Mohammad Jahanzeb

Non-small cell lung cancer.

Most patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced cancer. These guidelines only include information about stage IV NSCLC. Patients with widespread metastatic disease (stage IV) are candidates for systemic therapy, clinical trials, and/or palliative treatment. The goal is to identify patients with metastatic disease before initiating aggressive treatment, thus sparing these patients from unnecessary futile treatment. If metastatic disease is discovered during surgery, then extensive surgery is often aborted. Decisions about treatment should be based on multidisciplinary discussion.

Endocrine Therapy for Hormone Receptor–Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline

PURPOSE To develop recommendations about endocrine therapy for women with hormone receptor (HR) -positive metastatic breast cancer (MBC). METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC. RECOMMENDATIONS Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2-positive MBC, human epidermal growth factor receptor 2-targeted therapy plus an AI can be effective for those who are not chemotherapy candidates.

Southwest Oncology Group S0802: A Randomized, Phase II Trial of Weekly Topotecan With and Without Ziv-Aflibercept in Patients With Platinum-Treated Small-Cell Lung Cancer

PURPOSE Development of new therapies for previously treated small-cell lung cancer (SCLC) is a major unmet need. Here, we describe a randomized, phase II trial of weekly topotecan with or without ziv-aflibercept (VEGF-trap) in this clinical setting. PATIENTS AND METHODS Patients with previously treated SCLC (one line of platinum-based chemotherapy), performance status of 0 to 1, adequate organ function, treated brain metastases, and no recent vascular events or bleeding diatheses were eligible. Eligible patients were stratified as platinum-sensitive or platinum-refractory and randomly assigned to receive weekly topotecan 4 mg/m(2) intravenously (IV) with or without ziv-aflibercept 6 mg/kg IV every 21 days. Progression-free survival (PFS) at 3 months was the primary end point. RESULTS In 189 randomly assigned patients, treatment arms were well balanced with regard to clinical characteristics. The 3-month PFS was significantly improved with the addition of ziv-aflibercept in patients who had platinum-refractory disease (27% v 10%; P = .02) but not in patients with platinum-sensitive disease (24% v 15%; P = .22). Although response rate was low, disease control rate was higher with combination therapy than with topotecan alone in patients who had platinum-sensitive disease (37% v 18%; P = .05) and in those who had platinum-refractory disease (25% v 15%; P = .14). Overall survival (OS) was not significantly improved in either strata. Grades 3 to 5 toxicities were more common with the addition of ziv-aflibercept. CONCLUSION Ziv-aflibercept improved the 3-month PFS in patients who had platinum-refractory SCLC, but its addition increased toxicity. OS was similar with combined ziv-aflibercept and topotecan compared with topotecan in both strata.

Safety and effectiveness of bevacizumab-containing treatment for non-small-cell lung cancer: final results of the ARIES observational cohort study.

Introduction: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor, was approved by the US Food and Drug Administration for the treatment of advanced non–small-cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. ARIES (Avastin Regimens: Investigation of Effectiveness and Safety), a prospective observational cohort study, evaluated outcomes in a large, community-based population of patients with first-line NSCLC. Methods: From 2006 to 2009, ARIES enrolled patients with locally advanced or metastatic NSCLC who were eligible for bevacizumab, excluding those with predominantly squamous histology. Patients were required to provide informed consent and to have initiated bevacizumab with chemotherapy within 4 months before enrollment. There were no protocol-defined treatments or assessments. The dosing of bevacizumab and chemotherapy, and the choice of chemotherapy regimen, was at the discretion of the treating physician. Results: ARIES enrolled 1967 patients with first-line NSCLC. At study closure, median follow-up was 12.5 months (range, 0.2–65.5). Median age was 65 years (range, 31–93), and 252 patients (12.8%) identified as never smokers. Median progression-free survival was 6.6 months (95% confidence interval, 6.3–6.9), and median overall survival was 13.0 months (95% confidence interval, 12.2–13.8) with first-line bevacizumab plus chemotherapy. Incidences of bevacizumab-associated adverse events (19.7% overall) were consistent with those in randomized controlled trials of bevacizumab in NSCLC. Conclusion: Results from ARIES demonstrate similar outcomes to randomized controlled trials of bevacizumab when added to standard chemotherapy in a real-world patient population with advanced NSCLC.

Blockade of the HER Family of Receptors in the Treatment of HER2-Positive Metastatic Breast Cancer

Breast cancer is the most common type of cancer among women and the second leading cause of cancer death in the United States. Metastatic breast cancer is considered incurable, and treatment is aimed at palliating symptoms, achieving remission, and prolonging survival. Treatment options for metastatic disease vary based on tumor surface markers and clinical factors in an individual patient and include cytotoxic chemotherapy, hormonal therapy, biological therapy, or some combination of these. An important molecular determinant of therapy is the human epidermal growth factor receptor 2 (HER2) positivity of the tumor, which affects response to HER2-targeted treatment. HER2 is a member of the human epidermal growth factor receptor family of receptor tyrosine kinases, also known as the HER family, which activates signaling that promotes tumorigenic cellular processes such as proliferation and evasion of apoptosis. Several targeted agents, including monoclonal antibodies and tyrosine kinase inhibitors that inhibit one or more HER family receptors have been developed that affect signaling through this pathway. Some of these, such as trastuzumab and lapatinib, have been approved for breast cancer treatment. Resistance to therapy is a challenge that limits the duration of benefit achieved with these agents. Therefore, combinations of HER family-targeted agents with other therapies such as cytotoxic agents, hormonal therapy, or inhibitors of other cellular pathways, are being developed to exploit synergy and overcome resistance mechanisms. Here we review the HER family-targeted agents currently approved or in development for HER2-positive metastatic breast cancer with a focus on strategies to overcome tumor resistance.

The Potential Application of Zoledronic Acid as Anticancer Therapy in Patients With Non–Small-Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) is frequently characterized by metastases to bone. Bisphosphonates have demonstrated efficacy in reducing the risk of skeletal-related events in cancer patients with bone metastases, including those with NSCLC. Zoledronic acid (ZA) is one of the most potent bisphosphonates and is approved for the first-line treatment of patients with multiple myeloma and bone metastases from solid tumors. Recent preclinical and clinical data suggest that ZA may also have direct and indirect anticancer effects. Several preclinical studies have provided insight into the potential mechanisms responsible for the anticancer activity of ZA, including inhibiting farnesyl pyrophosphate or geranylgeranyl pyrophosphate and activation of immune-mediated anticancer response by γδ T cells. In patients with NSCLC, ZA has been shown to reduce vascular endothelial growth factor levels with a direct correlation to clinical response. Clinical studies in this setting have shown that ZA may also provide a survival benefit and prolong time to progression. Ongoing studies are evaluating the efficacy of ZA for anticancer activity and prevention of bone metastases. Bisphosphonates, particularly ZA, are generally well tolerated and may likely offer an adjunct therapeutic option for patients with NSCLC.

Does Race Affect Outcomes in Triple Negative Breast Cancer

Curcumin is a compound with anti-tumor effects in a tolerable dose. A recent paper by Rowe et al described that curcumin induced DNA damage in triple negative breast cancer cells and regulated BRCA1 protein expression and modification.1 Related research and potential use of curcumin will be discussed in this article.The molecular classification for breast carcinomas has been used in clinical studies with a simple surrogate panel of immunohistochemistry (IHC) markers. The objective of this current project was to study the molecular classification of commonly used breast cancer cell lines by IHC analysis. Seventeen breast cancer cell lines were harvested, fixed in formalin and made into cell blocks. IHC analyses were performed on each cell block with antibodies to estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, CK5/6, Ki-67 and androgen receptor (AR). Among the 17 cell lines, MCF-7 and ZR-75-1 fell to Luminal A subtype; BT-474 to Luminal B subtype; SKBR-3, MDA-MD-435 and AU 565 to HER2 over-expression subtype; MDA-MB-231, MCF-12A, HBL 101, HS 598 T, MCF-10A, MCF-10F, BT-20, 468 and BT-483 to basal subtype. MDA-MB-453 belonged to Unclassified subtype. Since each subtype defined by this IHC-based molecular classification does show a distinct clinical outcome, attention should be paid when choosing a cell line for any study.I would like to welcome breast cancer research community to the first editorial of our newest journal “Breast Cancer: Basic and Clinical Research”. In pursuit of breast cancer culprits, we have come a long way since the early 90’s when the first breast cancer susceptibility gene BRCA1 was mapped and cloned. In the past few years, several new loci associated with the various degree of breast cancer risk have been identified using “Candidate Gene Association Study (CGAS) and Genome-Wide Association Study (GWAS)” approaches. This editorial is meant to quickly glance over recent findings of these population-based association studies.Among women, the most prevalent type of cancer is breast cancer, affecting 1 out of every 8 women in the United States; in Puerto Rico, 70 out of every 100,000 will develop some type of breast cancer. Therefore, a better understand of the potential risk factors for breast cancer could lead to the development of early detection tools. A gene that has been proposed as a risk factor in several populations around the world is Apolipoprotein E (apoE). ApoE functions as a mechanism of transport for lipoproteins and cholesterol throughout the body, with 3 main isoforms present in humans (apoE2, apoE3, and apoE4). Whether or not apoE4 is a risk factor for breast cancer remains controversial. Previous studies have either included test subjects of all ages (20–80) or have focused on late-onset (after age 50) breast cancer; none has concentrated specifically on early-onset (aged 50 and younger) breast cancer. The objectives of this study was to examine (in a Puerto Rican population) the differences in the relative frequency of occurrence of apoE4 in non-breast cancer versus breast cancer patients and to examine, as well, the potential differences of same in early- versus late-onset patients. We found an increased frequency of apoE4 (odds ratio 2.15) only in early-onset breast cancer survivors, which is similar to the findings of those studies that combined or adjusted for age as well as for an association between apoE4 and decreased tumor size. ApoE is also a potential risk factor for long-term cognitive effects after chemotherapy and affects response to hormone replacement. Our data supports the theory that knowing the apoE genotype of women who are at risk of developing breast cancer may be beneficial, as such knowledge would aid in the prediction of tumor size and the development of treatment regimens.The provasopressin protein (proAVP) is expressed by invasive breast cancer and non-invasive breast cancer, or ductal carcinoma in situ (DCIS). Here we demonstrate the ability of the monoclonal antibody MAG1 directed against the C-terminal end of proAVP to identify proAVP in all cases examined of human invasive cancer and DCIS (35 and 26, respectively). Tissues were chosen to represent a relevant variation in tumor type, grade, patient age, and menopausal status. By comparison, there was 65% positive staining for estrogen receptor, 61% for progesterone receptor, 67% for nuclear p53, and 39% for c-Erb-B2 with the invasive breast cancer sections. Reaction with the normal tissue types examined (67) was restricted to the vasopressinergic magnocellular neurons of the hypothalamus, where provasopressin is normally produced, and the posterior pituitary, where these neurons terminate. The breast epithelial tissue sections on the tissue microarray did not react with MAG1. Previously, we demonstrated that polyclonal antibodies to proAVP detected that protein in all breast cancer samples examined, but there was no reaction with breast tissue containing fibrocystic disease. The results presented here not only expand upon those earlier results, but they also demonstrate the specificity and effectiveness of what may be considered a more clinically-relevant agent. Thus, proAVP appears to be an attractive target for the detection of invasive breast cancer and DCIS, and these results suggest that MAG1 may be a beneficial tool for use in the development of such strategies.

Oral versus intravenous administration of vinorelbine as a single agent for the first-line treatment of metastatic nonsmall cell lung carcinoma (NSCLC): A randomized phase II trial

Objectives:Many patients with metastatic nonsmall cell lung carcinoma (NSCLC) cannot tolerate intravenous chemotherapy. Orally active agents would be more convenient and thus could improve their quality of life. Methods:A total of 189 patients were randomized 2:1, 181 patients received treatment, 120 PO and 61 IV vinorelbine, 158 patients had stage IV and 31 stage IIIB disease. Among patients who received PO vinorelbine, the median age was 72 years, 62% were males; the Karnofski Performance Status (KPS) was 80–100 in 71%. These compare with a median age of 70 years, 56% male, and KPS of 80–100 in 65% of patients who received IV vinorelbine. Oral vinorelbine 60 mg/m2 was to be dose-escalated to 70 mg/m2 after the initial 3-weekly doses if there was no unacceptable toxicity. Intravenous vinorelbine was to be given 30 mg/m2 weekly. Results:Five patients (4%) on PO and 8 (13%) on IV vinorelbine had a confirmed partial response, 56 (44%) and 29 (46%) had stable disease, respectively. Median time-to-disease-progression was 16.6 weeks (PO) versus 23.9 weeks (IV), and the median survival was 26 weeks (PO) versus 40.9 weeks IV vinorelbine. Median survival on PO vinorelbine for patients with KPS 60–70 was 8.3 weeks versus 43 weeks (IV). On PO vinorelbine 59 patients (57%) were dose escalated, 9 (7.5%) were dose reduced, and 10 (8.3%) did not receive PO vinorelbine at week 4. Pharmacokinetic studies confirmed PO vinorelbine exposure was significantly less than IV exposure. Conclusion:The inability to escalate the dose of PO vinorelbine above 60 mg/m2 weekly resulted in inferiority to IV vinorelbine at 30 mg/m2 weekly, especially in patients with poor performance status.

Bisphosphonates as anticancer therapy for early breast cancer.

Bisphosphonates (BPs) are approved for preventing the skeletal-related events associated with malignant bone disease. Several studies indicate that they may also prevent cancer therapy-induced bone loss. Multiple preclinical and early clinical studies provide evidence of the anticancer activity of BPs, including an inhibition of tumor cell proliferation and survival, a reduction of angiogenesis, and a stimulation of innate anticancer immunity. In addition to their evident single-agent activity, BPs may also act synergistically with other antineoplastic agents. Translational studies corroborate the effects of bisphosphonates on angiogenesis and innate immunity. Moreover, many of these anticancer effects occur at clinically relevant drug concentrations. Indeed, clinical data suggest that in addition to being well-tolerated and efficacious in maintaining bone health, BPs including clodronate, pamidronate, and zoledronic acid also improve cancer-related outcomes such as tumor response, disease-free survival, and overall survival in patients with breast cancer. Among the BPs, zoledronic acid is the most extensively studied in the adjuvant and neoadjuvant settings and has accumulated the most data pointing to anticancer activity, although a survival benefit has not been documented. Future studies are necessary to elucidate the anticancer activity of BPs. Other aspects of BP therapy that require further study include the optimization of dosing regimens for single agents and combinations in various clinical settings and the identification of prognostic factors that predict treatment outcomes. This review summarizes the preclinical and clinical evidence of anticancer activity of BPs, with a focus on zoledronic acid.

Use of Cytotoxic Chemotherapy in Metastatic Breast Cancer: Putting Taxanes in Perspective

Agents that target microtubule (MT) dynamics have been used extensively for the treatment of metastatic breast cancer (MBC). Among these agents are taxanes (solvent-based paclitaxel [sb-paclitaxel], docetaxel, and nab-paclitaxel) and non-taxanes, such as eribulin and ixabepilone. Although these agents have been approved for the treatment of MBC, questions regarding the ideal agent, regimen (single agent vs. combination vs. sequential), and schedule still remain. This systematic review examined pivotal trials for taxanes, eribulin, and ixabepilone as well as first-line taxane trials in MBC. Only randomized trials that enrolled ≥ 100 patients were included. Publications on combination regimens with targeted agents were excluded unless they also included a comparison between nontargeted regimens. The studies were grouped into taxane versus taxane, sb-paclitaxel versus non-taxane, and docetaxel versus non-taxane regimens. In taxane versus taxane comparisons, the efficacy of sb-paclitaxel and docetaxel appeared similar, nab-paclitaxel every 3 weeks (q3w) appeared superior to sb-paclitaxel q3w, and weekly nab-paclitaxel appeared superior to docetaxel. In general, taxane regimens demonstrated higher overall response rates (ORRs) versus non-taxane regimens; however, only 2 trials demonstrated longer overall survival (OS) for taxane regimens. Taxanes will likely continue to be used in earlier lines of therapy, whereas eribulin and ixabepilone may be more appropriate for later lines of treatment. Ongoing research may identify biomarkers that could help in selecting the appropriate MT-targeted agent for a given patient.