How Do I Treat…?
Practical perspectives on cancer treatment by thought leaders, explaining how they would approach the treatment of a patient in their area of expertise.
Tuesday, November 24, 2015
BY COURTNEY D. DINARDO, MD, MSCE; AND FARHAD RAVANDI, MD
Standard intensive therapy for newly diagnosed patients with acute myeloid leukemia (AML) consists of the nucleoside analogue cytarabine in combination with an anthracycline as induction chemotherapy, followed by consolidation therapy with repeated cycles of high-dose cytarabine and/or stem cell transplant to maintain complete remission (CR). With such intensive chemotherapy (IC) approaches, remissions are common, but unfortunately durable long-term cures occur only in a minority of adult patients with AML. This is especially true in older patients--typically those older than 60 or 65 years of age at diagnosis--which constitute the majority of patients diagnosed with AML.
There are currently no FDA-approved therapies for patients with relapsed/refractory AML. The only drug historically approved in this setting, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin (GO), was withdrawn from the market in 2010 due to concerns for treatment-related toxicity. Thus, there is a clear and unmet need for effective treatment options for patients with relapsed/refractory AML.
In the past decade, extraordinary progress has been made in understanding cancer biology and mechanisms of leukemogenesis. With the advent and streamlining of modern techniques such as next-generation sequencing, recurrent genomic alterations including cytogenetic abnormalities and somatic mutations can be routinely identified in over 95 percent of AML cases.
Increased knowledge of genomic abnormalities has already led to improved prognostic classification of patients with AML at diagnosis--i.e., the updated European Leukemia Net (ELN) classification system. In addition to improved AML risk-stratification, improved understanding of clonal AML architecture is leading to rationally designed treatment strategies to improve upon both the initial and salvage treatment regimens.
Treatment Options for Relapsed/Refractory AML
Relapsed/refractory AML can be (rather simplistically) divided into two groups: (1) AML that is sensitive to the conventional chemotherapeutic agents--i.e., cytarabine and anthracyclines; and (2) AML that is intrinsically resistant to or has developed secondary resistance to standard IC. Notably, there are certain AML subgroups, such as the core-binding factor leukemias (inv(16) or t(8;21)) and perhaps the newly defined ELN favorable subgroups that are exceptionally sensitive to high-dose cytarabine-based regimens; dose intensification may benefit these patients. Additionally, if a long time has elapsed between initial complete response from a conventional IC regimen before relapse (often considered > 12 months) re-challenging the patient with IC is a warranted and often successful strategy.
For patients with relapsed or refractory AML who fall into the second category, several investigational treatment approaches exist. Detailed AML characterization at the time of relapse is essential, in terms of immunohistochemistry and cytogenetic and molecular annotation, to fully consider all novel agents available on the existing clinical trials.
Avenues of Salvage Therapy/Clinical Trials:
Molecularly Targeted therapy
Identification of recurrent somatic mutations in AML has improved our understanding of AML pathophysiology, and our awareness of functional AML subsets can now be used to inform rational treatment strategies. Clinical trials with tyrosine kinase inhibitors (e.g., sorafenib, quizartinib, midostaurin, and crenolanib) for patients with activating FLT3 mutations are well underway, with demonstrable activity both as monotherapy and in combination regimens in the front-line and relapsed setting. IDH1 or IDH2 mutations are recurrently identified in about 20 percent of AML patients, with an increased incidence with increasing patient age, and targeted small molecule IDH1 and IDH2 inhibitors are now available in clinical trials with promising early efficacy as monotherapy in relapsed patients.
Somatic mutations in NRAS or KRAS are also frequent in AML patients, and combination strategies of PI3K/AKT-signaling inhibition and RAS/RAF/MEK/ERK pathway inhibition are ongoing strategies for RAS-mutated AML.
Monoclonal antibodies against commonly expressed myeloid antigens are currently under development, and can be regarded as akin to the anti-CD19, -CD20, and –CD22 antibodies available for patients with lymphoid malignancies.
While the initial anti-CD33 immunotoxin GO is no longer clinically available, novel anti-CD33 compounds including innovative bispecific T-cell engaging (BITE) therapies are now available within clinical trials. Monoclonal antibodies directed against the IL-3R (anti-CD123) are also under clinical development.
As in lymphoid neoplasms, where the addition of monoclonal antibodies to the standard cytotoxic regimens have improved outcomes significantly, it is hoped that the addition of effective antibody-based therapies to AML-specific regimens will improve the outcomes for the majority of patients with AML who express these surface antigens.
The frequency of genomic alterations leading to aberrant epigenetic regulation (i.e., mutations in IDH1/2, DNMT3A, TET2, EZH2, ASXL1, MLL, and others) supports the dysregulation of epigenetic machinery as a fundamental component of leukemogenesis. Treatment with the hypomethylating agents azacitidine and decitabine, provides an important approach in both the front-line and relapsed settings (particularly in the elderly population due to the better tolerability of these agents), with responses seen regardless of the identification of epigenetic mutations. Second-generation hypomethylating agents (SGI-110) are also under clinical development, with a randomized Phase III study ongoing.
Additional Salvage Treatment Options
An exhaustive list of currently available and promising clinical trials for patients with relapsed/refractory AML is outside the scope of this brief review, as the speed of scientific discovery in the past decade has led to the development of numerous exciting compounds with unique mechanisms of action and improved safety profiles.
Some notable compounds include the small molecule BCL2 inhibitor (venetoclax), MDM2 inhibitors, the selective inhibitor of nuclear export (SINE) compound selinexor (KPT-330), and the Polo-like kinase-1 inhibitor volasertib. Referral of patients with AML and relapsed/refractory disease to academic leukemia centers of excellence for consideration of appropriate investigational clinical trials is paramount.
We expect that the future of AML therapy will incorporate well-designed and target-specific molecules into current treatment strategies in an individualized manner, founded upon a detailed understanding of the specific genomic aberrations and aberrant signaling pathways unique to each individual patient.
With improved identification of patient-specific leukemia-promoting pathogenic processes as well as the expanding armamentarium of effective therapeutic options, we will likely witness continued progress in the management of patients with relapsed/refractory AML.
Courtney D. DiNardo, MD, MSCE, is Assistant Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center; and Farhad Ravandi, MD, is Professor of Medicine and Chief of the Section of Developmental Therapeutics in the Department of Leukemia at the University of Texas MD Anderson Cancer Center.
Friday, May 29, 2015
BY RICHARD GORLICK, MD
Professor of Pediatrics and Molecular Pharmacology,
The Albert Einstein College of Medicine of Yeshiva University;
Vice Chairman of Pediatrics and Division Chief of Pediatric Hematology, Oncology and Marrow and Blood Cell Transplantation, The Children’s Hospital at Montefiore, Bronx, NY
All cancers in children and young adults are fortunately rare. Even in their period of most frequent incidence, during the second decade of life, bone tumors are not the most common malignancy of childhood. For sarcoma oncologists, most patients referred to your practice have a high enough probability of having cancer that everyone can be more thoroughly assessed, which is not the case for primary care providers.
It can be very challenging for the pediatrician and orthopedic surgeons to consider a bone cancer as a possible diagnosis in the myriad patients who present complaining of pain or a mass more often resulting from benign etiologies. Trauma, growing pains, and osteomyelitis are all more common than bone cancer.
The advice given to primary care providers is that in patients with persistence of pain or the association of the pain with a mass, particularly when symptoms are becoming more severe over time, further evaluation with a plain radiograph of the site is warranted.
The two most common bone cancers in younger patients are osteosarcoma and Ewing sarcoma family tumors, with approximately 400 and 200 new pediatric cases per year, respectively, in North America. Although they can occur in any bone in the body, approximately half of osteosarcomas occur in the region around the knee. The majority of Ewing sarcoma family tumors occur in the appendicular skeleton even though this entity’s tropism away from the axial skeleton is not as pronounced as for osteosarcoma. This, coupled with the age distribution of these cancers, dictates a higher level of concern for malignancy in teenagers with symptoms and physical exam findings around their knees.
Once a plain radiograph is obtained, bone tumors usually have a dramatic appearance, and a completely negative radiograph is reassuring that a cancer is not present. Osteosarcomas often have soft tissue extension with a periosteal reaction that is classically described as having a “sun-burst” appearance in the metaphyseal region of the bone.
Ewing sarcoma family tumors are permeative, leading to a periosteal reaction that is lamellar or “onion skinning” in appearance in the diaphyseal or metaphyseal region of bones. Occasionally patients with bone cancer will present more dramatically with pathological fractures, but even in some of these cases, a reported history of trauma may muddy the picture, leading to confusion and misdiagnosis, so a high index of suspicion always needs to be maintained to avoid delays in diagnosis.
Once a diagnosis of a bone cancer is suspected prompt referral to a group with expertise in sarcomas is strongly recommended as these patients require complex multidisciplinary care.
Multidisciplinary Sarcoma Care
All bone cancers require multidisciplinary care by physicians with expertise in their management. For this purpose, all new patients seen at our sarcoma center are seen right from the first encounter by both a pediatric/medical oncologist and an orthopedic oncologist, at the same time, in shared clinic space.
A history and physical examination along with plain radiographs dictates further evaluation. One needs to consider the benign entities that can mimic more aggressive lesions as well as variant osteosarcoma and Ewing sarcoma family tumor appearances, which can misleadingly suggest a benign lesion.
In most patients at least additional imaging is warranted, which is typically magnetic resonance imaging of the site, with and without gadolinium contrast including the entire bone to capture skip lesions that may be present. This is best done prior to the biopsy to assist in decision making and biopsy placement and so that the appearance of the lesion prior to its disruption by the biopsy can be appreciated.
In patients strongly suspected of having osteosarcoma or a Ewing sarcoma family tumor, high-resolution chest computed tomography is obtained prior to biopsy to avoid issues of postoperative atelectasis creating challenges in interpretation of findings within the lungs, as this is the site in which metastases are most likely to occur.
In all patients being biopsied at least a chest radiograph is warranted. Elevated alkaline phosphatase and lactate dehydrogenase supports a probable diagnosis of a bone cancer.
I am a strong advocate of open biopsies, but many institutions have core needle biopsies performed by interventional radiologists or orthopedic surgeons with this topic being immensely controversial.
Universally endorsed is the belief that the biopsy needs to be performed by someone with experience in resecting bone cancer, with the critical issue being consideration of the surgical plan for definitive resection. If the pathology reveals a cancer of bone, the needle, or incision tract will need to be removed along with the tumor en block, to abrogate the risk of seeding the site with tumor cells.
Osteosarcoma is diagnosed by a bone tumor pathologist based on the histologic appearance of a malignant spindle cell tumor that produces osteoid. Ewing sarcoma family tumors are small round blue cell tumors which typically express CD99 and possess one of a number of recurrent chromosomal translocations most commonly involving the EWS and FLI genes on chromosomes 11 and 22 detected via FISH or PCR and are disease defining.
Once the diagnosis is made, the staging workup is completed with a technetium bone scan, and additionally, in the case of Ewing sarcoma family tumors multiple site bone marrow aspirates and biopsies.
The role of PET scans in routine clinical practice for bone sarcomas remains undefined. A central venous catheter is required for the types of systemic chemotherapy that are typically utilized, and additional pre-treatment assessments of organ function are performed appropriate to the planned treatment. Fertility preservation methods need to be discussed with all patients.
Systemic and Local Therapy
The standard of care for all patients with high-grade osteosarcoma and Ewing sarcoma family tumors is the use of neoadjuvant chemotherapy, followed by local control and subsequently additional adjuvant chemotherapy. Systemic therapy is needed because of the high frequency of micro-metastases in patients with radiographically localized disease.
Routine clinical practice for younger patients with bone cancers is heavily dictated by Children’s Oncology Group clinical trials. If a Phase III trial is active for newly diagnosed patients offering participation is routine. In the absence of a front-line study the superior arm of the last Phase III trial is used typically as standard therapy.
For osteosarcoma patients, front-line studies are not active at present, with the standard arm of the last international Phase III study, the EURAMOS study, being superior to the experimental arms. As such, the standard induction and adjuvant chemotherapy is comprised of cisplatin and doxorubicin alternating with two consecutive weeks of high-dose methotrexate in accordance with the schema in the EURAMOS study.
Local control requires a complete surgical resection of the tumor as osteosarcoma is relatively radiation resistant. These resections typically do not require amputation, and considerable advances have been made in the surgery as well as the typically metallic internal prostheses yielding numerous functional enhancements.
The field of orthopedic oncology is highly specialized, interesting, and beyond the scope of the present discussion. The degree of necrosis in the resected tumor samples is prognostic but thus far has been shown to be of no clinical value for tailoring subsequent therapy. In patients with osteosarcoma and pulmonary metastases the nodules need to be resected. In our institution this is performed as bilateral staged thoracotomies but considerable variation in practice exists.
For patients with newly diagnosed Ewing sarcoma family tumors, active Children’s Oncology Group clinical trials are ongoing. All patients are given intensively timed cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide as this resulted in superior survival in the last Phase III trial and represents the standard of care.
In patients with localized disease the randomized question is whether the addition of cyclophosphamide, topotecan, and vincristine improves survival. In patients presenting with metastatic disease the randomized question is whether the addition of ganitumab, an antibody to IGF-1R, improves survival. Local control is performed after neoadjuvant chemotherapy but, unlike osteosarcoma, can involve either surgery or radiation therapy or both. Whether a patient receives surgery or radiation therapy frequently is decided based on the functional consequences and late effects of each. Considerable variation exists in institutional practice. In patients with metastatic disease radiation therapy is more frequently utilized.
Care of Patients with Recurrent Osteosarcoma and Ewing Sarcoma
Approximately 60 to 70 percent of patients presenting with localized high-grade osteosarcoma or Ewing sarcoma family tumors will have long-term disease-free survival with the aforementioned therapy. For the 20 percent of patients who present with radiographically visible metastatic disease, the prognosis is markedly worse and further influenced by the extent of the metastatic disease. Similarly the prognosis of patients with recurrent disease is poor.
In patients with recurrent osteosarcoma, metastectomy has been shown to be of clinical benefit with a small percentage of patients having durable disease-free survival with resection alone. The value of salvage chemotherapy, typically ifosfamide and etoposide is controversial. In Ewing sarcoma family tumors radiation therapy is employed for local control with cyclophosphamide, topotecan, and vincristine or temozolomide, irinotecan, and vincristine being the most typical salvage therapies.
Numerous clinical trials of novel agents are being performed in patients with recurrent osteosarcoma and Ewing sarcoma family tumors, and participation in these trials can be offered. It is hoped that some of these ever-changing menu of agents will prove effective in the therapy of patients with recurrent bone cancer, and will improve survival when added to upfront therapy of newly diagnosed patients, which will need to be proven in the context of future randomized Phase III trials.
Tuesday, February 24, 2015
BY Sandy Srinivas, MD
Associate Professor of Medicine (Oncology)
Stanford University Medical Center
Prostate cancer spans a spectrum like all cancers, ranging from localized disease to metastatic disease. As with breast cancer, prostate cancer is exquisitely sensitive to hormonal manipulation, and from a practical point of view is divided into hormone-naïve versus castrate-resistant disease.
Recurrent Prostate Cancer Post-localized Disease
Recurrent post-localized prostate cancer is usually manifested by a climbing serum prostate-specific antigen (PSA) after therapy for localized disease. Typically, I stage patients with a CT scan and bone imaging, either with a bone scan or a F18 PET scan. When PSA doubling time (PSA DT) becomes less than six months, androgen-deprivation therapy (ADT) is initiated.
In general, if scans show no metastases, I start patients on LHRH analogs such as leuprolide or gosserlin. There are LHRH antagonists commercially available that can be used as well. I tend to offer patients intermittent ADT as long as patients appear to be reliable and motivated for follow-ups.
I do not use a specific PSA level to reinitiate therapy but rather look at the rate at which the PSA rises. Every time it takes a sharp rise, I tend to reimage, and do not do scans on a set schedule.
Metastatic Prostate Cancer
Due to the current controversies about PSA screening, we are seeing more patients with newly diagnosed metastatic prostate cancer now than five years ago. Based on the CHARTERED trial, which showed a significant survival advantage to the use of chemotherapy along with ADT, I do offer docetaxel x 6 cycles in addition to ADT for these patients with bone or visceral metastases.
For patients with recurrent prostate cancer following localized disease, I start them on ADT. I offer intermittent ADT even in patients with metastatic disease after having a discussion with patients regarding their goals and tolerability to ADT.
Ultimately, castrate resistance--defined as a rising serum PSA despite low testosterone--develops in almost all patients starting ADT. I will reimage them to set a new baseline, and if the patient remains non-metastatic, I would use drugs such as bicalutamide first. In general responses are variable, and if serum PSA rises, I will initiate anti-androgen withdrawal and then reimage again. If patients are non-metastatic, I would pursue older drugs such as nilutamide or even ketoconazole/hydrocortisone--surveillance alone may also be appropriate in certain cases.
Metastatic Castrate-Resistant Prostate Cancer
Management of patients with metastatic castrate-resistant prostate cancer has become challenging, as there are several FDA-approved drugs for this group of patients. These include sipuleucel-T, abiraterone, enzlautamide, radium 223, as well as chemotherapy. I use Provenge or sipuleucel-T when patients have slow-rising PSA with long PSA DT and when they are asymptomatic and not too concerned about PSA values.
I use enzalutamide if patients have issues with diabetes or poorly controlled hypertension and abiraterone with prednisone if they have pain and would benefit from the prednisone use. Typically I do not use these drugs back to back, as there is a very low chance of response.
After failure of either enzalutamide or abiraterone, I re-scan. If patients have bone-only disease, I would recommend alpharadin (radium-223, Xofigo) for six cycles. If patients have bulky nodal disease or visceral disease, I would recommend chemotherapy with docetaxel.
I typically stop chemotherapy after six to eight cycles and give patients a chemotherapy holiday. I will treat with additional hormonal agents such as abiraterone or enzalutamide if patients have never received that drug. For patients progressing after this, I will re-treat with docetaxel if it has been more than a year since the last treatment; otherwise I recommend cabazitaxel.
While mitoxantrone is an old drug, I still use it in patients who have progressed on taxanes or those who have had an allergic reaction to taxanes.
Bone health is a vital part of the care of patients with prostate cancer. I use bone-modifying drugs in patients with castrate metastatic prostate cancer but not in those with newly diagnosed bone metastases. A randomized trial from CALGB did not support the use of zoledronic acid in newly diagnosed metastatic prostate cancer patients. I will use zoledronic acid or denosumab every three months along with a GNRH analog, which I continue as well.
Wednesday, July 09, 2014
By Elena Elimova, MD, MSC; Brian Badgwell, MD; Prajnan Das, MD, MS, MPH; Jeannelyn Estrella, MD; Aurelio Matamoros Jr., MD; and Jaffer A. Ajani, MD
Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10 percent realized by adjunctive treatments to surgery is unacceptable as more than 50 percent of patients with localized gastric cancer succumb to their disease.
Either postoperative chemoradiotherapy (in the United States), pre-and post-operative chemotherapy (in Europe), and adjuvant chemotherapy after a D2 resection (in Asia) can all be regarded as standards of care in the localized management of the disease. For patients with metastatic disease, the addition of trastuzumab to chemotherapy is standard of care in HER2-positive disease. In the HER2-negative population, the treatments remain limited.
In the first-line setting, the standard of care is a combination of fluoropyrimidine and platinum-containing chemotherapy, with or without epirubicin or docetaxel. Finally there is a minimal overall survival benefit in treating patients with metastatic disease in the second-line setting, with either irinotecan, docetaxel, or ramucirumab with or without chemotherapy.
Our approach to the treatment of patients with gastric cancer begins with appropriate clinical staging to determine if the cancer is localized or advanced. This involves full imaging, including CT of the chest/abdomen/pelvis, PET-CT, endoscopic ultrasound (EUS), and finally a staging laparoscopy.
EUS is the most reliable nonsurgical method to evaluate the depth of invasion, with concurrent evaluation of regional lymph nodes of primary gastric cancers and is therefore instrumental; however, things are not as simple as doing an EUS because this technique is really only useful in the hands of a skilled operator.
The PET/CT scan is most useful in detecting occult distant metastasis, thereby helping avoid high morbidity surgery in a sub-group of patients. Laparoscopy should be considered for patients who appear to have locoregional disease (other than stage IV, Tis or T1a stage) after conventional radiographic and EUS staging. However, because it is sometimes difficult to differentiate T2 and T3 lesions on EUS, it is reasonable to perform a laparoscopy for any medically fit patient who appears to have more than a T1 lesion on EUS, no histologic confirmation of stage IV disease, and who would not otherwise require a palliative gastrectomy because of symptoms. This is because 20 to 30 percent of patients with greater than T1 EUS disease will be found to have peritoneal metastasis despite having negative CT and PET scans.
In our center the clinical staging is followed by a multidisciplinary discussion in all localized gastric cancer cases:
Localized Gastric Cancer
In terms of localized gastric cancer, a curative resection (R0) offers the best chance of cure, and is best managed at high-volume centers and by high-volume surgeons. We strongly believe that a multidisciplinary approach and preoperative therapy is the cornerstone of management in the West.
Although gastrectomy is the recommended treatment in relatively early-localized gastric cancer (T1b), in more advanced disease (T2N0, T1aN+, or T1b-T3N+) we recommend adjunctive therapy in addition to gastrectomy. As previously mentioned, postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the management of localized gastric cancer. However, at our institution, we use a combination of these approaches in the pre-operative setting, because in our experience post-operative therapy is much harder to deliver.
Our general approach is to start with pre-operative chemotherapy with a platinum-based doublet or triplet (depending on the performance status of the patient) for two to three months, followed by chemoradiation also given preoperatively with 5-fluorouracil ± taxanes or platinum, finally followed by surgery. This approach is based on Phase II study data and results in R0 resection in 70 to 78 percent of our patients and five-year overall survival rates at least comparable to those reported in the Intergroup 0116 and MAGIC clinical trials.
In terms of post-treatment surveillance, there is no data to provide guidance, and arbitrary surveillance strategies are used.
Metastatic Gastric Cancer
In terms of our approach to metastatic gastric cancer, clearly in the context that this is no longer a curative situation our approach is to the palliation of symptoms and prolongation of life:
Otherwise, we would treat differently based on HER2 status. Clearly in HER2-positive gastric cancer there is an overall survival benefit to the addition of anti-HER2 therapy to first line chemotherapy.
It is our practice to typically use trastuzumab and not lapatinib because of the negative results of the lapatinib trial in combination with platinum-based doublet. Although no convincing data exists as to the benefit of the addition of HER2 therapy in gastric cancer, we extrapolate from the breast cancer trials and continue anti-HER2 therapy beyond progression, typically switching to an alternative agent such as pertuzumab.
In the context of HER2-negative metastatic disease, our options continue to be limited. In a select subgroup of patients who have small-volume disease and who are asymptomatic, a careful watch-and-wait strategy is reasonable as long as the patient is comfortable with this approach. In symptomatic patients, a reasonable option in the first-line setting is a platinum-based doublet with the addition of docetaxel or epirubicin, depending on the performance status of the patient or clinical trials.
In the second-line setting, we often use irinotecan-based doublets, but with the recent approval of ramucirumab, this agent in combination with chemotherapy will have a role in our practice.
Genetic profiling of tumors is becoming a more widely used tool in the treatment of gastric cancer, as it is in other cancers. Patients are often found to have multiple and even more often non-targetable mutations. Even when a potentially targetable mutation is found and the patient is treated with a given drug, we have found that responses are rare--likely because of our poor knowledge of driver mutations. Therefore we do not consider a genetic evaluation a critical part of treatment, but rather emphasize the enrollment of patients into available clinical trials.
In summary, we strongly feel that all patients with localized gastric cancer in a potentially curable situation should be evaluated in a multidisciplinary way and in a high-volume center, so that they can have the benefit of a surgery performed by a high-volume surgeon. In metastatic disease at our institution we put emphasis of enrollment of patients on clinical trials in hopes of improving outcomes.
The authors are all from the University of Texas MD Anderson Cancer Center: Elena Elimova, MD, MSC, Department of Gastrointestinal Medical Oncology; Brian Badgwell, MD, Department of Surgical Oncology; Prajnan Das, MD, MS, MPH, Department of Radiation Oncology; Jeannelyn Estrella, md, Department of Pathology; Aurelio Matamoros Jr., md, Department of Diagnostic Radiology; and Jaffer A. Ajani, md, Department of Gastrointestinal Medical Oncology.
Saturday, July 05, 2014
BY Geoffrey R. Oxnard, MD
Assistant Professor of Medicine
Dana-Farber Cancer Institute
Harvard Medical School
T790M is a point mutation in the EGFR gene that is associated with resistance to epidermal growth factor receptor (EGFR) kinase inhibitors like erlotinib and gefitinib. Some of the most exciting results presented at this year’s American Society of Clinical Oncology Annual Meeting have to do with new inhibitors targeting the EGFR T790M mutation. Given that this appears to be an emerging biomarker in the treatment of lung cancer patients, it is worth reviewing the management of patients carrying this mutation. Importantly, it can be seen in several different clinical circumstances where it can mean different things.
Baseline EGFR T790M
The EGFR T790M mutation is rarely seen in a lung cancer at initial diagnosis, prior to treatment with an EGFR kinase inhibitor. The prevalence of baseline T790M is debated in the scientific literature, but using conventional testing methods it is generally though to occur in one to two percent of all EGFR-mutant lung cancers. When seen in this setting, it is most commonly identified in addition to a second drug-sensitive EGFR mutation. Despite that, lung cancers with baseline EGFR T790M are unlikely to respond to standard EGFR kinase inhibitors and should be treated in the first-line setting with standard chemotherapy. Interestingly, the presence of baseline T790M indicates a high likelihood of an underlying germline T790M mutation, discussed further below.
Acquired EGFR T790M
The more common setting where the T790M mutation is seen is as an acquired mutation in EGFR-mutant lung cancer after treatment with an EGFR kinase inhibitor. A repeat tumor biopsy in this setting can identify a new T790M mutation more than half the time. Previous data has suggested that T790M-mediated resistance can be associated with an indolent growth and a relatively favorable prognosis when compared with other types of resistance. Interestingly, there are some types of that resistance less likely to carry T790M – such as progression in the brain only, or recurrence after stopping adjuvant erlotinib – suggesting that these situations may not be fully resistant, and that further treatment with an EGFR kinase inhibitor might make sense.
While there was hope that irreversible EGFR kinase inhibitors like afatinib or dacomitinib might inhibit T790M, response rates to these drugs have been low in patients with resistance to erlotinib or gefitinib. A higher response rate of 30 percent was reported with afatinib plus the EGFR antibody cetuximab, though this activity was seen both in T790M positive and negative resistance.
At ASCO this year, data were presented regarding a new class of drugs called “mutant-selective irreversible EGFR kinase inhibitors” which target T790M-mediated drug resistance. These drugs potently inhibit mutant EGFR protein without inhibiting wildtype EGFR, aiming to induce responses while avoiding EGFR-related toxicities. Data from three trials of three different drugs in this class (AZD9291, CO-1686, and HM61713) were presented, and each drug reported dramatic tumor responses in patients with EGFR-mutant lung cancers after resistance to standard EGFR kinase inhibitors.
In the largest trial, studying AZD9291, a striking difference in activity was seen between tumors with T790M-mediated resistance (a 65% response rate) and those with T790M-negative resistance (a 22% response rate). Additional phase II data will be needed to better understand any differences in activity between these drugs, but T790M does appear to be an emerging biomarker suggesting drug sensitivity.
Clinical trials are ongoing around the world (NCT01802632; NCT01526928; NCT01588145) and are an attractive alternative to standard chemotherapy for these patients.
Germline EGFR T790M
The rarest setting where EGFR T790M can be seen is as a germline mutation where it has been found to be associated with familial lung cancer, particularly in non-smokers. However, the risk of lung cancer in healthy individuals carrying such an inherited mutation is not well understood. Given how rare this condition is – associated with less than 1 in 1000 lung cancers – germline testing is not widely available and is not part of standard practice. In my practice, I only test for germline EGFR T790M when a patient presents with baseline EGFR T790M, a setting where the prevalence of germline mutations is estimated at approximately 50 percent.
To better understand this condition, and to offer patients free genetic counseling and germline testing, my institution has teamed up with the Addario Lung Cancer Medical Institute (ALCMI) to open a prospective trial titled INHERIT: Investigating Hereditary Risk from T790M. Individuals can present to the study website for more information: www.dana-farber.org/T790Mstudy/. If a lung cancer patient harboring baseline T790M undergoes germline testing and is found to be positive for an inherited mutation, they can then invite their relatives to be tested, allowing study of entire families. If we can demonstrate that these families are at a high risk of lung cancer, then perhaps they should be undergoing CT-screening much as is recommended for individuals with a significant smoking history.
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