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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Just Diagnosed with Advanced Lung Cancer: What Now?

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Howard (Jack) West, MD
Associate Clinical Professor in Medical Oncology and Executive Director of Employer Services at City of Hope Comprehensive Cancer Center

A new cancer diagnosis is overwhelming. Patients often ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks lung cancer expert Howard (Jack) West, MD, how he would handle his own diagnosis of advanced lung cancer. Dr. West is a Princeton- and Harvard-educated oncologist with additional training and experience in Boston and Seattle focusing on lung cancer. He is now an Associate Clinical Professor in Medical Oncology and Executive Director of Employer Services at City of Hope Comprehensive Cancer Center in Duarte, California.

Curious Dr. George: What would you do if you personally were discovered on a routine chest X-ray to have a unilateral pleural effusion which was found by cytopathology to contain mixed squamous and adenocarcinoma cells? How would you proceed?

Dr. West: Though I’m a never-smoker, we know that is no guarantee of immunity from lung cancer, the cancer type I’ve focused on for the past two decades. Perhaps I develop a persistent cough and worsening shortness of breath over a few months. I get a chest X-ray that shows a large right pleural effusion, and a same-day chest CT confirms this and bilateral lung nodules, perhaps along with several enlarged right hilar and mediastinal lymph nodes. The effusion is drained, and the pathologist gives my doctor and me the immediate feedback that this is a carcinoma, and we quickly learn that the immunohistochemistry profile is consistent with an adenocarcinoma. Where do we go from here?

My next step is to order broad next-generation sequencing, which may entail a new biopsy, either CT-guided or an endobronchial ultrasound and biopsy of whatever is accessible. We need sufficient tissue to send off for broad molecular testing that includes a look for all of the growing collection of lung cancer “driver mutations.” These include long-established markers like a mutation in the epidermal growth factor receptor (EGFR) gene or a rearrangement in the anaplastic lymphoma kinase (ALK) gene, but now also a rearrangement in ROS1, mutation of BRAF V600E, a MET exon 14 skipping mutation, RET fusion, or fusion in the TRK gene. These genetic alterations are found in approximately 0.5% to 10% each in patients with non-small cell lung cancer (NSCLC) and far more commonly in patients with a non-squamous NSCLC tumor. They all have FDA-approved oral targeted therapies with efficacy that generally exceeds what we could expect with our best standard non-targeted approaches involving immunotherapy with or without chemotherapy. Most of these targeted therapies also better tolerated and can work for a prolonged period that may reach the range of years.

This mutation testing typically takes at least 2 to 4 weeks, but the importance of identifying one of these mutations, when present, makes it critical to seek this information at the time of initial diagnosis. Moreover, in addition to the array of markers we currently have targeted therapies for, we expect an FDA approval for an inhibitor of KRAS G12C-mutated NSCLC, seen in about 12% to 13% of advanced NSCLC, in the coming months; all in all, comprehensive molecular testing guides us to an optimal targeted therapy for at least 20% of patients, and that proportion will continue to increase as new targets with effective therapies become available.

In the hypothetical scenario of my own diagnosis, as this testing is being done we’re also testing for tumor PD-L1 expression, which identifies tumors most likely to respond well to immune checkpoint inhibitors, potentially sparing patients first line chemotherapy if they don’t receive a targeted therapy. And I’d seek to complete imaging with a PET/CT and brain MRI, in order to identify whether the cancer has spread to other sites beyond those already identified.

Once these tests are completed, I’d prioritize a targeted therapy if my tumor harbors a driver mutation. If not, I’d generally favor pembrolizumab monotherapy if my cancer is among the approximately 28% to 30% that demonstrates high tumor PD-L1 expression (greater than 50%). Otherwise, if my cancer has neither a driver mutation nor high tumor PD-L1 expression, I’d generally favor a platinum-based chemotherapy doublet with pembrolizumab—an option I would also favor in a patient with a tumor that doesn’t harbor a driver mutation and with high tumor PD-L1 if that patient had many cancer-related symptoms or otherwise showed a pattern of rapid progression in the early weeks of the workup. Though I’d be happy to sequence the immunotherapy with subsequent chemotherapy in patients in whom I’m confident they will still have the performance status to tolerate platinum doublet chemotherapy after progressing on chemotherapy, I’d favor “front-loading” with chemo-immunotherapy together in patients in whom I’m concerned I may only have “one shot on goal.”

Dr. West can be reached at JackWestMD@gmail.com or on Twitter at @JackWestMD.

Related Links:

Molecular Testing Guides Treatment for Claudius’s Lung Cancer

What’s New in Immunotherapy for Non-Small Cell Lung Cancer?

Comprehensive Molecular Testing Needed for Stage IV Lung Cancer

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Manage Her Own Advanced Colorectal Cancer

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Christina Wu, MD Associate Professor of Hematology and Medical Oncology, Emory University

When facing a new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Cancer Commons Expert Physician Advisor Christina Wu, MD, how she would handle her own diagnosis of metastatic colorectal cancer. Dr. Wu is Associate Professor of Hematology/Oncology and Associate Division Director of Medical Oncology at Winship Cancer Institute of Emory University.

Curious Dr. George: As an experienced academic and practicing clinical oncologist at Emory University, you have particular interest, training, and experience in colorectal cancer. What would you do if you personally were discovered to have an asymptomatic, unsuspected, non-obstructing adenocarcinoma of the ascending colon that had already metastasized to your liver?

Dr. Wu: Colorectal cancer is the third most common cancer in the U.S., and one of the leading causes of cancer deaths. However, every patient with metastatic colon cancer to the liver is treated individually because there are various systemic and liver-directed treatment options. If I were diagnosed with colon cancer and liver metastasis, I would want a multi-pronged approach to include the following:

Next-generation sequencing: First of all, I would want to know if I could benefit from immunotherapy so that I could be spared the side effects of chemotherapy. I would test for mismatch repair protein status or microsatellite instability. I would want to know the tumor’s KRAS/NRAS/BRAF mutation status, because I would be a candidate for anti-EGFR therapy if my tumor was RAS wild-type and the primary cancer was left-sided. The presence of a BRAF mutation would direct me to targeted therapies, such as encorafenib and an anti-EGFR antibody or vemurafenib, irinotecan, and an anti-EGFR antibody. If the tumor was RAS wild-type with HER2 amplification, I would be interested in HER2-targeted therapies. In addition, if I had the rare NTRK fusion mutation, I would be a candidate for larotrectinib. There are also ongoing clinical trials testing drugs that target KRAS mutations, such as KRAS G12C.

Multi-disciplinary tumor board: I would want high-quality imaging and experts from medical oncology, surgical oncology, radiation oncology, gastroenterology, radiology, and interventional radiology reviewing my case in a tumor board. It would be meaningful to know upfront whether the liver metastasis was surgically resectable, because I may opt to receive systemic chemotherapy followed by surgical resection. If I required conversion therapy, I would consider triplet chemotherapy (FOLFOXIRI) to get more of a response so that I could get to surgery. However, if I had clearly unresectable disease, I would choose doublet chemotherapy such as FOLFOX or FOLFIRI with a biologic agent to improve my quality of life. With unresectable disease, I could also consider radiation, Y90 treatment, or ablation to the liver tumors, should I have good control or surgical resection of the extrahepatic disease.

Genetic counseling: There are hereditary syndromes that lead to colon cancer development, including Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis. All patients with a new diagnosis of colorectal cancer are recommended to have universal screening for Lynch syndrome, and identifying a hereditary syndrome may help family members with early detection.

Palliative care: This is such an important team that treats the symptoms patients have from their cancer as well their cancer treatment. They also provide great support to patients and their caregivers in navigating their way through their cancer diagnosis.

Clinical trials: I personally would want to be part of clinical trials that could help move new drugs forward for colorectal cancer patients, and thus I would consider this an essential team in my cancer care.

Final thoughts: As I reflect on all the teamwork and different moving pieces that have to come together for one cancer patient, I am certainly grateful for all the multi-disciplinary clinical staff and physicians who are caring for cancer patients.

Dr. Wu can be reached at Christina.wu@emoryhealthcare.org.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.