Era Of Molecular Targeted Therapy Research Articles

Philadelphia Chromosome as a Clinically Favorable Prognostic Factor of B-cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma in Transplant-Ineligible Elderly Patients in the Era of Molecular-Targeted Therapy

Philadelphia Chromosome as a Clinically Favorable Prognostic Factor of B-cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma in Transplant-Ineligible Elderly Patients in the Era of Molecular-Targeted Therapy

Prognosis of non-small cell lung cancer with postoperative regional lymph node recurrence.

Regional lymph node recurrence after radical surgery for non-small cell lung cancer (NSCLC) is an oligo-recurrent disease; however, no treatment strategy has been established. In the present study we aimed to determine the clinical outcomes of postoperative regional lymph node recurrence and identify prognostic predictors in the era of molecular-targeted therapy. We retrospectively analyzed data on clinical characteristics and outcomes of patients with regional lymph node recurrence after surgery who underwent treatment for NSCLC between 2002 and 2022. A total of 53 patients were included in this study. The median time between surgery and detection of recurrence was 1.21 years. Radiotherapy (RT) alone and chemoradiotherapy (CRT) were performed in 38 and six patients, respectively. Driver gene alterations were detected in eight patients (EGFR: 6, ROS1:1, and BRAF: 1) and programmed death-ligand 1 (PD-L1) expression was examined in 22 patients after 2016. Median progression-free survival (PFS) and overall survival (OS) after lymph node recurrences were 1.32 and 4.34 years, respectively. Multiple lymph node recurrence was an independent prognostic factor for PFS, whereas driver gene alteration was the only prognostic factor for OS. There was no significant difference in the OS between patients stratified according to the initial treatment modality for lymph node recurrence. Our results suggest that the number of tumor recurrences may correlate with PFS, while detection of driver gene alterations could guide decision-making for the appropriate molecular-targeted therapy to achieve longer OS.

Changes in Real-World Outcomes in Patients with Metastatic Renal Cell Carcinoma from the Molecular-Targeted Therapy Era to the Immune Checkpoint Inhibitor Era.

Knowledge of changes in the outcome in patients with metastatic renal cell carcinoma from the molecular-targeted therapy era to the immune checkpoint inhibitor (ICI) era remains limited in the real-world setting. We aimed to clarify outcome changes from the previous molecular-targeted therapy era to the current ICI era in patients with metastatic renal cell carcinoma using multi-institution real-world data. We retrospectively evaluated 415 patients with metastatic renal cell carcinoma who received first-line systemic therapy at five Japanese institutions between January 2008 and August 2021. We divided the patients into two groups based on the treatment era: molecular-targeted therapy era (January 2008-August 2018) and ICI era (September 2018-August 2021). According to the era, progression-free survival, overall survival, and objective response rate from first-line systemic therapy were compared. Overall, 304 (73.3%) and 111 (26.7%) patients were categorized into the molecular-targeted therapy and ICI eras, respectively. The proportion of patients without prior nephrectomy (p=0.0030) or those with low Karnofsky Performance Status scores [≤70] (p=0.0258) were significantly higher in the ICI era group. The patients in the ICI era group had significantly longer overall survival (median: not reached vs 23.2 months, p=0.0001) and a higher objective response rate (47.8% vs 24.7%, p<0.0001) than those in the molecular-targeted therapy era group, and progression-free survival tended to be longer in the ICI era group (median: 13.3 vs 8.75 months, p=0.0579). Multivariate analysis further showed that the treatment era (ICI vs molecular-targeted therapy) was an independent factor for overall survival and objective response (both, p<0.0001). The present multi-institution real-world data showed the improved outcome of previously untreated patients with metastatic renal cell carcinoma in the ICI era group compared with that in the molecular-targeted therapy era group. These findings strongly encourage the use of ICI-based treatment for patients with metastatic renal cell carcinoma in the real-world setting. Further studies with extended follow-up periods are needed to confirm our findings.

Assessing improvements in metastatic renal cell carcinoma systemic treatments from the pre-cytokine to the immune checkpoint inhibitor eras: a retrospective analysis of real-world data.

Studies assessing outcome improvements over a long period according to systemic therapy strategies for metastatic renal cell carcinoma using real-world data, including the results of the recent era of immune checkpoint inhibitors, are limited. Herein, we retrospectively evaluated patients who were diagnosed with metastatic renal cell carcinoma over a 40-year span. Patients were classified into four groups based on when their metastases were diagnosed as follows: (i) the pre-cytokine era (1980-1986), (ii) the cytokine era (1987-2007), (iii) the molecular-targeted therapy (mTT) era (2008 to August 2016) and (iv) the immune checkpoint inhibitor era (September 2016 to 2018). The immune checkpoint inhibitor era consisted of second- or later-line nivolumab. Overall survival from the diagnoses of metastases was evaluated. In total, 576 patients were evaluated, including 22 (3.82%), 231 (40.1%), 253 (43.9%) and 70 (12.2%) patients from the pre-cytokine, cytokine, molecular-targeted therapy and immune checkpoint inhibitor eras, respectively. The overall survival significantly improved with each successive era (median: 13.1 vs. 24.5 vs. 44.4months vs. not reached in pre-cytokine vs. cytokine vs. molecular-targeted therapy vs. immune checkpoint inhibitor eras, P<0.0001). The implementation of molecular-targeted therapy improved overall survival compared with that of cytokine (cytokine vs. molecular-targeted therapy eras, P<0.0001). Multivariate analysis demonstrated that the era was an independent factor for overall survival (P<0.0001), together with histopathological type; metastasis status (i.e. synchronous or metachronous); systemic therapy status (i.e. absence or presence) and bone, liver or lymph node metastasis status (all, P<0.05). This retrospective study of real-world data indicated that metastatic renal cell carcinoma outcomes improved with successive systemic therapy paradigms.

Hematopoietic stem cell transplantation in the era of molecular targeted therapy.

Recent developments in the field of molecular targeted therapy are certainly remarkable. However, the role of hematopoietic stem cell transplantation (HSCT) cannot be the same in this trend of targeted therapy. In the past, HSCT was the sole and ultimate treatment for refractory hematological malignancies, mainly because the conditioning regimens were strong and administering any additional therapy was impossible. In recent years, the conditioning regimens have become less intensive, thus enabling the use of additional therapies post-transplantation. In this review, we have discussed the use of each targeted therapy, such as TKIs for Philadelphia chromosome positive disease, Flt3 inhibitors, checkpoint inhibitors, monoclonal antibodies, and hypomethylating agents, in the context of using them with HSCT. Furthermore, we have discussed the importance of the intensity of chemotherapy and conditioning for HSCT and whether the depth of remission and the time of achieving deep remission are important. MRD tests can help to further delineate this point. Molecular targeted therapy will be more prevalent in the near future in the treatment of hematological malignancies where each new agent may impact the GVHD/GVL effect. Thus, clinical trials in the next decade will mostly focus on the role of HSCT and on the methods of combining it with targeted agents to provide the best therapeutic option to patients.

Cutaneous angiosarcoma of the head and face: a single-center analysis of treatment outcomes in 43 patients in Japan.

For a better understanding of angiosarcoma, we summarized our 30-year experience of conventional treatment outcomes before the era of molecular-targeted therapy. We conducted a retrospective review of our 43 patients with cutaneous angiosarcoma of the head and face, and investigated the prognostic factors including the treatment strategy. Disease-specific survival (DSS) and event-free survival (EFS) were estimated using the Kaplan-Meier method, together with multivariate analyses using the Cox proportional hazard regression model. All patients were Japanese (25 males and 18 females), with a mean age of 72.1. For the initial treatment of the primary lesion, 34 patients underwent radiotherapy with or without taxanes (docetaxel and/or paclitaxel); only 6 patients underwent surgical excision. As the systemic adjuvant therapy, 19 patients were treated with taxanes and 15 with interleukin-2. Interestingly, patients who underwent the continued chemotherapy with taxanes had significantly prolonged DSS (5-year DSS, 57.0 vs. 19.6%; median survival, 62.2 vs. 17.7months; P=0.0049) and EFS (5-year EFS, 34.9 vs. 5.6%; median survival, 46.7 vs. 12.4months; P=0.0024) than the others. The continuous use of taxanes was also a prognostic factor in multivariate analyses. Neither radiotherapy nor surgical excision significantly influenced the patients' outcome. Among five patients who survived more than 5years, three underwent surgical excision of the primary tumor or lung metastasis. Our results suggest that continued chemotherapy with taxanes is important for patient survival.

Clinicopathological characteristics and oncological outcomes in patients with renal cell carcinoma registered in 2007: The first large-scale multicenter study from the Cancer Registration Committee of the Japanese Urological Association.

To describe the clinicopathological features and oncological outcomes of renal cell carcinoma diagnosed in Japan in 2007, the results of the large-scale renal cell carcinoma registration study carried out by the Japanese Urological Association are reported. The renal cell carcinoma survey was carried out by the Japanese Urological Association in 2012 to register newly diagnosed renal cell carcinoma cases in 2007 from 340 institutions nationwide. The survey included clinicopathological details, such as sex, age, family history, past history, smoking history, body mass index, reason for diagnosis, TNM classification, stage, histopathology, treatment and clinical outcomes. A total of 3663 cases diagnosed in 2007 were registered in this renal cell carcinoma registry program from 340 institutions. A total of 15 patients with a final diagnosis of oncocytoma were excluded, and 3648 cases of renal cell carcinoma were analyzed to evaluate oncological outcomes. The patients' median age was 63.9 years (range 5.9-95.1 years). Clear cell renal cell carcinoma was the most common histological subtype (77.2%), followed by papillary (5.0%) and chromophobe (3.2%) renal cell carcinoma. The most common initial treatment was radical nephrectomy (72.6%), and the most common secondary treatment was cytokine therapy (13.1%). Five-year overall survival rates in stages I, II, III, and IV were 94.8%, 90.2%, 78.8% and 39.6%, respectively. The 5-year overall survival rates for clear cell, papillary and chromophobe renal cell carcinomas, and carcinoma of the collecting ducts of Bellini were 88.6%, 79.8%, 93.0% and 40.0%, respectively. The present report is the first nationwide large-scale study to describe the clinicopathological characteristics and oncological outcomes of patients with renal cell carcinoma in Japan. Oncological outcomes depend on the clinical stage and histological subtype. Further investigations will be required to show improved oncological outcomes in the molecular targeted therapy era using the results of the present study as a baseline.

Prognostic factors and risk classifications for patients with metastatic renal cell carcinoma.

The introduction of molecular-targeted therapy has made dramatical changes to treatment for metastatic renal cell carcinoma. Currently, there are four vascular endothelial growth factor receptor-tyrosine kinase inhibitors and two mammalian target of rapamycin inhibitors in Japan. For the appropriate clinical use of these molecular-targeted drugs, the identification of prognostic and/or predictive factors in patients who received these drugs is required. Although molecular biological and genetic factors that determine the prognosis of patients with metastatic renal cell carcinoma have been reported, most of these factors are problematic in that the number of patients analyzed was small. In contrast, clinicopathological prognostic factors, including the practice of cytoreductive nephrectomy, pathological findings, metastatic sites and metastasectomy, and abnormal inflammatory response, have been identified by analyzing a relatively large number of patients. Several prognostic classification models that were developed by combining these clinicopathological factors are widely used in not only clinical trials, but also routine clinical practice. However, the quality of these prognostic models is considered to be insufficient regarding prognostic prediction of metastatic renal cell carcinoma patients and, thus, requires further improvements. Recently, basic and clinical studies have been extensively carried out for the identification of promising informative markers and for understanding molecular mechanisms of resistance to molecular-targeted drugs in metastatic renal cell carcinoma patients. The present review considers ongoing translational research efforts on clinicopathological, molecular biological, and genetic prognostic and/or predictive factors for metastatic renal cell carcinoma patients in the era of molecular-targeted therapy, and discusses the clinical implications of these findings.

TaqMan based real time PCR assay targeting EML4-ALK fusion transcripts in NSCLC

ObjectivesLung cancer with the ALK rearrangement constitutes only a small fraction of patients with non-small cell lung cancer (NSCLC). However, in the era of molecular-targeted therapy, efficient patient selection is crucial for successful treatment. In this context, an effective method for EML4-ALK detection is necessary. We developed a new highly sensitive variant specific TaqMan based real time PCR assay applicable to RNA from formalin-fixed paraffin-embedded tissue (FFPE). Materials and methodsThis assay was used to analyze the EML4-ALK gene in 96 non-selected NSCLC specimens and compared with two other methods (end-point PCR and break-apart FISH). ResultsEML4-ALK was detected in 33/96 (34%) specimens using variant specific real time PCR, whereas in only 23/96 (24%) using end-point PCR. All real time PCR positive samples were confirmed with direct sequencing. A total of 46 specimens were subsequently analyzed by all three detection methods. Using variant specific real time PCR we identified EML4-ALK transcript in 17/46 (37%) specimens, using end-point PCR in 13/46 (28%) specimens and positive ALK rearrangement by FISH was detected in 8/46 (17.4%) specimens. Moreover, using variant specific real time PCR, 5 specimens showed more than one EML4-ALK variant simultaneously (in 2 cases the variants 1+3a+3b, in 2 specimens the variants 1+3a and in 1 specimen the variant 1+3b). In one case of 96 EML4-ALK fusion gene and EGFR mutation were detected. All simultaneous genetic variants were confirmed using end-point PCR and direct sequencing. ConclusionOur variant specific real time PCR assay is highly sensitive, fast, financially acceptable, applicable to FFPE and seems to be a valuable tool for the rapid prescreening of NSCLC patients in clinical practice, so, that most patients able to benefit from targeted therapy could be identified.

Comparison of Survival Rates in Patients with Metastatic Renal Cell Carcinoma According to Treatment Era Including Cytokine and Targeted Therapy

We compared the survival rates in patients with metastatic renal cell carcinoma between the cytokine and molecular targeted therapy era. The study included 321 patients who were diagnosed with metastatic renal cell carcinoma between 1987 and 2011. The patients were divided into two groups according to when they started therapy for metastatic renal cell carcinoma: in the cytokine era (1987-2007) and in the targeted therapy era (after 2008). The beginning of the follow-up period was defined as the time of discovery of metastasis occurrence. Cytokine and targeted therapy eras included 235 and 86 patients, respectively. Seventy-five percent of the patients in the cytokine era actually received cytokine therapy. Eighty-one percent of the patients in the targeted therapy era received targeted therapy and 14% received both cytokine and targeted therapy. There were no significant differences in overall survival rates (cytokine 29 months, targeted 38 months, P = 0.1789).

Complete remission of renal cell carcinoma with lung metastases in two hemodialysis patients after low-dose interferon therapy

A standard immunotherapy strategy for metastatic renal cell carcinoma (RCC) in dialysis patients has yet to be established. In this study, we report complete remission of RCC with lung metastases in 2 hemodialysis patients after low-dose interferon therapy (Sumiferon® 3 × 10⁶ international unit 3 times a week). These results suggest that interferon therapy is important for clear cell RCC with lung metastases in dialysis patients, even in the era of molecular-targeted therapies.

EGFR mutation: Significance as a stratification factor in the era of molecular-targeted therapy

Somatic mutations of epidermal growth factor receptor (EGFR) are the strongest predictive markers for the response to EGFR-tyrosine kinase inhibitors (TKIs). Patients with EGFR mutations generally receive EGFR-TKI treatment, and their survival has been significantly improved compared with that before the development of EGFR-TKIs. This study aimed to clarify the impact of EGFR mutational status on the survival of patients with non-small cell lung cancer (NSCLC) receiving cytotoxic agents, but not EGFR-TKIs, as their first-line chemotherapy. In addition, we analyzed patients with EGFR mutations to determine whether the timing of EGFR-TKI administration affects overall survival (OS). A total of 83 NSCLC patients with stage IIIB/IV who received chemotherapy alone and whose EGFR mutational status was known were investigated. Univariate and multivariate analysis for OS was performed using parameters such as age, gender, performance status (PS), histology, disease stage, smoking status, EGFR mutational status and administration of a first-line regimen. Among the 52 patients with EGFR mutations who received EGFR-TKIs, OS between those who received EGFR-TKIs as their first-line treatment and after chemotherapy were similar. Among the 83 patients who received cytotoxic agents as their first-line chemotherapy, the multivariate analysis showed OS to be significantly associated with PS (p<0.001), histology (p=0.039) and EGFR mutational status (p=0.040). OS was almost similar among the 52 patients with EGFR mutations who received EGFR-TKIs in a first- and second-line setting (25.6 vs. 26.8 months, p=0.914). The EGFR mutational status had a significant impact on the survival of NSCLC patients, although these patients did not receive EGFR-TKIs as their first-line chemotherapy. In future randomized trials, even when EGFR-TKIs are not included in experimental regimens, patients may need to be stratified by EGFR mutational status in order that study results be evaluated appropriately.

Systemic treatment and targeted therapy in patients with advanced hepatocellular carcinoma

Background:Advanced hepatocellular carcinoma (HCC) is a malignancy of global importance: it is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Despite decades of efforts by many investigators, systemic chemotherapy or hormone therapy has failed to demonstrate improved survival in patients with HCC.. Ongoing studies are evaluating the efficacy and tolerability of combining Sorafenib with erlotinib and other targeted agents or chemotherapy.Aims:On the basis of placebo-controlled, randomized phase III trials, Sorafenib has shown improved survival benefits in advanced HCC and has set a new standard for future clinical trials. The successful clinical development of Sorafenib in HCC has ushered in the era of molecularly targeted agents in this disease, which is discussed in this educational review.Material and Methods:Many molecularly targeted agents that inhibit angiogenesis, epidermal growth factor receptor, and mammalian target of rapamycin are at different stages of clinical development in advanced HCC. Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention. Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patients’ treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents.Results:Systemic therapy with various classes of agents, including hormone and cytotoxic agents, has provided no or marginal benefits. Improved understanding of the mechanism of hepatocarcinogenesis, coupled with the arrival of many newly developed molecularly targeted agents, has provided the unique opportunity to study some of these novel agents in advanced HCC.Conclusions:The demonstration of improved survival benefits by Sorafenib in advanced HCC has ushered in the era of molecular-targeted therapy in this disease, with many agents undergoing active clinical development.

Development of new drug strategies in infrequent digestive tumors: esophageal, biliary tract, and anal cancers

In the last years, interesting advances have been reported in the treatment of infrequent digestive tumors. The increasing development of new targeted therapies in human cancer has also impacted in these rare gastrointestinal malignancies providing a wide range of possibilities in the design of future clinical trials. The inhibition of angiogenesis and the blockage of the epidermal growth factor receptor pathway have provided the most interesting activity in recently reported studies for esophageal and biliary tract carcinomas. Additionally, several targeted therapies have been developed to target the main kinase proteins of the most important pathways of these malignancies. The results of the biggest phase III trial in locally advanced anal carcinoma have been recently published. Finally, the inhibition of epidermal growth factor receptor has also showed promising activity in anal carcinomas. Recent advances in the knowledge of molecular mechanism of carcinogenesis have led to meaningful changes in the management of gastrointestinal cancers. Although the major advances in targeted therapy have been introduced in the treatment of colorectal cancer, new interesting approaches have been reported in less frequent gastrointestinal tumors such as esophageal, biliary tract, and anal canal carcinoma opening a new hope in the treatment of these rare tumors in the molecular targeted therapy era.

Some Lessons Learned from Imatinib Mesylate Clinical Development in Gastrointestinal Stromal Tumors

Imatinib mesylate is a molecular-targeted agent, shown to be effective in chronic myeloid leukemia and gastrointestinal stromal tumors (GIST). The latter may currently serve as a model on which speculating how the future of molecular-targeted therapy in solid tumors will be. So far, some lessons have been learnt. 1) Molecular-targeted therapy can be effective in the advanced disease setting, resulting in major tumor responses. 2) Patterns of tumor responses may be peculiar, radiologically and pathologically. 3) Anti-tumor activity may be highly predictable by assessing tumor molecular biology. 4) The methodology of clinical development of molecular-targeted agents may differ from standard chemotherapy in some respects, because, say, the preclinical rationale may be stronger, thus increasing the Bayesian prior probability of efficacy, or the optimal dose cannot be determined separately from the assessment of activity and efficacy. 5) Molecular-targeted agents will hardly remain “orphan drugs”, if effective. 6) While an obvious impact on survival in the advanced disease setting has been clearly demonstrated, the biologic and clinical impact of molecular-targeted therapy still needs to be elucidated. Its eradicating capabilities, as well as the implications of secondary resistance, are to be understood. 7) Integrated, multimodality approaches, including surgery, may still be of value in the molecular-targeted therapy era.