J.D. Palmer

Targeting brain metastases in ALK-rearranged non-small-cell lung cancer

The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

What is the ideal radiotherapy dose to treat prostate cancer? A meta-analysis of biologically equivalent dose escalation

PURPOSE To determine if increasing the biologically equivalent dose (BED) via various radiation fractionation regimens is correlated with clinical outcomes or toxicities for prostate cancer. METHODS AND MATERIALS We performed a meta-analysis that included 12,756 prostate cancer patients from 55 studies published from 2003 to 2013 who were treated with non-dose-escalated conventionally fractionated external beam radiation therapy (non-DE-CFRT), DE-CFRT, hypofractionated RT, and high dose rate brachytherapy (HDR-BT; either mono or boost) with ⩾5-year actuarial follow-up. BEDs were calculated based on the following formula: (nd[1+d/(α/β)]), where n is the number of fractions, and d is dose per fraction; assuming an α/β of 1.5 for prostate cancer and 3.0 for late toxicities. Mixed effects meta-regression models were used to estimate weighted linear relationships between BED and the observed percentages of patients experiencing late toxicities or 5-year freedom from biochemical failure (FFBF). RESULTS Increases in 10 Gy increments in BED (at α/β of 1.5) from 140 to 200 Gy were associated with 5-unit improvements in percent FFBF. Dose escalation of BED above 200 Gy was not correlated with FFBF. Increasing BED (at α/β of 3.0) from 98 to 133 Gy was associated with increased gastrointestinal toxicity. Dose escalation above 133 Gy was not correlated with toxicity. CONCLUSIONS An increase in the BED to 200 Gy (at α/β of 1.5) was associated with increased disease control. Doses above 200 Gy did not result in additional clinical benefit.

MicroRNA expression altered by diet: Can food be medicinal?

As the link between metabolism and major disease processes becomes more well-defined, the identification of key molecular targets is leading to new therapeutic strategies. As a result, small non-coding RNA molecules that regulate gene expression via epigenetic alterations, microRNAs have been identified as regulators of these metabolic processes. In the last decade, dietary interventions have been used to change metabolism and to potentially alter disease progression and clinical outcomes. These interventions have been linked, at a molecular level, to microRNAs. This review will summarize the role of various dietary strategies on the expression of several microRNA families.

Current Management of Locally Advanced Head and Neck Cancer: The Combination of Chemotherapy With Locoregional Treatments

This review will discuss the evolution of the role of chemotherapy in the treatment of locally advanced head and neck cancer (HNC), over the last few decades. Studies were identified by searching PubMed electronic databases. Surgery followed by radiotherapy (RT) or definitive RT are potentially curative approaches for locally advanced HNC. While chemotherapy itself is not curative, it can improve cure rates when given as an adjunct to RT. The benefit of combining chemotherapy with RT is related to the timing of the chemotherapy. Several prospective randomized trials have demonstrated that concurrent delivery of chemotherapy and RT (CRT) is the most promising approach, given that locoregional recurrence is the leading pattern of failure for patients with locally advanced HNC. Induction chemotherapy before CRT has not been shown to be superior to CRT alone and the added toxicity may negatively impact the compliance with CRT. Sequential chemotherapy administration, in the form of induction chemotherapy followed by RT or CRT, has been successful as a strategy for organ preservation in patients with potentially resectable laryngeal and hypopharyngeal cancer. Systemic chemotherapy delivered concurrently with RT is used as a standard treatment for locally advanced HNC.

Molecular markers to predict clinical outcome and radiation induced toxicity in lung cancer

The elucidation of driver mutations involved in the molecular pathogenesis of cancer has led to a surge in the application of novel targeted therapeutics in lung cancer. Novel oncologic research continues to lead investigators towards targeting personalized tumor characteristics rather than applying targeted therapy to broad patient populations. Several driver genes, in particular epidermal growth factor receptor (EGFR) and ALK fusions, are the earliest to have made their way into clinical trials. The avant-garde role of genomic profiling has led to important clinical challenges when adapting current standard treatments to personalized oncologic care. This new frontier of medicine requires newer biomarkers for toxicity that will identify patients at risk, as well as, new molecular markers to predict and assess clinical outcomes. Thus far, several signature genes have been developed to predict outcome as well as genetic factors related to inflammation to predict toxicity.

Breast and lung metastasis from pancreatic neuroendocrine carcinoma

Pancreatic neuroendocrine tumors (PNETs) are an uncommon malignancy, accounting for a small percentage of all pancreatic malignancies. Due to their insidious course, most PNETs present with metastatic disease. Although reports in the literature describe PNET metastasis to the liver, lung and brain, to date there are no reports of stage IV disease involving the breast. Moreover, the lack of consensus regarding classification and treatment of this entity leaves practitioners without standards of practice or a firm base from which to formulate prognosis. In this report, the case of a previously healthy 51-year-old woman with stage IV PNET is examined. After combined neoadjuvant therapy with 5-fluorouracil, carboplatin, etoposide and radiation, surgical resection revealed metastatic PNET to the breast and lung, with no microscopic evidence of residual disease within the pancreas. An extensive analysis of the presentation, diagnosis, imaging modalities, treatment options, and prognosis is included in the discussion. As demonstrated by our review, there is a need for further studies to delineate inconclusive evidence with respect to subtype classification, treatment and prognosis of PNETs.

Large prostate gland size is not a contraindication to low-dose-rate brachytherapy for prostate adenocarcinoma.

PURPOSE Prostate volume greater than 50cc is traditionally a relative contraindication to prostate seed implantation (PSI), but there is little consensus regarding prostate size and clinical outcomes. We report biochemical control and toxicity after low-dose-rate PSI and compare outcomes according to the prostate size. METHODS AND MATERIALS A total of 429 men who underwent low-dose-rate PSI between 1998 and 2009 were evaluated. Median followup was 38.7 months. Patients were classified by prostate volume into small, medium, and large subgroups. Differences were analyzed using the Mann-Whitney and Pearsons χ(2) tests for continuous and categorical variables, respectively. Cox proportional hazards regression models were used to evaluate effect of prostate size on outcomes. RESULTS Patient pretreatment factors were balanced between groups except for age (p=0.001). The 10-year actuarial freedom from biochemical failure for all patients treated with PSI was 96.3% with no statistically significant difference between large vs. small/medium prostate size (90% vs. 96.6%, p=0.47). In a multivariate analysis, plan type (hazard ratio [HR]=0.25, p=0.03), dose to 90% of the gland (D90: HR=0.98, p=0.02), volume receiving 200Gy (V200: HR=0.98, p=0.026), and biologic effective dose (HR=0.99, p=0.045), but not prostate size (HR=2.27, p=0.17) were significantly associated with freedom from biochemical failure. Prostate size was not significantly associated with time to maximum American Urologic Association score. CONCLUSION In men with large prostates, the PSI provides biochemical control and temporal changes in genitourinary toxicity that are comparable with men having smaller glands. Accurate dose optimization and delivery of PSI provides the best clinical outcomes regardless of gland size.

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling.

Insulin-like growth factor binding protein 3 (IGFBP3) modulates cell growth through IGF-dependent and -independent mechanisms. Reports suggest that the serum levels of IGFBP3 are associated with various cancers and that IGFBP3 expression is significantly decreased in cisplatin (CDDP)-resistant lung cancer cells. Based on these findings, we investigated whether Igfbp3 deficiency accelerates mouse lung tumorigenesis and if expression of IGFBP3 enhances CDDP response by focusing on the IGF1 signaling cascade. To this end, an Igfbp3-null mouse model was generated in combination with KrasG12D to compare the tumor burden. Then, IGF-dependent signaling was assessed after expressing wild-type or a mutant IGFBP3 without IGF binding capacity in non–small cell lung cancer (NSCLC) cells. Finally, the treatment response to CDDP chemotherapy was evaluated under conditions of IGFBP3 overexpression. Igfbp3-null mice had increased lung tumor burden (>2-fold) and only half of human lung cancer cells survived after expression of IGFBP3, which corresponded to increased cleaved caspase-3 (10-fold), inactivation of IGF1 and MAPK signaling. In addition, overexpression of IGFBP3 increased susceptibility to CDDP treatment in lung cancer cells. These results, for the first time, demonstrate that IGFBP3 mediates lung cancer progression in a KrasG12D mouse model. Furthermore, overexpression of IGFBP3 induced apoptosis and enhanced cisplatin response in vitro and confirmed that the suppression is in part by blocking IGF1 signaling. Implications: These findings reveal that IGFBP3 is effective in lung cancer cells with high IGF1 signaling activity and imply that relevant biomarkers are essential in selecting lung cancer patients for IGF1-targeted therapy. Mol Cancer Res; 15(7); 896–904. ©2017 AACR.

Immune biomarkers of treatment failure for a patient with renal cell carcinoma on a Phase I trial of pembrolizumab plus radiotherapy

Meeting abstracts Pembrolizumab is an antibody designed against programmed cell-death protein-1 (PD-1), which is expressed on the surface of activated T cells. Tumor cells can upregulate PD-L1, which binds to PD-1 and mediates T cell anergy. By antagonizing the PD-1/PD-L1 binding, pembrolizumab can

Identification of a KRAS mutation in a patient with non-small cell lung cancer treated with chemoradiotherapy and panitumumab

RTOG 0839 is a Phase II study of pre-operative chemoradiotherapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigational agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody that improves progression-free survival in chemorefractory metastatic colorectal cancer (mCRC). Recently, both KRAS mutational status (i.e., mutated or not) and subtype (i.e., activating or inactivating) have been shown to be predictive of response to anti-EGFR therapy in mCRC. However, in NSCLC, it is unknown if KRAS mutational status or subtype predict benefit to anti-EGFR therapies because of unique genetic and epigenetic factors unique to each cancer. We present a patient with stage III NSCLC containing a KRAS G12D activating mutation who had a partial pathologic response, with disappearance of a minor KRAS mutant clone. This case suggests possible eradication of the G12D KRAS lung cancer clones by concurrent chemoradiation with panitumumab.