Patients with ROS1 rearrangement-positive non-small-cell lung cancer benefit from pemetrexed-based chemotherapy

Abstract

ROS1 gene-rearrangement in non-small-cell lung cancer (NSCLC) patients has recently been identified as a driver gene and benefited from crizotinib treatment. However, no data are available for ROS1-positive NSCLC about chemotherapeutic options and prognostic data. We investigated pemetrexed-based treatment efficacy in ROS1 translocation NSCLC patients and determined the expression of thymidylate synthetase (TS) to provide a rationale for the efficacy results. We determined the ROS1 status of 1750 patients with lung adenocarcinoma. Patients' clinical and therapeutic profiles were assessed. In positive cases, thymidylate synthetase (TS) mRNA level was performed by RT-PCR. For comparison, we evaluated the TS mRNA status and pemetrexed-based treatment efficacy from 170 NSCLC patients with anaplastic lymphoma kinase (ALK) translocation (n = 46), EGFR mutation (n = 50), KRAS mutation (n = 32), and wild-type of EGFR/ALK/ROS1/KRAS (n = 42). Thirty-four ROS1 translocation patients were identified at two institutions. Among the 34 patients, 12 with advanced stage or recurrence were treated with pemetrexed-based first-line chemotherapy. The median progression-free survivals of pemetrexed-based first-line chemotherapy in ROS1 translocation, ALK translocation, EGFR mutation, KRAS mutation, and EGFR/ALK/ROS1/KRAS wild-type patients were 6.8, 6.7, 5.2, 4.2, and 4.5 months, respectively (P = 0.003). The TS mRNA level was lower in patients with ROS1-positive than ROS1-negative patients (264 ± 469 × 10⁻⁴ vs. 469 ± 615 × 10⁻⁴, P = 0.03), but similar with ALK-positive patients (264 ± 469 × 10⁻⁴ vs. 317 ± 524 × 10⁻⁴, P = 0.64). Patients diagnosed with ROS1 translocation lung adenocarcinoma may benefit from pemetrexed-based chemotherapy. TS mRNA level enables the selection of therapeutic options for ROS1 translocation patients.

This study determined 34 patients with ROS1 rearrangement positive from 1750 samples with lung cancer. They found PFS of pemetrexed-based chemotherapy in ROS1-positive patients is longer than ROS1-negative and the TS mRNA level was lower in patients with ROS1-positive than in ROS1-negative patients.

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Gallium-68 perfusion positron emission tomography/computed tomography to assess pulmonary function in lung cancer patients undergoing surgery

Abstract

Background

Pre-operative evaluation of lung cancer patients relies on calculation of predicted post-operative (PPO) lung function based on split lung function testing. Pulmonary perfusion (Q) PET/CT can now be performed by substituting Technetium-99 m labeling of macroaggregated albumin (MAA) with Gallium-68. This study compares Q PET/CT with current recommended methods of pre-operative lung function assessment.

Methods

Twenty-two patients planned for curative surgical resection (mean FEV1 77 %, SD 21 %; mean DLCO 66 %, SD 17 % predicted) underwent pre-operative Q PET/CT. Sixteen patients also underwent conventional lung scintigraphy. Lobar and lung split PPO lung function were calculated using Q PET/CT and current recommended methods, i.e. calculation based on anatomical segments for lobar function, and conventional perfusion scan for pneumonectomy. Bland-Altman statistics were used to calculate agreement between methods for PPO FEV1 and PPO DLCO.

Results

While mean split lobar functions were comparable, there was variation on an individual level between Q PET/CT and the anatomical method, with absolute difference over 5 % and 10 % in 37 % and 11 % of patients, respectively. For lobectomy the mean difference in PPO FEV1 was−1.2, but limits of agreement were−10 to 8.1 %. For DLCO, values were−1.1 % and−9.7 to 7.5 %, respectively. For pneumonectomy, PPO FEV1 values were−0.4 and−5.9 to 5.1 %. For DLCO, values were 0.3 % and−5.1 to 4.6 %.

Conclusions

While anatomic estimation provides "fixed" results, split lobar functions computed with Q PET/CT vary widely, reflecting the intra and inter-individual variability of regional lung function. Further studies to assess the role of Q PET/CT in predicting peri-operative risk in lung cancer patients planned for lobectomy are warranted.

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Antibody Drug Conjugates (ADCs): Changing the Treatment Landscape of Lymphoma

Opinion statement

While strides advancing cancer treatment have made it possible to cure some malignancies, the effort to strike an intricate balance between attaining higher efficacy and lower toxicity has been difficult to accomplish, especially with conventional chemotherapy agents. Introduction of antibody drug conjugates (ADCs) has brought us a step closer to this goal and made it possible to target the cancer cells and to minimize effects on normal tissue. Continued efforts have led to approval of two ADCs for cancer therapy, while many others are in various stages of clinical development. The design of ADCs allows them to be internalized into the cancer cells where the drug payload is released and leads to cell death. The key is to identify targets that are exclusively expressed on malignant cells with minimal or no expression on normal cells, which allows for selective killing of tumor cells. Development and approval of more potent ADCs could change the landscape of cancer therapy and possibly eliminate traditional chemotherapy agents from treatment algorithms. In this review, we discuss the ADCs that are being investigated in early and late stage clinical trials for the treatment of B cell non-Hodgkin lymphoma (NHL).

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Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines

Abstract

Purpose

Dihydropyrimidine dehydrogenase (DPD) is a critical determinant of 5-fluorouracil pharmacology, and reduced activity of DPD as a result of deleterious polymorphisms in the gene encoding DPD (DPYD) can result in severe treatment-related toxicity. Dosing recommendations to individualize treatment have been provided for three DPYD variants (DPYD*2A, c.2846A>T, and c.1679T>G). A fourth variant, c.1129-5923C>G/HapB3, has been shown to increase the risk of fluoropyrimidine-associated toxicity, but little is known about the functional effects of this variant.

Methods

By performing a large retrospective screen for DPYD variants, we identified three patients who were homozygous for c.1129-5923C>G/HapB3. We describe their clinical course of treatment and analyzed DPD activity and DPYD gene expression, to provide insight into the phenotypic effects of c.1129-5923C>G/HapB3.

Results

DPD activity could be measured in two patients and was 4.1 and 5.4 nmol/mg/h (DPD activity 41 and 55 % compared to controls, respectively). The fluoropyrimidine dose had to be reduced during treatment in both patients. In line with partial DPD deficiency in both patients, sequence analysis of DPD cDNA demonstrated a normal-sized (wild type) cDNA fragment of 486 bp, as well as a larger-sized (mutant) 530-bp fragment containing an aberrant 44-bp insertion in intron 10. Patient three tolerated treatment well, but DPD activity measurement was not possible as the patient had deceased at the time of performing the study.

Conclusions

The presented functional and clinical data indicate that the c.1129-5923C>G variant is both functionally and clinically relevant, and support an upfront dose reduction of the fluoropyrimidine starting dose in patients carrying c.1129-5923C>G homozygously.

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A phase II study of topotecan and cisplatin with sequential thoracic radiotherapy in elderly patients with small-cell lung cancer: Okayama Lung Cancer Study Group 0102

Abstract

Purpose

The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial.

Methods

In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m², days 1–3) and cisplatin (20 mg/m², days 1–3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR).

Results

The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47–89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3–4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %).

Conclusions

This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.

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INGs are potential drug targets for cancer

Abstract

Purpose

The inhibitor of growth (ING) family consists of ING1, ING2, ING3, ING4 and ING5, which function as the type II tumor suppressors. INGs regulate cell proliferation, senescence, apoptosis, differentiation, angiogenesis, DNA repair, metastasis, and invasion by multiple pathways. In addition, INGs increase cancer cell sensitivity for chemotherapy and radiotherapy, while clinical observations show that INGs are frequently lost in some types of cancers. The aim of the study was to summarize the recent progress regarding INGs regulating tumor progression.

Methods

The literatures of INGs regulating tumor progression were searched and assayed.

Results

The regulating signaling pathways of ING1, ING2, ING3 or ING4 on tumor progression were shown. The mechanisms of INGs on tumor suppression were also assayed.

Conclusions

This review better summarized the signaling mechanism of INGs on tumor suppression, which provides a candidate therapy strategy for cancers.

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Differential somatostatin and CXCR4 chemokine receptor expression in MALT-type lymphoma of gastric and extragastric origin

Abstract

Purpose

Whereas the different somatostatin receptor (SSTR) subtypes and the chemokine receptor CXCR4 are known to be expressed in a wide variety of human malignancies, comprehensive data are still lacking for MALT-type lymphomas.

Methods

Overall, 55 cases of MALT-type lymphoma of both gastric and extragastric origin were evaluated for the SSTR subtype and CXCR4 expression by means of immunohistochemistry using novel monoclonal rabbit antibodies. The stainings were rated by means of the immunoreactive score and correlated with clinical data.

Results

While the CXCR4 was detected in 92 % of the cases investigated, the SSTR subtypes were much less frequently present. The SSTR5 was expressed in about 50 % of the cases, followed by the SSTR3, the SSTR2A, the SSTR4 and the SSTR1, which were present in 35, 27, 18 or 2 %, respectively, of the tumors only. Gastric lymphomas displayed a significantly higher SSTR3, SSTR4 and SSTR5 expression than extragastric tumors. A correlation between CXCR4 and Ki-67 expression was seen in gastric lymphomas, whereas primarily in extragastric tumors SSTR5 negativity was associated with poor patient outcome.

Conclusions

The CXCR4 may serve as a promising target for diagnostics and therapy of MALT-type lymphomas, while the SSTRs appear not suitable in this respect.

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