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Luis E. Raez
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IASLC Pre-Conference School of Thoracic Oncology (ID 1)
- Event: LALCA 2019
- Type: Invited Speaker Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2019, 09:00 - 15:30, Castillo A 1-2
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PC1.02 - LATAM Activities (ID 2)
09:00 - 15:30 | Author(s): Luis E. Raez
- Abstract
Abstract not provided
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LATAM General Group Meeting (ID 9)
- Event: LALCA 2019
- Type: Invited Speaker Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2019, 18:00 - 18:45, Castillo A 1-4
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T4.01 - Meeting (ID 1401)
18:00 - 18:45 | Presenting Author(s): Luis E. Raez
- Abstract
Abstract not provided
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Session 10: Poster Discussion # 2: Metastatic Disease (ID 24)
- Event: LALCA 2019
- Type: Poster Discussion Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2019, 16:15 - 17:15, Castillo A 5-6
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F10.01 - PD-L1 and Other Potential Predictive Biomarkers Measured in Plasma by RT-PCR in cfRNA and cfDNA to Monitor Clinical Responses in Metastatic Lung Cancer Patients (ID 96)
16:15 - 17:15 | Author(s): Luis E. Raez
- Abstract
Background:
We have shown before that cell-free circulating tumor RNA (cfRNA) extracted from plasma of cancer patients (pts) can measure dynamic changes in gene expression that can help to evaluated disease status and predict outcome to anti-tumoral therapy in solid tumors [T. Ishiba et al. Biochem Biophys Res Commun. 2018 Jun 7; 500 (3):621-625]. We want to show here that PD-L1 and other biomarkers assessed by RNA RT-PCR can be use as predictive markers that can be used to follow Immunotherapy and chemotherapy responses in non-small cell lung cancer (NSCLC).
Method:
We enrolled 54 pts with advanced NSCLC undergoing systemic therapy (STX) and we follow them for 1-year. cfRNA was extracted from resulting plasma and generated random-primed cDNA. Total cfRNA was quantitated by qPCR of ?-actin, and correlated with pt clinical response (CR/PR/SD/PD) determined by CT scans. All gene expressions were measured relative to ?-actin. Changes in PD-L1 expression were used to monitor response to immunotherapy in lung cancer pts. Ten milliliters of blood were collected in each of two tubes and transferred to Liquid Genomics, Inc. Blood was drawn every 6-8 weeks with an average of 5 collections were done per pt.
Results:
Of the 54 enrolled pts, 30 completed 1-3 lines of STX with outcomes. The overall mutation frequency was 33% (10/30), with 27% in KRAS and 6% in EGFR. Increases or emergence of mutant allele fractions were predictive of PD status (later determined by imaging), while decreases or disappearance of mutations were predictive of SD and PR status after treatment. PD-L1 expression was detected in 87% (26/30) of pts in at least one blood draw. Immunotherapy: (Nivolumab, pembrolizumab, atezolizumab), 11/30 pts underwent immunotherapy (IO) txt. Changes in PD-L1 during IO were associated with STX outcomes. Increases in PD-L1 were associated with PD, while decreases or no changes in PD-L1 were associated with SD and PR. Of the 23 blood draws from these 11 pts, the overall concordance between changes in PD-L1 and IO outcome was 91% (21/23). Chemotherapy: 19/30 pts were given carboplatin/pemetrexed as first line therapy. Increases or decreases in PD-L1 across 28 blood draws during therapy were likewise associated with resistance or sensitivity to STX outcome (increases infer resistance; decreases infer sensitivity) in 24/28 (86%).
Conclusion:
We demonstrated a strong concordance between clinical responses and changes in plasma PD-L1 done by RT-PCR RNA levels in NSCLC pts treated with IO or chemotherapy. Monitoring cfRNA expression levels of PD-L1 is a reliable method for predicting response and resistance to IO as well as chemotherapy irrespective of KRAS and EGFR.
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Session 13: Targeted Therapy (ID 32)
- Event: LALCA 2019
- Type: Invited Speaker Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/19/2019, 14:00 - 15:45, Castillo A 1-4
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S3.05 - NTRK Fusion Proteins (ID 113)
14:00 - 15:45 | Author(s): Luis E. Raez
- Abstract
We have a new approach to cancer therapy the Agnostic Tumor approach. Molecular mechanisms (DNA mutations, translocations, deletions, fusions, etc.) are now the ones responsible of the origin and behavior of most of the tumors, instead of the location of the tumor as we used to think. We are in the beginning of changing the focus of cancer therapy from a single organ to a molecular marker envision. One of the best example are the NTRK fusion proteins, NTRK genes encode for the Trk-family proteins: TrkA, TrkB, and TrkC (encoded by NTRK1, NTTRK2, and NTRK3). Normally, the NTRK family plays a role in the development of the nervous system, however, NTRK fusions are also present in solid tumors as fusion proteins responsible for growth of cancer cells, and the presence of these oncogenes is associate with poor survival in lung cancers and other tumor types. It is not surprising that these oncogenes are present in several different tumors (They are actionable in at least 17 tumor types) including adults and children. These genomic alterations are becoming a great example why the tumor agnostic approach might be the new paradigm in fighting cancer. However, there are still many challenges ahead; first for example, the diagnostic of these genetic aberrations: we can do fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse-transcriptase polymerase chain reaction (RT-PCR) and next generation sequencing (NGS) of DNA or RNA (or cfDNA in blood: liquid biopsies). Each of these approaches has strengths and weaknesses, but we also have to play this in the context of workups for other genetic abnormalities, and keeping into consideration that tumor tissue specimen is very limited in many instances. Nowadays, for example, we do FISH for ALK and ROS-1 translocations, if we add three more FISH tests for each of the NTRK alterations (and maybe one more for RET fusions) will markedly increase the costs of workup in a lung cancer patient, and the gene fusion partner, that might become relevant, still might not be identified if we dont have the right probe. RT-PCR is a great technique, but we will need a lot of primers (there are more than 60 NTRK fusions documented) to cover all the NTRK genetic abnormalities. Probably the solution is to develop better IHC? as we are doing for ALK translocations and hopefully get one day as IHC for ROS-1 and the other NTRK oncogenes so we can have a more cost-effective work up. A more practical approach might be to establish NGS in tissue or blood as the standard of care that can detect all these genetic alterations at once at the time of the diagnosis of the patient? Later we can do a more limited work up if we are looking for ALK and now NTRK resistant variants in patients that have failed treatment clinically. Nonetheless, for those who are not fans of NGS and dont advocate this approach we can say that several NTRK 1-3 introns are not well covered by NGS. Then, we need to do whole genome gene sequencing to find them increasing the costs of the workup. These are some of the questions that remain open while we make all these diagnostic techniques more accurate and more cost effective. Some of these reason are responsible to consider the treatment for NTRK challenging: how we can treat a patient if we cant discover the genetic aberration? We are fortunate to have two agents: entrectenib and larotrectenib that have already been FDA approved for NTRK fusions with acceptable toxicities regardless of tumor type, patient age, and fusion type, and more data coming from other agents in development CEP-701, ARRRY-470 DS-6051b, TPX-0005. Probably LOXO 195 is the one that has been more studied for now and its able to rescue patients that develop resistance mutations during the treatment with larotrectenib or entrectinib.
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Session 4: Novel Diagnostic and Prognostic Markers (ID 16)
- Event: LALCA 2019
- Type: Invited Speaker Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2019, 10:30 - 11:30, Castillo A 5-6
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F4.02 - New Technologies for Liquid Biopsies and Looking for Cost Effective Options for LATAM (RT-PCR, cfRNA, Exosomes, ECVs and CTCs) (ID 76)
10:30 - 11:30 | Author(s): Luis E. Raez
- Abstract
Liquid Biopsies have been going to the front lines in the diagnosis of cancer. They are more accepted and the health care providers are getting used to use them as alternative or complement of tissue biopsies. Our 2018 IASCL guidelines in liquid biopsies written by Rolfo et al in the Journal of Thoracic Oncology suggest the use of liquid biopises in cases that there is not enough tissue or a new biopsy is not feasible. But now that we have been discovering resistant mutations in the EGFR gene (T790m, c797, etc), ALK fusions and others it is becoming necessary to repeat the NGS analysis to find the best therapy for the patient, then to repeat or do multiple tissue biopsies to accomplish this goal and that becomes very cumbersome and difficult. In the specific case of lung cancer, biopsies are not easy because they can cause pneumothorax and lung cancer patients are not totally healthy most of them are smokers and they have already emphysema and/or COPD that increases the chances of complications if the biopsies dont go well. However there are still concerns about liquid biopsies how reliable are? and if they can totally replace tissue biopsies one day?. Our own experience already published in more than 80 patients showed that tissue biopsies are not enough or dont have any extra tissue in around 21% of the patients and all of these patients benefited of the liquid biopsy approach (NGS in cfDNA) however, there were cases that the liquid biopsy was unable to find the molecular aberration and the tissue did, then its for now safe to say that they are complementary. Another problem of the liquid biopsies is the cost specially for Latin America (LATAM), the NGS platforms are very expensive despite the fact that the prices have been decreasing in the last years but are still not affordable for the majority of the LATAM population; hence the options to do in LATAM hotspot testing, RT-PCR, FISH, exosomes and other technologies. However there are challenges, we know for example that hotspot testing that is commonly use in LATAM due to its lower cost, its not very comprehensive and miss frequently mutations or genetic aberrations. RT-PCR is very sensitive and reliable but probably is a better test to find a specific genetic aberration than to do a panel analysis of several genetic aberrations at the same time unless we have the probes for all genes; and a similar problem we have with FISH: now we can use FISH to diagnose ALK, ROS1, NTRK1-3 and RET however that means that we will need to do at least 6 different FISH tests! Only to cover these genetic aberrations and we still have to test the patient for EGFR and other genes something that makes them more expensive than running NGS one time. Probably IHC is a good alternative for LATAM for now, we have good validation of IHC for ALK diagnosis and soon we hope to have one for ROS-1; there are also several attempts to make NTRK 1-3 IHC better but probably with so many variants is a very hard task and still will not cover other genetic aberrations like BRAF, KRAS and others. These are exiting times for LATAM and other countries giving the patients there the opportunity to access molecular targets but we are far from adequate coverage of most of the patients.
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Session 9: Poster Discussion # 1: Diagnosis, Early Stage and Locally Advanced (ID 23)
- Event: LALCA 2019
- Type: Poster Discussion Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2019, 16:15 - 17:15, Castillo A 1-4
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F9.06 - Improving Survival of Oligometastatic NSCLC with Stereotactic Body Radiation Therapy (ID 95)
16:15 - 17:15 | Author(s): Luis E. Raez
- Abstract
Background:
Stereotactic body radiation therapy (SBRT) can allow non-small cell lung cancer (NSCLC) patients (pts) to stay longer with the same therapy by eliminating oligometastatic progression (OMP) improving progression free survival (PFS) and overall survival (OS).
Method:
One hundred pts with metastatic NSCLC undergoing chemotherapy (CHEMO), immunotherapy (IMMUNO) or target therapy (TARGET) that had OMP defined as less than four sites of metastasis and underwent SBRT were evaluated for PFS and OS. PFS1: Time between initiation of systemic therapy and development of OMP. PFS2: Time between OMP treated with SBRT and development of further PD requiring a change in systemic therapy. Pts received IMMUNO for second line and beyond. Robotic SBRT was delivered in 1-5 fractions on consecutive days or every other day. SBRT doses were determined based on the disease site and dose tolerance of the adjacent organs.
Results:
Brain metastasis (BM) were seen in 45 pts and 55 pts had extracranial metastasis (EM). 34 pts were receiving CHEMO, 34 Target and 32 IMMUNO at the time of OMP. Main endpoints (m) are shown (Table). Pts with BM that received SBRT were able to continue the same therapy for a period of 6.5-9 extra months due to the control of BM. Pts with EM that have developed PD were able to continue the same therapy an 17-21 extra months due to the ablation of OMP by SBRT. Overall PFS was: 16.5m for BM and 34m for EM and the OS were: 31m and 53m respectively.
Conclusion:
Significant prolongation in PFS/OS was observed compared with historical controls thanks to the use of SBRT in pts that develop OMP while on systemic therapy. SBRT allowed patients to continue with the same systemic treatment. Our CHEMO cohort is composed of long term survivors under therapy and may not represent the average PFS/OS of pts on CHEMO. Survival data from prospective trials is needed to verify these results.
