scholarly journals Targeted Therapy Recommendations for Therapy Refractory Solid Tumors—Data from the Real-World Precision Medicine Platform MONDTI

2020 ◽  
Vol 10 (4) ◽  
pp. 188
Author(s):  
Hossein Taghizadeh ◽  
Matthias Unseld ◽  
Martina Spalt ◽  
Robert M. Mader ◽  
Leonhard Müllauer ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Precision Medicine ◽  
Solid Tumors ◽  
Real World ◽  
Molecular Profile ◽  
Tumor Type ◽  
Therapy Recommendations ◽  
Dismal Prognosis ◽  
Advanced Therapy ◽  
Therapy Recommendation

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men (p = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors.

scholarly journals Outcome of Targeted Therapy Recommendations for Metastatic and Recurrent Head and Neck Cancers

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3381
Author(s):  
Hossein Taghizadeh ◽  
Robert M. Mader ◽  
Leonhard Müllauer ◽  
Thorsten Fuereder ◽  
Alexandra Kautzky-Willer ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Head And Neck ◽  
Precision Medicine ◽  
Head And Neck Cancers ◽  
Molecular Profile ◽  
Therapy Recommendations ◽  
Advanced Therapy ◽  
Cancer Tumor ◽  
Generation Sequencing ◽  
Recurrent Head

Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients’ molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with R/M head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, microsatellite instability (MSI) testing, and immunohistochemistry (IHC). In 31 cases (62.0% of all patients), a molecular-driven targeted therapy approach was recommended. Eventually, 14 patients (28%) received the suggested targeted therapy. Six of fourteen patients (43%) achieved stable disease conditions and four patients (29%) experienced a progressive disease. The median time to treatment failure was 2.8 months. Therapy recommendations were significantly more often issued for men (p = 0.037) than for women. This analysis demonstrated that precision medicine provided the basis for molecular-driven therapy recommendations in over half of the patients with advanced therapy refractory head and neck cancers, with significantly more therapy recommendations for men. Our analysis showed that although precision medicine approaches are implementable and feasible for the management of recurrent/metastatic head and neck cancers in daily clinical routine, there are major limitations and challenges that have to be overcome.

Clinical utility of molecular testing to select therapy in relapsed/refractory non-Hodgkin lymphoma: Mayo Clinic Center for Individualized Medicine experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11571-11571
Author(s):  
Nabila Nora Bennani ◽  
Stephen Maxted Ansell ◽  
Thomas E. Witzig ◽  
Andew L. Feldman ◽  
Tammy M McAllister ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Targeted Therapy ◽  
Precision Medicine ◽  
Mayo Clinic ◽  
Individualized Medicine ◽  
Tumor Board ◽  
Current Therapy ◽  
Molecular Profile ◽  
Molecular Testing ◽  
Molecular Alterations

11571 Background: Relapsed/refractory (R/R) non-Hodgkin lymphomas (NHL) have a poor prognosis with limited treatment options. Our expanding knowledge of molecular alterations seen in R/R NHL allows identification of patients that potentially may benefit from a precision medicine approach. However, experience in routine clinical implementation of precision medicine has been limited. Here, we summarize our clinical experience in molecular characterization of RR NHL targeted therapy (TT) using next-generation sequencing (NGS), and selection of targeted therapy (TT) based on molecular profile. Methods: We conducted a prospective study in RR NHL through the Center for Individualized Medicine at Mayo Clinic. Consenting patients underwent NGS using FoundationOne Heme panel from biopsies done at time of relapse. Results of NGS were discussed at the Genomic Tumor Board and recommendations for TT were given based on matching specific molecular alteration(s) with potential agent(s) predicted to be active based on NGS. The agents could include FDA-approved, off-label use and clinical trial therapies. Results: 28 cases were enrolled: 18 aggressive NHL, 10 follicular lymphoma (FL). Molecular alterations were present in all cases. In aggressive B-cell NHL, CDKN2A/B gene cluster alterations were seen in 73% (8/11), while seen in only 1/7 T-cell lymphomas (TCL), and 1/10 FL. TP53 deletions were second most common genomic alterations in DLBCL (57%) and seen in 40% FL. JAK-STAT and ERBB pathways were altered in TCL (2/7 each). IGH-BCl-2 gene rearrangement were common in FL (70%), followed by MLL gene alterations (50%). Targetable mutations were present in 86% (24/28) of cases. A TT was recommended in all 24 cases, but received by 2 patients only. Remaining patients did not due to benefit from current therapy (10/24), ineligibility or lack of clinical trial (7/24) or interim clinical deterioration (5/24). Conclusions: Targetable mutations were identified in most cases of RR NHL with TT recommended for all cases. However, access to TT limits potential clinical benefit of molecular-based matching strategy. More studies are needed to assess impact on clinical outcomes.

The genomic landscape of gene fusions across solid tumors and clinical outcome of targeted therapies: A real-world retrospective analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3132-3132
Author(s):  
Yumeng Zhang ◽  
Bindiya G Patel ◽  
Todd C Knepper ◽  
Dung-Tsa Chen ◽  
Jhanelle Elaine Gray ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Real World ◽  
Targeted Therapies ◽  
Gene Fusion ◽  
Treatment Modalities ◽  
Gene Fusions ◽  
Sequencing Data ◽  
Off Label

3132 Background: Oncogenic gene fusions can be observed across numerous solid tumor types with therapies targeting fusion events emerging as important treatment modalities. The occurrence of rare fusion events and response to targeted therapy inclusive of off-label drug use has not been fully elucidated. We describe a real-world (RW) landscape of gene fusions in solid tumors and treatment outcomes of targeted therapies. Methods: Patients with solid tumors harboring a gene fusion or rearrangement were retrospectively identified through review of a clinical molecular database housing sequencing data on 6,800 patients from a single-center between 1/1/2015 – 12/31/2019. Patients who received targeted therapy for gene fusions were divided into three arms: off-label, on-label, and clinical trial use. Clinical characteristics were summarized using descriptive statistics. Overall survival (OS) and Progression free survival (PFS) between the three arms were compared using the Kaplan-Meier estimates. Results: A total of 336 (4.9%) patients had a fusion positive solid tumor with 197 (2.9%) having a fusion event predicted to be oncogenic and could be targeted with a drug. Thirty different cancer types had targetable fusions with the three most common types being lung adenocarcinoma (41%), glioblastoma (10.2%), and melanoma (7.1%). The most common observed targetable fusions included ALK (21.3%), RET (11.7%), ROS1 (9.1%), and FGFR2 (8.1%). A total of 71 patients received targeted therapy; 37 (52%) received therapies on-label, 20 (28%) off-label, and 14 (20%) on-trial (Table). The median PFS was 4 months for off-label, 16 months for on-label, and 9 months for on trial-therapy (p=0.02). The median OS was 8 months for off-label, 51 months for on-label, and 11 months for on-trial therapy (p=0.001). Seven out of twenty patients (35%) in the off-label group had PFS for at least 6 months. Three patients had a response for more than one year. However, higher toxicity related discontinuation rate was observed (30%, 8%, 7% for off-label, on-label, and on-trial, p=0.03). Conclusions: Off-label targeted therapy had shorter PFS and OS when compared to on-label therapy. However, 35% patients in the off-label group had at least 6 months PFS. Off-label therapy remained a valuable option for patients who were not candidate for clinical trials or with rare fusions. Further studies are needed to determine which patients are most likely to benefit from targeting gene fusion events.[Table: see text]

Molecular profile of ampulla of vater carcinoma (AVC): A rare tumor type with meaningful molecular alterations.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4119-4119
Author(s):  
João Pinto ◽  
Helena Verdaguer ◽  
Maria Teresa Salcedo ◽  
Anna Pedrola ◽  
Jorge Hernando-Cubero ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stage Iv ◽  
Molecular Profile ◽  
Tumor Type ◽  
Phase I Clinical Trials ◽  
Histological Subtypes ◽  
Rare Type ◽  
Molecular Alterations ◽  
Dismal Prognosis ◽  
Stage Iv Disease

4119 Background: AVC is a rare type of cancer with dismal prognosis and limited therapeutic options due to the lack of specific clinical trials. Two histologic subtypes predominate, namely pancreatobiliary and intestinal. A variety of molecular alterations have been described in AVC, but their clinical and therapeutic implications have not been studied in detail. Methods: Retrospective cohort study of patients (pts) diagnosed with AVC treated in our institution from 2010 to 2018. We routinely performed Next Generation Sequencing in all AVC tumors. Our main objectives were to describe the molecular profile of AVC and correlate with clinical outcomes. Results: Out of 26 pts with AVC, 13 pts were male (50%), median age 65 (range 43-83), 7 pts (27%) had stage IV disease at diagnosis. Histologic type was pancreatobiliary in 18 pts (69%), intestinal in 7 pts (27%) and mixed in one case (4%). We identified KRAS mutations (mut) in 10 pts (7 pancreatobiliary, 2 intestinal, 1 mixed), TP53 mut in 6 pts (4/1/1), PIK3CA mut in 3 pts (3/0/0), ERBB2 mut in 3 pts (2/1/0), CTNNB1 mut in 3 pts (2/1/0). In pancreatobiliary we found single cases with RNF43, BRCA1 and CHEK2 mut; while in intestinal we found single cases with NRAS and BRAF mut. One tumor of intestinal subtype had microsatellite instability (MSI). Three pts were included in phase I clinical trials, 2 of them with trials based on tumor profile (ERBB2 mut with pan-HER inhibitor and MSI with immunotherapy). Median overall survival (OS) was 21 months for pts with stage I, II and III disease (95% CI 12.37-not reached) and 13.2 months for stage IV disease at diagnosis (95% CI 5.73-not reached). In cox models, median OS was not dependent on KRAS or TP53 mutation status, or histological subtypes. Conclusions: AVC is a rare type of cancer with two differentiated histological subtypes harboring unique molecular alterations that can be matched to investigational therapies. A broader knowledge of the biology of these tumors is needed to improve patient outcomes.

Biomarkers of Chinese advanced cancer patients based on real-world data: Actionable genomic alterations and tumor mutational burden.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14280-e14280
Author(s):  
HaiTao Wang ◽  
Huina Wang ◽  
Rongyun Guo ◽  
Mingwei Li ◽  
Yanrui Zhang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Real World ◽  
Cell Cancer ◽  
Objective Response ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Tumor Type ◽  
Mutational Burden ◽  
Esophagogastric Cancer ◽  
Tumor Mutational Burden

e14280 Background: Biomarkers would enrich patients(pts) with responsiveness to both targeted treatments and immunotherapy which have become a priority. However, molecular heterogeneous in actionable gene alterations and mutational loads need to be explored. In this study, based on a real world setting, Cancer Gene Panel (CGP） analysis was performed in a series samples of Chinese pts with advanced solid tumors, to delineate the landscape of actionable mutations and tumor mutational burden (TMB). Methods: 176 advanced pts were enrolled encompassing 19 common tumor types. All tissue samples were analyzed using next-generation sequencing with Acornmed panel including 808 genes. Results: The frequencies of genetic alterations among the most common driver genes were comparable to those reported by MSK-IMPACT (2018) ( TP53: 51.7% vs 44.8%; APC: 9.7% vs 9.8%; EGFR: 12.5% vs 7.7%; KRAS: 16.5% vs 13.6%; PIK3CA: 4.6% vs 12.0%; VHL: 4.0% vs 6.7%). 58.3% of pts with refractory solid tumors had at least one actionable mutation. Among those pts, 16.7% of them including CDK4, CDK6 or CDKN2A/B could benefit from palbociclib, and 32.1% of them including mTOR, PIK3CA, PTEN or STK11 could benefit from everolimus, and 61.9% of them including BRCA2, ARID1A, MSH1/2/6 or ATM could benefit from olaparib. Across all the specimens, the top 20% of TMB was 17.23 mutations/Mb, with a range of 0-48 mutations/Mb. The top 20% of TMB for each tumor type was 21.67(Bladder cancer), 17.23(Lung cancer), 16.45(Colorectal cancer), 11.04 (Renal cell cancer), 16.25 (Prostate cancer) , 19.70 (Hepatobiliary cancer), 14.78 (Esophagogastric cancer), 7.80 (Pancreatic cancer), 25.31 (undefined tumor) mutations/Mb respectively. Conclusions: This study indicates that most of pts with advanced refractory solid tumors have at least one actionable mutation, and matched therapies may confer clinical benefit. TMB fluctuated wildly across different cancer types, illustrating the unequal objective response rate of immunotherapy across various cancer type. Furthermore, CGP analysis in advanced pan-cancer pts can provide opportunities for targeted therapies and immunotherapy, especially in those with refractory cancer.

Druggable fusion gene landscape in solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13517-e13517
Author(s):  
Gareth Haydn Williams ◽  
Robert Paul Thatcher ◽  
Borja Nevado Polo ◽  
Tiffany Eira Haddow ◽  
Keeda-Marie Hardisty ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Fusion Gene ◽  
Real Life ◽  
Rare Event ◽  
Unknown Primary ◽  
Precision Oncology ◽  
Tumor Type ◽  
Fusion Genes ◽  
Fda Approval

e13517 Background: Kinases activated by gene fusions represent an important class of oncogenes in solid tumors highlighted by the unique site agnostic FDA approval of larotrectinib for NTRK gene rearrangements. However, the frequency and types of druggable fusions in solid tumors are not well characterized from the clinical perspective. Methods: Oncofocus is a clinically validated precision oncology platform that includes analysis of 399 druggable driver-partner oncogenic fusion genes linked to 140 unique targeted therapy protocols. A retrospective analysis of Oncofocus trending data in a real-life cohort of 1111 patients has been used to determine the actionable fusion gene landscape in solid tumors. Results: Eighty nine actionable fusion genes were identified in 1111 samples of solid tumors linked to 73 targeted therapy protocols. Seven of the samples harbored multiple fusion genes. Eighty two of the 1111 samples tested had at least one actionable fusion gene representing a frequency of 7.38%. The highest frequency of actionable fusions were observed in glioblastoma (23%), head and neck (12%), kidney (11%) and prostate (10%) cancers. Four of the seven samples with multiple actionable fusions were found in glioblastoma. Pancreatic, lung and endometrial cancers and cancer of unknown primary (CUPs) had an actionable fusion gene frequency ranging from 7-9%. TBL1XR1-PIK3CA, MET-MET, WHSC1L1-FGFR1 and EGFR VIII fusions were identified as the most common druggable fusions. All actionable fusion genes were found to interact with one or more of the following pathways RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT. Although a targeted agent for TRK fusions now has FDA approval, this rearrangement appears to be a rare event. In contrast, inhibitors targeting the TBL1XR1-PIK3CA, MET-MET, WHSC1L1-FGFR1 fusions and linked downstream signalling pathways appear to offer much broader clinical utility. Conclusions: Druggable fusions were identified at an unexpectedly high frequency and should therefore be included as part of routine comprehensive precision oncology testing. Notably, many of the actionable fusions are not tumor type specific reinforcing the “site agnostic” approach to profiling and supporting the concept of “molecular basket” clinical trials. Precision oncology trending data also provides actionable mutational landscapes which can be used to refine precision oncology testing, patient selection for targeted therapy protocols and enhancement of clinical trial design.

scholarly journals Molecularly guided treatment of metastatic parotid gland carcinoma in adults

2020 ◽  
Author(s):  
Hossein Taghizadeh ◽  
Leonhard Müllauer ◽  
Robert M. Mader ◽  
Thorsten Füreder ◽  
Gerald W. Prager
Keyword(s):  
Targeted Therapy ◽  
Parotid Gland ◽  
Poor Prognosis ◽  
Treatment Approach ◽  
Molecular Profiling ◽  
Disease Entity ◽  
Advanced Therapy ◽  
Therapy Recommendation ◽  
Gland Carcinoma ◽  
Parotid Gland Carcinoma

Summary Background Advanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies. Methods In this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies. Results We identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p‑mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months. Conclusion A total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.

scholarly journals p65BTK Is a Novel Biomarker and Therapeutic Target in Solid Tumors

2021 ◽  
Vol 9 ◽  
Author(s):  
Emanuela Grassilli ◽  
Maria Grazia Cerrito ◽  
Sara Bonomo ◽  
Roberto Giovannoni ◽  
Donatella Conconi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Colon Cancer ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Low Grade ◽  
Tumor Type ◽  
Drug Resistant ◽  
Btk Inhibitors

Bruton’s tyrosine kinase (BTK) is a non-receptor intracellular kinase playing a key role in the proliferation and survival of normal and malignant B-lymphocytes. Its targeting by Ibrutinib, the first specific inhibitor, represented a turning point for the therapy of certain types of B-cell leukemias/lymphomas and several more BTK inhibitors are today in the clinic or advanced clinical trials. BTK expression was successively found to occur also outside of the hematopoietic compartment. In fact, we identified p65BTK, a novel 65 kDa isoform lacking an N-term stretch of 86 amino acids (compared to the 77 kDa protein expressed in B cells) as highly expressed in colon cancer patients. We demonstrated that p65BTK is a powerful oncogene acting downstream of the RAS/MAPK pathway and necessary for RAS-mediated transformation. Notably, the kinase domain is conserved and therefore inhibited by the available BTK-targeting drugs (Ibrutinib, Spebrutinib, etc.) which we used to demonstrate that p65BTK is an actionable target in drug-resistant colorectal carcinomas. We found p65BTK expressed also in >50% non-small cell lung cancers (NSCLC) and demonstrated that it is an actionable target in KRAS-mutated/EGFR-wild type drug-resistant NSCLC models (for which no targeted therapy is available). We also reported a significant correlation between p65BTK expression and low-grade tumors and overall survival of patients with grade III gliomas and showed that its targeting induced a significant decrease in the viability of in glioma stem cells. Finally, in ovarian cancer patients, p65BTK expression levels correlate with early relapse and shorter progression-free survival, both indicators of resistance to therapy. Remarkably, Ibrutinib is more effective than standard of care (SOC) therapeutics in in vitro and ex vivo settings. On the whole, our preclinical data indicate that, depending on the tumor type, BTK inhibitors used alone can induce cytotoxicity (gliomas), be more effective than SOC chemotherapy (ovarian cancer) or can kill drug-resistant tumor cells when used in combination with SOC chemotherapy (colon cancer and NSCLC) or targeted therapy (NSCLC and ovarian cancer), thus suggesting that p65BTK may be an actionable target in different solid tumors. In addition, our data also give the proof-of-concept for starting clinical trials using BTK inhibitors, alone or in combination, to improve the therapeutic options for solid tumors treatment.

scholarly journals Interim analysis of a real-world precision medicine platform for molecular profiling of metastatic or advanced cancers: MONDTI

ESMO Open ◽  
2019 ◽  
Vol 4 (4) ◽  
pp. e000538 ◽  
Author(s):  
Markus Kieler ◽  
Matthias Unseld ◽  
Daniela Bianconi ◽  
Fredrik Waneck ◽  
Robert Mader ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Growth Factor ◽  
Precision Medicine ◽  
Molecular Profiling ◽  
Solid Tumours ◽  
High Rate ◽  
Molecular Profile ◽  
Individual Treatment ◽  
Tumour Board ◽  
Hodgkin's Lymphomas

BackgroundHigh-throughput genomic profiling of tumour specimens facilitates the identification of individual actionable mutations which could be used for individualised targeted therapy. This approach is becoming increasingly more common in the clinic; however, the interpretation of results from molecular profiling tests and efficient guiding of molecular therapies to patients with advanced cancer offer a significant challenge to the oncology community.Experimental designMONDTI is a precision medicine platform for molecular characterisation of metastatic solid tumours to identify actionable genomic alterations. From 2013 to 2016, comprehensive molecular profiles derived from real-time biopsy specimens and archived tumour tissue samples of 295 patients were performed. Results and treatment suggestions were discussed within multidisciplinary tumour board meetings.ResultsThe mutational profile was obtained from 293 (99%) patients and a complete immunohistochemical (IHC) and cytogenetic profile was obtained in 181 (61%) and 188 (64%) patients. The most frequent cancer types were colorectal cancer (12%), non-Hodgkin’s lymphomas (9.8%) and head and neck cancers (7.8%). The most commonly detected mutations were TP53 (39%), KRAS (19%) and PIK3CA (9.5%), whereas ≥1 mutation were identified in 217 (74%) samples. Regarding the results for IHC testing, samples were positive for phospho-mammalian target of rapamycin (phospho-mTOR) (71%), epidermal growth factor receptor (EGFR) (68%), mesenchymal epithelial transition (MET) (56%) and/or platelet-derived growth factor alpha (PDGFRα)-expression (48%). Of the 288 tumour samples with one or more genetic alteration detected, 160 (55.6%) targeted therapy recommendations through 67 multidisciplinary tumour board meetings were made; in 69 (24%) cases, an individual treatment concept was initiated.ConclusionsThe results reveal that the open concept for all solid tumours characterised for molecular profile and immunotherapy could not only match individualised treatment concepts at a high rate but also underscores the challenges encountered when offering molecularly matched therapies to a patient population with an advanced stage cancer.

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