Daniela Molena, M.D.
Dr. Daniela Molena is an experienced thoracic surgeon with expertise in diagnosing and treating people with cancers of the chest, including the lungs, esophagus, mediastinum, and pleura. As Director of Memorial Sloan Kettering’s Esophageal Program, Dr. Molena leads a team that helps people with esophageal cancer understand what to expect during their journey, prepares them for surgery, and helps them recover as quickly as possible.
In her research, Dr. Molena studies and integrates new technology and novel surgical approaches to make surgery more precise and effective. Her research focuses on zeroing in on ways to improve clinical and functional outcomes after surgery, designing clinical pathways to decrease costs and improve results, and identifying racial and socioeconomic disparities that limit access to excellent care.
In the past, most people diagnosed with esophageal cancer had squamous cell cancer, which affects the lining of the esophagus. The squamous cell form, primarily caused by smoking and heavy alcohol use, has seen a slight decline in incidence in recent decades.
Today esophageal cancer is more often linked to gastroesophageal reflux disease (GERD) and obesity. GERD is common among people who are overweight and is triggered by stress. Longstanding GERD raises the risk of Barrett’s esophagus, a condition in which esophageal cells that have been bathed in acid for a long time begin to thicken as a defense mechanism. These changes can lead to esophageal adenocarcinoma.
Not everyone with GERD will develop Barrett’s esophagus, and among those who do, only a small number will develop cancer. An endoscopy can help guide their care. A gastroenterologist with specialized training inserts a flexible tube with a camera at its tip through the patient’s mouth and into the esophagus to examine the lining. MSK offers a screening program for people with Barrett’s esophagus, including endoscopy every three to five years in those with no evidence of precancerous cells and periodic monitoring. Precancerous cells can often be removed or destroyed with extreme cold (cryotherapy) or heat (radiofrequency ablation) using advanced endoscopic techniques, preventing their progression to cancer.
However, as rates of this condition rise, more people may be at risk for developing esophageal cancer. Screening for Barrett’s esophagus has led to an increase in the diagnosis of early-stage cancers over the past decade.
Physicians are also faced with the question of whether to treat patients using advanced endoscopic procedures or surgery that removes just the portion of the esophagus containing the tumor. Dr. Molena works as part of a multidisciplinary team at MSK to determine the best treatment for each patient with early-stage disease. She considers key factors, such whether cancer has invaded nearby lymph nodes, which raises the risk of recurrence and spread.
An Evolution in Standards of Care
Many people with esophageal cancer are treated with chemotherapy and radiation therapy before surgery to shrink their tumors. This approach, called neoadjuvant therapy, may improve the likelihood of completely removing the cancer, is well tolerated by patients, and often relieves swallowing problems, a common source of discomfort for people with esophageal cancer. Neoadjuvant therapies are part of the standard of care for esophageal cancer in most hospitals around the world, based on the results of clinical trials led by MSK and its peers.
Dr. Molena’s expertise includes minimally invasive and robotic surgical techniques, which use small incisions that result in less discomfort and allow patients to recover more quickly than after traditional open surgery.
Newer treatments — such as immunotherapy, which boosts a person’s immune system to find and destroy cancer cells — have been approved for some esophageal cancers. Yet success in the care of those with metastatic disease, which often becomes resistant to treatment, remains elusive.
MSK’s efforts to diagnose esophageal and other gastrointestinal cancers early and treat them more effectively include the 2021 launch of the Lisa and Scott Stuart Center for Adolescent and Young Adult Cancers. Designed to meet the specific needs of people under 50 with these disease types, it offers a dedicated clinic and specialized support programs.
Identifying Molecular Targets to Improve Care
MSK is a recognized leader in precision oncology, the practice of identifying genetic mutations that drive a person’s cancer and then matching that person with the most appropriate treatments. MSK-IMPACT™, the FDA-authorized tumor-sequencing test that recognizes 505 mutations associated with cancer, has provided a foundation for developing more effective therapies for the disease, from the most common to the rarest. The test is also providing a gateway for determining cancer risk in individuals and families.
Dr. Molena is collaborating with teams across MSK to identify specific molecular targets in esophageal cancer to help prevent the disease as well as enhance its diagnosis, surveillance, and treatment. With unparalleled resources for laboratory, translational, and clinical research, MSK offers an ideal environment for this endeavor.
Immunotherapy
Dr. Molena and her colleagues have been using MSK-IMPACT in clinical trials to identify immunotherapeutic targets in people with esophageal cancer that persists despite surgery and chemotherapy.
A current study compares treatment with the immunotherapies pembrolizumab (Keytruda®) and trastuzumab (Herceptin®) to trastuzumab alone. Trastuzumab is used to treat people with tumors that contain high levels of the protein HER2. Pembrolizumab targets the protein PD-1, which releases the brakes on the immune system so it can detect and destroy cancer cells.
By measuring levels of circulating tumor DNA (ctDNA), small pieces of DNA released from tumor cells into the bloodstream, Dr. Molena and her team can often determine a regimen’s effectiveness without invasive tumor biopsies. And ctDNA is predictive as well. The higher the level of ctDNA, the more likely it is that the cancer will recur.
Dr. Molena is also a co-investigator in an MSK phase III study initiated in October 2020. It is comparing the effectiveness of the immunotherapy durvalumab (Imfinzi®) with a four-chemotherapy combination given before and after surgery in people with operable gastric (stomach) or gastroesophageal (the junction between the stomach and the esophagus) cancer.
In a previous study that monitored 295 patients with metastatic esophagogastric tumors for several years, Dr. Molena and her colleagues learned which genetic features were most likely to predict patients’ responses to particular chemotherapy regimens and immunotherapy.
All of this work forms a building block of research that moves us closer to care that disrupts the growth of esophageal cancer in patients living with or facing the likelihood of metastatic disease.
New Collaborations
Single-Cell Research
Michael Roehrl, MD, PhD, Director of the MSK Precision Pathology Biobanking Center, is a physician-scientist who specializes in studying the biology of gastrointestinal solid tumors, identifying molecular markers in cancers that can inform treatment decisions and improve disease monitoring.
Dr. Molena and Dr. Roehrl are harnessing MSK’s global leadership in single-cell sequencing and deep protein analysis to characterize the biomarkers that transform low-risk Barrett’s esophagus to a high-risk disease and the molecular events that underlie progression from a primary tumor to metastatic disease.
By working with a team of other basic and translational scientists and medical and surgical clinicians, they aim to pinpoint the specific biomarkers that signal early-stage cancers as well as tailor interventions to the molecular profile of each person’s disease.
Cancer Exosomes
Exosomes are small sac-like structures that contain proteins, DNA, and RNA. They exist within many types of cells, including cancer cells. When released into the bloodstream, exosomes travel to other parts of the body, where they can transfer their holdings into other cells. Cancer cell exosomes have recently been found to play a part in the establishment of tumor microsites at primary and metastatic locations, although their role in esophageal cancer remains unclear.
Dr. Molena and David Lyden, MD, PhD, a physician-scientist at Weill Cornell Medicine, are investigating tumor-derived exosomes to understand their function in cancer and determine if they can potentially serve as biomarkers for early esophageal cancer detection as well as to monitor their use in evaluating treatment response and recurrence. Their investigation will evaluate certain blood exosome profiles before, during, and after surgery to detect any changes during treatment and follow-up periods.
Genomic Signatures
A genomic signature refers to the activity of a group of genes, and in cancer, these signatures can help determine how likely it is for certain cancers to grow, metastasize, or recur. Dr. Molena and MSK thoracic surgeon Smita Sihag, MD, MPH, plan to identify genomic signatures in people with gastroesophageal adenocarcinoma to enhance prognostic modeling based on clinical variables alone — and potentially provide data that helps inform therapeutic decision-making. Clinical variables may include cancer stage, age, sex, prior treatments, and other factors.
Additional Avenues of Discovery
The Microbiome
The microbiome encompasses the billions of bacteria and other microorganisms that live on and in the human body. Each person’s microbiome is different, and in 2020, an MSK study demonstrated for the first time that the gut microbiota directly shapes the makeup of the human immune system.
Dr. Molena is exploring microbiome alterations in Barrett’s esophagus, which may play a role in creating the inflammatory conditions that can lead to cancer in the colon and elsewhere in the digestive tract. In a prospective study, Dr Molena will evaluate the microbiome in the esophagus and its changes during cancer’s development. The data generated may lead to treatments that use a person’s microbiome to strengthen their immune response to esophageal cancer.
Molecular Imaging
Molecular imaging makes it possible to observe and measure biological processes in living cells or tissues over time. MSK has pioneered some of the major advances in this field — including MRI and PET scans — which have transformed the way cancers are diagnosed, monitored, and treated.
Dr. Molena plans to use targeted optical imaging probes to study the PARP1 family of proteins, which is involved in DNA repair. These proteins have long been identified as therapeutic targets in cancer, and people with Barrett’s esophagus have an excess of them.
In a 24-month study that will include approximately 100 patients with varying stages of esophageal cancer, Dr. Molena and her team will test the feasibility of using a fluorescence imaging technology to map the different phases of the disease. The data generated will inform the design of a clinical diagnostic tool that could help improve early detection.
Lymph Node Mapping
Lymph nodes are small glands in the neck, underarms, chest, abdomen, and groin that serve as filters for the lymphatic system. These glands also contain lymphocytes, white blood cells that fight infection and disease. Despite their presence, many types of cancer can spread through the lymphatic system. The sentinel lymph node is the first node that cancer cells are likely to spread to from a primary tumor.
Lymph node mapping and sentinel node removal have helped physicians improve the lives of people with certain cancers. In esophageal adenocarcinoma, the presence and number of lymph node metastases are two of the most important predictors of survival.
Dr. Molena is studying whether lymph node mapping and partial or full node removal has applications for esophageal cancer, which presents challenges since the sentinel node can be difficult to identify. She will use sophisticated, near-infrared image-guided lymphatic mapping and sentinel lymph node identification to assess patterns of lymphatic drainage in patients.
She and her colleagues will then surgically remove node tissues for analysis. By comparing the incidence of malignant disease in the sentinel nodes and the other lymph nodes sampled, Dr. Molena will determine if the sentinel node concept applies and offers benefits to people with esophageal cancer. As part of this study, the team plans to determine the proportion of nodes that test positive for the presence of cancer cells.
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