast Cancer Therapy Expert Group (BCTEG)

PurposeTo provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community.MethodsA recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice.ResultsLevel 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started.ConclusionsThus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2−, mBC.xa0 The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation.

Endocrine therapy and related issues in hormone receptor-positive early breast cancer: a roundtable discussion by the breast cancer therapy expert group (BCTEG)

PurposeManagement of breast cancer is a rapidly evolving field, and, although evidence-based guidelines are available for clinicians to provide direction on critical issues in patient care, clinicians often left to address these issues in the context of community practice situations with their patients. These include the patient’s comorbid conditions, actual versus perceived benefit of treatments, patient’s compliance as well as financial/reimbursement issues, and long-term tolerability of therapy.MethodsA meeting of global oncology experts was convened in January 2017 with the belief that there is a gap in clinical practice guidance on several fundamental issues in breast cancer care, particularly in the community setting, where oncologists may encounter multiple tumor types. The goal was to discuss some of the most important questions in this area and provide some guidance for practicing oncologists.ResultsTopics addressed included risk of contralateral breast cancer recurrence in patients with estrogen receptor-positive early breast cancer who have undergone 5xa0years of adjuvant endocrine therapy, adverse events associated with endocrine therapy and their management, emergent data on adjuvant bisphosphonate therapy and its apparent benefit in reducing breast cancer recurrence, recent findings of extended adjuvant endocrine therapy trials, and the use of currently available genomic biomarker tests as a means of further informing treatment decisions.ConclusionsA summary of the discussion on these topics and several ‘expert opinion statements’ are provided herein in an effort to convey the collective insights of the panel as it relates to current standard practice.

F-18 FDG PET/CT in the assessment of recurrent anaplastic T-cell lymphoma of the external auditory canal.

We report a case of pathologically proven recurrent cutaneous anaplastic T-cell lymphoma of the ear. The patient had been previously treated with local radiotherapy 3 years prior. Recently, the patient presented with worsening pain and swelling of the left external auditory meatus. The patient underwent a workup, which included clinical, radiologic, and pathologic correlation. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography confirmed metabolically active disease in the primary lesion and local lymph node involvement, which was subsequently proven to be recurrent anaplastic Tcell lymphoma.

Detecting germline BAP1 mutations in patients with peritoneal mesothelioma: benefits to patient and family members

Germline mutations in the BRCA-1 associated tumor protein 1 (BAP1) increase susceptibility to mesothelioma and other cancers. We describe a patient with a family history of peritoneal mesothelioma, who developed malignant peritoneal mesothelioma at age 45 in the absence of known asbestos exposure. These findings lead us to hypothesize that the mesothelioma occurred in the setting of germline a BAP1 mutation. This was confirmed by genetic testing. The subsequent therapeutic choices for the patient and testing of at-risk family members highlight the importance of recognizing this genetic syndrome and screening for individuals at high risk.

Safety and pharmacokinetics of veliparib extended-release in patients with advanced solid tumors: A phase I study

The poly(ADP‐ribose) polymerase‐1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended‐release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib‐ER up to 800 mg once daily or 600 mg twice daily. Dose‐limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28‐day cycles). Seventy‐one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single‐dose veliparib‐ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration‐time curve compared with veliparib immediate‐release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib‐ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment‐related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib‐ER, versus veliparib‐IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA‐mutated breast cancers.

Malignant acrospiroma: a case report in the era of next generation sequencing

BackgroundMalignant acrospiroma is a rare tumor of the eccrine sweat glands accounting for around 6% of all malignant eccrine tumors. Typically, it presents as large ulcerated nodules, and diagnosis can be challenging as it has great overlap with its benign counterpart.Case presentationWe herein report a case of acral malignant acrospiroma, initially treated with surgical excision and adjuvant radiotherapy. After metastatic disease was confirmed, subject received multiple lines of chemo- as well as targeted therapy. Genomic testing was also done using next generation sequencing.ConclusionTo the best of our knowledge, this is the first case of acral malignant acrospiroma with reported next generation sequencing results.

BRCA1-Associated Protein 1 Testing in Cancer

To the Editor: I read with great interest the consensus report of the 2015 Weinman International Conference on Mesothelioma— specifically, the suggested guidelines for BRCA1-associated protein 1 (BAP1) genetic screening. In recent years, there has been a growing interest in BAP1cancer syndrome, and I have been involved in diagnosing and treating several patients who developed mesothelioma and other malignancies in the setting of germlineBAP1mutations. Based on my experience, this entity is often overlooked by many physicians because of the lack of familiarity with this novel familial cancer syndrome. The consensus group suggests a basic and simple approach to screening for this mutation and I suggest a broader screening strategy to better understand the extent of the disease and develop better screening along with preventive and treatment strategies. I further suggest approaching the BAP1 cancer syndrome fromtwodifferent angles. Thefirst isbyprotocols that allow