KRAS mutation predict response and outcome in advanced non-small cell lung carcinoma without driver alterations receiving PD-1 blockade immunotherapy combined with platinum-based chemotherapy: a retrospective cohort study from China.

Background: The selection of patients for immunotherapy remains challenging given the lack of highly specific and highly sensitive biomarkers. Kirsten rat sarcoma (KRAS) mutation is the most frequent molecular alteration found in advanced non-small cell lung carcinoma (NSCLC). We explored whether KRAS mutation status predicted the effects of first-line immune checkpoint inhibitor (ICI) treatment and platinum-based chemotherapy in Chinese patients with advanced NSCLC. Methods: Clinical data were extracted from medical records of patients with advanced NSCLC at the First Affiliated Hospital of Guangzhou Medical University in China between January 2019 and March 2020. Overall survival (OS) and progression-free survival (PFS) rates were compared via log-rank tests, and independent prognostic factors were identified via Cox regression. Results: Patients with advanced NSCLC without driver alterations who were treated with ICI and platinum-based chemotherapy (N=80) were identified, including 28.7% with KRAS mutations and 71.3% with non-KRAS mutations. Tumor programmed death-ligand 1 (PD-L1) expression was analyzed using a 1% cutoff, and 32.5% of patients were negative and 67.5% were positive. The median tumor mutational burden (TMB) was 7.29 mutations per megabase (muts/Mb) (range, 0.08-44.8 muts/Mb), with 32.5% of cases <5 muts/Mb and 67.5% ≥5 muts/Mb. The median PFS and OS for the entire cohort were 9.8 (95% CI: 9.1-10.5) and 17.6 (95% CI: 14.4-20.8) months, respectively. The 6-month PFS rate was 67.5% and the 1-year OS rate was 72.5%. Thirty-five patients survived until the last follow-up. The OS and PFS of patients with KRAS mutations were significantly higher than those in the non-KRAS mutant group (P<0.05). The Cox multivariate analyses showed that brain metastasis [hazard ratio (HR) =0.232, 95% CI: 0.102-0.530; P=0.001], TMB (HR =5.675, 95% CI: 1.948-16.535; P=0.001), KRAS mutation (HR =2.552, 95% CI: 1.141-5.708; P=0.023) were independent predictors of OS in patients treated with ICIs and platinum-based chemotherapy. Liver metastasis (HR =0.344, 95% CI: 0.191-0.619; P<0.001) and KRAS/tumor protein p53 (TP53) co-mutation (HR =0.220, 95% CI: 0.067-0.725; P=0.013) were the prognostic factor for PFS of qualified patients. Conclusions: This work provides evidence that KRAS mutation in advanced NSCLC may be served as a potential predictive biomarker for immunotherapeutic efficacy.

Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations.

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

Advances in Therapeutic Approaches for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), defined as breast cancer lacking expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), accounts for up to 20% of all breast cancer, and it occurs at a higher frequency in younger, African American, and Hispanic women. Compared to breast cancers that are hormone receptor and/or HER2 positive, TNBC has an aggressive clinical course and worse prognosis. Because TNBC is by definition unresponsive to endocrine therapy (eg, tamoxifen, aromatase inhibitors) and HER2-directed therapies (eg, trastuzumab), chemotherapy continues to play an important role. TNBC constitutes a molecularly heterogeneous group of tumors that can vary in response to treatment, and clinical management can be challenging, particularly for the practicing community oncologist, for whom breast cancer may be only one of many tumor types encountered. In January 2020, the Breast Cancer Therapy Expert Group (BCTEG) convened a roundtable discussion on the topic of advances in the treatment of TNBC. Topics discussed included histopathologic classification/definition of TNBC, neoadjuvant strategies, adjuvant chemotherapy (with special emphasis on management of patients who do not experience a pathologic complete response), and treatment of metastatic disease. Also reviewed was the wide range of emerging pathways and therapies currently under investigation to expand TNBC treatment options, including immunotherapies and poly(ADP-ribose) polymerase (PARP) inhibitors. This article summarizes the BCTEG discussion and highlights the key opinions relating to the treatment of patients with TNBC.

Malignant Gastrointestinal Neuroectodermal Tumor (GNET) with Prolonged Disease-Free Survival after Platinum-Based Chemotherapy.

Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare disease with a handful of cases described in literature. GNET has only become a well-known/widely accepted entity in the recent years, but it is still not listed in the database of rare diseases. Due to the rarity of disease, there are no guidelines on standard therapeutic approaches in the adjuvant or metastatic setting. Here, we describe a unique case of GNET with a 7-year disease-free survival following adjuvant cisplatin and etoposide chemotherapy. This is the longest disease-free survival that has ever been described in literature and may support using this combination in a larger cohort of patients in the context of a global clinical trial. We will also review the histopathologic features of GNET and potential therapeutic options in the metastatic setting.

BAP1: role in carcinogenesis and clinical implications.

BRCA-1 associated protein 1 (BAP1) is a tumor suppressor gene that has been implicated in the pathogenesis of several malignancies and is gaining more recognition as a crucial gene that could be amenable to therapeutic manipulation. There is a growing interest in prevention and establishing cancer screening guidelines in patients with germline BAP1 mutations to aid with early detection and treatment of associated malignancies. We aim to give a concise review of BAP1 and its role in carcinogenesis, the BAP1 cancer predisposition syndrome and discuss clinical implications including suggested screening guidelines, and potential targeted therapeutic options.

A Roundtable Discussion of the Breast Cancer Therapy Expert Group (BCTEG): Clinical Developments and Practice Guidance on Human Epidermal Growth Factor Receptor 2 (HER2)-positive Breast Cancer.

Expression of human epidermal growth factor receptor 2 (HER2) in breast cancer defines a subset of patients (∼15%-20%) who are candidates for anti-HER2 therapies, most notably, trastuzumab, pertuzumab, antibody drug conjugates (eg, T-DM1), and tyrosine kinase inhibitor (TKI) drugs (eg, lapatinib and neratinib), all of which have dramatically changed the prognosis for this aggressive subtype of breast cancer. A roundtable meeting of the Breast Cancer Therapy Expert Group (BCTEG) was convened in March 2018 in an effort to discuss and clarify, from the perspective of the practicing community oncologist, recent developments in the diagnosis and treatment of HER2-positive (HER2+) breast cancer. Members of the group selected 4 key topics for discussion prior to the meeting, including diagnosis of HER2+ disease, and its treatment in the neoadjuvant, adjuvant, and metastatic settings. Approved testing methods, such as immunohistochemistry and fluorescence in situ hybridization, are used to demonstrate overexpression and/or amplification of HER2 in breast tumors, and established clinical guidelines are used to appropriately define treatment plans for patients with HER2+ disease. The panel acknowledges a range of treatment options now available for treatment of HER2+ breast cancer in the neoadjuvant, adjuvant, and advanced/metastatic settings, although it is noted that many controversies remain, including the optimal sequence of therapies, the most appropriate treatment(s) for subsets of patients with HER2+ disease (eg, hormone receptor-negative or -positive/HER2+), and uncertainties surrounding the diagnosis and definition of HER2+ disease. The current report summarizes the discussion of the BCTEG panel on this topic.

Case-Based Review and Clinical Guidance on the Use of Genomic Assays for Early-Stage Breast Cancer: Breast Cancer Therapy Expert Group (BCTEG).

In addition to classical clinicopathologic factors, such as hormone receptor positivity, human epidermal growth factor receptor 2 (HER2) status, and tumor size, grade, and lymph node status, a number of commercially available genomic tests may be used to help inform treatment decisions for early breast cancer patients. Although these tests improve our understanding of breast cancer and help to individualize treatment decisions, clinicians face challenges when deciding on the most appropriate test to order, and the advantages, if any, of one test over another. The Breast Cancer Therapy Expert Group (BCTEG) recently convened a roundtable meeting to discuss issues surrounding the use of genomic testing in early breast cancer, with the goal of providing practical guidance on the use of these tests by the community oncologist, for whom breast cancer may be only one of many tumor types they treat. The group recognizes that genomic testing can provide important prognostic (eg, risk for recurrence), and in some cases predictive, information (eg, benefit of chemotherapy, or extended adjuvant endocrine therapy), which can be used to help guide treatment decisions in breast cancer. The available tests differ in the types of information they provide, and in the patient populations and clinical trials that were conducted to validate them. We summarize the discussion of the BCTEG on this topic, and we also consider several patient cases and clinical scenarios in which genomic testing may, or may not, be useful to guide treatment decisions for the practicing community oncologist.

Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors.

PURPOSE: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors.Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3+3+3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. RESULTS: The safety analysis set included 111 patients who received ≥1 dose of AMG 337. Thirteen patients had ≥1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade ≥3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n = 6) and fatigue (n = 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%-17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%-50.2%) in MET-amplified patients; median (range) duration of response was 202 (51-1,430+) days in all patients and 197 (64-1,430+) days in MET-amplified patients. CONCLUSIONS: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation.See related commentary by Ma, p. 2375.

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.

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).

PURPOSE: To 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. METHODS: A 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. RESULTS: Level 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. CONCLUSIONS: Thus far, three CDK 4/6 inhibitors-palbociclib, ribociclib, and more recently, abemaciclib-have been approved for use in the setting of HR+, HER2-, mBC.  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.

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.

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

PURPOSE: Management 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. METHODS: A 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. RESULTS: Topics addressed included risk of contralateral breast cancer recurrence in patients with estrogen receptor-positive early breast cancer who have undergone 5 years 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. CONCLUSIONS: A 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.

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

BACKGROUND: Malignant 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 PRESENTATION: We 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. CONCLUSION: To the best of our knowledge, this is the first case of acral malignant acrospiroma with reported next generation sequencing results.

Antihistamine-Induced Hepatitis: 2 Cases Involving Loratidine.

Antihistamine-induced hepatitis is rare. We present 2 cases of antihistamine-induced hepatitis with autoimmune features, caused by loratidine. One case was confirmed by rechallenge. Identifying and discontinuing the offending agent are essential for treatment.

Successful use of Trastuzumab with anthracycline-based chemotherapy followed by trastuzumab maintenance in patients with advanced HER2-positive gastric cancer.

BACKGROUND: There is no standard chemotherapy regimen that is universally accepted for the treatment of advanced gastric cancer. Trastuzumab added to chemotherapy improves survival in patients with metastatic human epidermal growth factor receptor-2 (Her2/neu)-overexpressing gastric cancer. Data are lacking for the combination of trastuzumab with other chemotherapy regimens, apart from the cisplatin/fluorouracil backbone used in the pivotal TOGA trial. PATIENTS AND METHODS: In this retrospective analysis, we included patients with gastric cancer with HER2 overexpression who received trastuzumab in addition to their first-line chemotherapy, with or without trastuzumab maintenance therapy. The end-points were response and tolerance to treatment. RESULTS: We identified seven patients who met the search criteria; six had metastatic disease and one had locally advanced unresectable disease. Four patients received epirubicin/oxaliplatin/capecitabine/trastuzumab, and the others had non-anthracycline-based chemotherapy with trastuzumab. All patients had radiological responses to treatment - one had a complete response and six had partial responses. Among the four patients who received anthracycline-based chemotherapy with trastuzumab, there was a transient decline in cardiac ejection fraction in three, but all resolved without sequelae. All patients received a period of chemotherapy induction followed by trastuzumab monotherapy for maintenance. The median progression-free survival was 14.6 months and median overall survival was 16.4 months. CONCLUSION: Trastuzumab is an important agent for the treatment of HER2-overexpressing gastric cancer. We recorded an acceptable safety and efficacy profile in this small cohort treated with anthracycline-based chemotherapy with trastuzumab followed by trastuzumab maintenance.

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.