{"product_id":"neratinib-for-her2-positive-breast-cancer-an-overlooked-treatment-option","title":"Neratinib for HER2-Positive Breast Cancer: An Overlooked Treatment Option","description":"\u003cp\u003eThis review article examines neratinib (Nerlynx), an oral medication approved for HER2-positive breast cancer. The authors summarize clinical trials showing that neratinib is effective in early and advanced HER2-positive breast cancer. Neratinib may help prevent or control cancer that has spread to the brain. The most common side effect is diarrhea, which can be managed with the anti-diarrheal medication loperamide. The article also discusses neratinib's potential use in HER2-negative and HER2-mutant breast cancers, and mechanisms of resistance to the drug.\u003c\/p\u003e\n\n\u003ch1\u003eNeratinib for HER2-Positive Breast Cancer: An Overlooked Treatment Option\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#her2\"\u003eUnderstanding HER2-Positive Breast Cancer\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#brain-metastasis\"\u003eThe Challenge of Brain Metastasis\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#neratinib\"\u003eWhat Is Neratinib?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#mechanism\"\u003eHow Neratinib Works\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#pharmacokinetics\"\u003eHow the Body Processes Neratinib\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#clinical-trials\"\u003eClinical Trials of Neratinib\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#phase1\"\u003ePhase 1 Trials: Finding the Right Dose\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#phase12\"\u003ePhase 1\/2 Trials: Early Efficacy Data\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#phase2\"\u003ePhase 2 Trials: Testing in Advanced Cancer\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#phase3\"\u003ePhase 3 Trials: Comparing Treatments\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#cns\"\u003eNeratinib and Central Nervous System Metastasis\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#her2-negative\"\u003eNeratinib for HER2-Negative and HER2-Mutant Cancers\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#resistance\"\u003eMechanisms of Resistance to Neratinib\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#safety\"\u003eSafety and Side Effects\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Evidence\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Future Directions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eNeratinib is an oral tyrosine kinase inhibitor approved for HER2-positive breast cancer, used as extended adjuvant therapy and in advanced disease with capecitabine.\u003c\/li\u003e\n\u003cli\u003eDiarrhea is the most common side effect, reported in up to 88% of patients in a phase 1 trial, and can be managed with loperamide and dose adjustments.\u003c\/li\u003e\n\u003cli\u003eIn the NEfERT-T trial, central nervous system recurrence was 8.3% with neratinib plus paclitaxel versus 17.3% with trastuzumab plus paclitaxel.\u003c\/li\u003e\n\u003cli\u003eThe ExteNET trial in 2,840 patients showed 5-year invasive disease-free survival of 90.2% with neratinib versus 87.7% with placebo.\u003c\/li\u003e\n\u003cli\u003eNeratinib has shown some activity in HER2-mutant breast cancers, but more research is needed to determine its optimal use in that setting.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eBreast cancer is the most common cancer among women worldwide. It is also the second leading cause of cancer-related death. Researchers have made significant progress in treating one particular subtype of breast cancer called HER2-positive breast cancer. However, challenges remain, especially when the cancer spreads to the brain.\u003c\/p\u003e\n\n\u003cp\u003eThis review article focuses on a medication called neratinib. The authors examined all published research on neratinib to understand its effectiveness, safety, and potential role in treating breast cancer. They paid special attention to how neratinib might help patients whose cancer has spread to the central nervous system (CNS), which includes the brain and spinal cord.\u003c\/p\u003e\n\n\u003cp\u003eThe central nervous system is protected by barriers that make it difficult for many cancer drugs to reach tumors there. This has been a major obstacle in treating breast cancer that spreads to the brain. The authors wanted to explore whether neratinib, because of its unique properties, could overcome this barrier and provide a new option for patients.\u003c\/p\u003e\n\n\u003ch2 id=\"her2\"\u003eUnderstanding HER2-Positive Breast Cancer\u003c\/h2\u003e\n\n\u003cp\u003eHuman epidermal growth factor receptor 2 (HER2) is a protein that helps cells grow and divide. In about 20% to 30% of breast cancer patients, this protein is overproduced, which is called HER2 overexpression. This makes the cancer grow more aggressively and makes it more resistant to traditional treatments.\u003c\/p\u003e\n\n\u003cp\u003eBefore doctors developed drugs that specifically target HER2, patients with HER2-positive breast cancer had a poor prognosis. The introduction of anti-HER2 treatments, such as the monoclonal antibody trastuzumab (Herceptin), dramatically improved outcomes for both early-stage and advanced HER2-positive breast cancer.\u003c\/p\u003e\n\n\u003cp\u003eHowever, trastuzumab is not without limitations. Many patients eventually develop resistance to trastuzumab, meaning the drug stops working. Additionally, trastuzumab is a large molecule that cannot effectively cross the blood-brain barrier. This means it cannot reach cancer cells that have spread to the brain.\u003c\/p\u003e\n\n\u003cp\u003eThis is where tyrosine kinase inhibitors (TKIs) like neratinib come in. TKIs are small molecules that can enter the central nervous system. They offer a potential advantage over monoclonal antibodies for treating cancer that has spread to the brain.\u003c\/p\u003e\n\n\u003ch2 id=\"brain-metastasis\"\u003eThe Challenge of Brain Metastasis\u003c\/h2\u003e\n\n\u003cp\u003eBreast cancer that has spread to the brain, called breast cancer brain metastasis (BCBM), is a serious complication. It is an important cause of illness and death in patients with metastatic breast cancer (MBC), which means cancer that has spread beyond the breast and nearby lymph nodes.\u003c\/p\u003e\n\n\u003cp\u003ePatients with HER2-positive breast cancer have a particularly high risk of developing brain metastases. This makes finding effective treatments for CNS involvement a critical priority.\u003c\/p\u003e\n\n\u003cp\u003eTreating brain metastases is complex. Doctors typically use a multidisciplinary approach, which means a team of specialists works together. The goals of treatment are to control the metastatic lesions, improve symptoms, maintain quality of life, and extend survival as much as possible.\u003c\/p\u003e\n\n\u003cp\u003eTreatment options for brain metastases include:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eSurgery to remove tumors\u003c\/li\u003e\n\u003cli\u003eRadiation therapy, including stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT)\u003c\/li\u003e\n\u003cli\u003eChemotherapy\u003c\/li\u003e\n\u003cli\u003eSupportive care to manage symptoms\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe general approach is to prioritize surgery and\/or radiation for CNS lesions when the patient's overall condition allows. Systemic therapy, which treats the whole body, is then considered.\u003c\/p\u003e\n\n\u003cp\u003eHowever, three major barriers limit how well drugs can reach tumors in the central nervous system:\u003c\/p\u003e\n\u003col\u003e\n\u003cli\u003eThe blood-brain barrier (BBB), which protects the brain from harmful substances in the blood\u003c\/li\u003e\n\u003cli\u003eThe blood-tumor barrier (BTB), which forms around tumors\u003c\/li\u003e\n\u003cli\u003eThe blood-cerebrospinal fluid barrier, which protects the fluid surrounding the brain and spinal cord\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThese barriers prevent many cancer drugs from reaching effective concentrations in the brain. This is why small-molecule drugs like neratinib are of great interest. They have the potential to cross these barriers and reach cancer cells in the central nervous system.\u003c\/p\u003e\n\n\u003ch2 id=\"neratinib\"\u003eWhat Is Neratinib?\u003c\/h2\u003e\n\n\u003cp\u003eNeratinib, sold under the brand name Nerlynx, is an oral medication approved by the US Food and Drug Administration (FDA) in 2017. It belongs to a class of drugs called tyrosine kinase inhibitors (TKIs).\u003c\/p\u003e\n\n\u003cp\u003eNeratinib is a pan-human TKI, which means it targets multiple human epidermal growth factor receptors. Specifically, it irreversibly binds to HER1 (also called EGFR), HER2, and HER4. This is different from some other TKIs that bind reversibly.\u003c\/p\u003e\n\n\u003cp\u003eNeratinib was developed from a compound called pelitinib. It is a second-generation TKI designed to be a small molecule that can enter cells and block specific signaling pathways that drive cancer growth.\u003c\/p\u003e\n\n\u003cp\u003eThe drug is manufactured by Puma Biotechnology Inc. in Los Angeles, California. It is available as an oral tablet, which makes it convenient for patients to take at home.\u003c\/p\u003e\n\n\u003ch2 id=\"mechanism\"\u003eHow Neratinib Works\u003c\/h2\u003e\n\n\u003cp\u003eNeratinib works by blocking the activity of HER1, HER2, and HER4 receptors. These receptors are located on the surface of cells and normally help regulate cell growth and division. In HER2-positive breast cancer, these receptors are overactive, leading to uncontrolled cancer growth.\u003c\/p\u003e\n\n\u003cp\u003eWhen neratinib binds to these receptors, it prevents them from sending signals that tell cancer cells to grow and multiply. Specifically, neratinib blocks the interaction between these receptors and adenosine triphosphate (ATP), which is the energy molecule that cells use to power many processes. By blocking this interaction, neratinib prevents the receptors from becoming activated.\u003c\/p\u003e\n\n\u003cp\u003eNeratinib also inhibits several downstream signaling pathways that are involved in cancer growth. These include:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eThe RAS-RAF-MEK-ERK pathway\u003c\/li\u003e\n\u003cli\u003eThe PI3K-AKT-mTOR pathway\u003c\/li\u003e\n\u003cli\u003eThe MAPK pathway\u003c\/li\u003e\n\u003cli\u003eThe AKT pathway\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese pathways regulate important cellular processes, including cell proliferation (growth) and apoptosis (programmed cell death). By blocking these pathways, neratinib can slow or stop cancer growth and promote cancer cell death.\u003c\/p\u003e\n\n\u003cp\u003eAdditionally, neratinib can reverse multidrug resistance through ATP-binding cassette (ABC) transporters. Multidrug resistance is a major problem in cancer treatment, where cancer cells become resistant to multiple drugs. By reversing this resistance, neratinib may help other cancer drugs work better.\u003c\/p\u003e\n\n\u003cp\u003eNeratinib also downregulates the expression of other receptor tyrosine kinases (RTKs) and mutant RAS proteins. It potently inhibits the proliferation of cells that express EGFR and HER2. This inhibition is associated with cell cycle arrest at the G1-to-S phase transition, meaning cancer cells stop dividing. Neratinib also induces apoptosis, which is programmed cell death.\u003c\/p\u003e\n\n\u003cp\u003eOther effects of neratinib include increasing the expression of a protein called Protein 27 and decreasing the expression of Cyclin D1. These changes also contribute to the drug's anticancer effects.\u003c\/p\u003e\n\n\u003ch2 id=\"pharmacokinetics\"\u003eHow the Body Processes Neratinib\u003c\/h2\u003e\n\n\u003cp\u003eUnderstanding how the body processes a drug, called pharmacokinetics, is important for determining proper dosing and predicting side effects.\u003c\/p\u003e\n\n\u003cp\u003eNeratinib is mainly metabolized (broken down) by an enzyme in the liver called CYP3A4. A smaller proportion is metabolized by another enzyme called Flavin containing Monooxygenase (FMO).\u003c\/p\u003e\n\n\u003cp\u003eThe drug is mainly excreted in feces. The half-life of neratinib, which is the time it takes for half the drug to be eliminated from the body, is 7 to 17 hours. The peak time of the drug, meaning when it reaches its highest concentration in the blood, is 2 to 8 hours after taking it.\u003c\/p\u003e\n\n\u003cp\u003eFood can affect how neratinib is absorbed. A high-fat meal increases the absorption of neratinib. The drug's absorption is also affected by gastric pH, which is the acidity level in the stomach. These factors may need to be considered when advising patients on how to take the medication.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-trials\"\u003eClinical Trials of Neratinib\u003c\/h2\u003e\n\n\u003cp\u003eThe effectiveness of neratinib for treating breast cancer has been investigated in numerous clinical trials. These include phase 1, phase 2, and phase 3 studies, which represent progressively larger and more rigorous stages of research.\u003c\/p\u003e\n\n\u003cp\u003ePhase 1 trials are small studies designed primarily to determine the safest dose of a drug and identify side effects. Phase 2 trials test whether the drug works in a larger group of patients. Phase 3 trials compare the new drug to existing treatments in even larger populations.\u003c\/p\u003e\n\n\u003ch2 id=\"phase1\"\u003ePhase 1 Trials: Finding the Right Dose\u003c\/h2\u003e\n\n\u003cp\u003eThe first-in-human phase 1 trial of neratinib was an open-label study. This means both researchers and patients knew which treatment was being given. The study was designed to determine the dose-limiting toxicity (DLT). DLT is the dose at which unacceptable side effects occur. The study also determined the maximum tolerated dose (MTD). MTD is the highest dose patients can take without severe side effects.\u003c\/p\u003e\n\n\u003cp\u003eThis trial enrolled 72 patients with HER2-positive or EGFR-positive solid tumors. The types of cancer included:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eBreast cancer (40% of patients)\u003c\/li\u003e\n\u003cli\u003eNon-small-cell lung cancer (NSCLC; 21%)\u003c\/li\u003e\n\u003cli\u003eOvarian cancer (8%)\u003c\/li\u003e\n\u003cli\u003eColorectal cancer (6%)\u003c\/li\u003e\n\u003cli\u003eGlioblastoma (6%)\u003c\/li\u003e\n\u003cli\u003eRenal cancer (4%)\u003c\/li\u003e\n\u003cli\u003ePancreatic cancer (3%)\u003c\/li\u003e\n\u003cli\u003eOther cancers (13%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003ePatients initially received single oral doses of neratinib ranging from 40 mg to 500 mg daily, taken with food. This was followed by a one-week observation period to assess the single-dose pharmacokinetic profiles and adverse events (AEs).\u003c\/p\u003e\n\n\u003cp\u003eNeratinib was well tolerated. The most common adverse event was diarrhea, which occurred in 88% of patients. Grade 3 or higher neratinib-related adverse events occurred in 39% of all patients. The maximum tolerated dose was determined to be 320 mg per day.\u003c\/p\u003e\n\n\u003cp\u003eAmong the 25 patients with breast cancer who were evaluated for treatment efficacy, partial response (PR) was observed in 8 patients (32%), and stable disease (SD) was observed in 1 patient (4%).\u003c\/p\u003e\n\n\u003cp\u003eAnother multicenter, open-label, dose-escalation phase 1 study was conducted in Japanese patients with advanced solid tumors. This study enrolled 21 patients, including 3 with breast cancer. The maximum tolerated dose of neratinib was also determined to be 320 mg. Two patients with breast cancer had partial responses. Grade 3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (loss of appetite). The safety, efficacy, and pharmacokinetic profiles of neratinib were consistent with those reported for non-Japanese patients.\u003c\/p\u003e\n\n\u003cp\u003eA third open-label phase 1 dose-escalation trial was conducted by the NSABP Foundation Research Program. This study recruited 21 patients to determine the maximum tolerated dose, safety, and efficacy of neratinib at doses of 120 to 240 mg per day. The drug was given in combination with trastuzumab and paclitaxel in patients with HER2-positive metastatic breast cancer who had been previously treated with anti-HER agents and a taxane.\u003c\/p\u003e\n\n\u003cp\u003eObjective responses occurred in 8 patients (38%). Complete response (CR) plus partial response plus stable disease for at least 24 weeks occurred in 11 patients (52%). The median time-to-tumor progression (TTP) was 3.7 months.\u003c\/p\u003e\n\n\u003cp\u003eIn terms of safety, gastrointestinal toxicity such as diarrhea remained the most common adverse event. Grade 3 diarrhea occurred in 8 patients (38%). No patients experienced grade 4 diarrhea.\u003c\/p\u003e\n\n\u003cp\u003eA subsequent multicenter, open-label, dose-escalation phase 1b study called NSABP Foundation Trial FB-10 evaluated trastuzumab-emtansine (T-DM1) plus neratinib in women with HER2-positive metastatic breast cancer. Five institutions enrolled 27 patients who had progressed on trastuzumab, pertuzumab, and a taxane.\u003c\/p\u003e\n\n\u003cp\u003ePatients were treated with T-DM1 at 3.6 mg\/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg per day orally. Among evaluable patients at all neratinib doses, 63% had an objective response, and 7% had a complete response.\u003c\/p\u003e\n\n\u003cp\u003eThe study also suggested that the mechanism of HER2 antibody resistance may involve the internalization of p185 HER2 and the high expression of p95 HER2. Diarrhea was the most common adverse event, with all grades occurring in 23 patients (93%) and grade 3 in 22%. Diarrhea that developed early during treatment could be easily controlled and well managed. Management included temporarily discontinuing or reducing the drug dose and\/or using intensive antidiarrheal medications as prophylaxis (preventive treatment).\u003c\/p\u003e\n\n\u003cp\u003eThe most common adverse event of neratinib was gastrointestinal toxicity such as diarrhea. In patients with breast cancer, the response rate of neratinib was at least 32%. The response rate was higher when neratinib was used together with other anti-HER2 agents, reaching 63% when combined with T-DM1.\u003c\/p\u003e\n\n\u003cp\u003eThese phase 1 data laid the foundation for further phase 2 studies to better determine the efficacy and safety of neratinib-based regimens. The maximum tolerated dose of neratinib in phase 1 was 320 mg per day. However, additional clinical experience indicated unacceptable rates of diarrhea at this dose. As monotherapy, the dose of 240 mg per day was used for phase 2 studies.\u003c\/p\u003e\n\n\u003ch2 id=\"phase12\"\u003ePhase 1\/2 Trials: Early Efficacy Data\u003c\/h2\u003e\n\n\u003cp\u003eA phase 1\/2 trial conducted by Awada A and colleagues evaluated the safety and efficacy of neratinib and vinorelbine in patients with solid tumors, including HER2-positive metastatic breast cancer. Twelve patients were enrolled in phase 1, and 79 patients were enrolled in phase 2.\u003c\/p\u003e\n\n\u003cp\u003eIn phase 1 with 12 patients, neratinib at 240 mg plus vinorelbine at 25 mg\/m2 was established as the maximum tolerated dose. In phase 2 with 79 patients, the objective response rate (ORR) was 41% in patients without prior lapatinib treatment and 8% in patients with prior lapatinib treatment.\u003c\/p\u003e\n\n\u003cp\u003eA total of 26 patients (29%) experienced grade 3 diarrhea. Three patients (3%) discontinued treatment due to diarrhea.\u003c\/p\u003e\n\n\u003cp\u003eIn another phase 1\/2, open-label, two-part study, the maximum tolerated dose was evaluated. The dose was oral neratinib at 240 mg once daily plus intravenous paclitaxel at 80 mg\/m2 on Days 1, 8, and 15 of each 28-day cycle. This study enrolled 110 patients with locally advanced or metastatic HER2-positive breast cancer. The objective response rate was 73%. The median progression-free survival (PFS) was 57 weeks.\u003c\/p\u003e\n\n\u003cp\u003eAnother phase 1\/2 study evaluated neratinib at 240 mg orally plus capecitabine at 1,500 mg\/m2 orally on Days 1 to 14 of a 21-day cycle. This study enrolled 105 patients with HER2-positive metastatic breast cancer. The objective response rate was 64% in patients without prior lapatinib treatment and 57% in patients with prior lapatinib treatment. The median progression-free survival was 40.3 weeks in patients without prior lapatinib and 35.9 weeks in patients with prior lapatinib.\u003c\/p\u003e\n\n\u003ch2 id=\"phase2\"\u003ePhase 2 Trials: Testing in Advanced Cancer\u003c\/h2\u003e\n\n\u003cp\u003eSeveral phase 2 trials have evaluated neratinib in various settings for breast cancer treatment.\u003c\/p\u003e\n\n\u003cp\u003eA multinational phase 2 trial conducted by Burstein HJ and colleagues evaluated neratinib at 240 mg orally daily in 136 patients with advanced HER2-positive breast cancer. The objective response rate was 24% in patients with prior trastuzumab treatment and 56% in patients without prior trastuzumab treatment. The median progression-free survival was 22.3 weeks in patients with prior trastuzumab and 39.6 weeks in patients without prior trastuzumab. The median overall survival (OS) was 19.7 months versus 23.6 months.\u003c\/p\u003e\n\n\u003cp\u003eAnother multinational phase 2 trial conducted by Martin M and colleagues compared neratinib at 240 mg orally daily versus lapatinib at 1,250 mg orally daily. Both drugs were combined with capecitabine at 2,000 mg\/m2 on Days 1 to 14 of each 21-day cycle. This study enrolled 233 patients with advanced HER2-positive breast cancer. The median progression-free survival was 4.5 months versus 6.8 months. The objective response rate was 29% versus 41%. The complete response rate was 8%.\u003c\/p\u003e\n\n\u003cp\u003eA multinational phase 2 trial conducted by Freedman and colleagues evaluated neratinib at 240 mg orally daily in 40 patients with HER2-positive breast cancer and brain metastases (BCBM). The median overall survival was 8.7 months. The median progression-free survival was 1.9 months. The response rate of the brain lesions was 8%, and only three patients had a partial response.\u003c\/p\u003e\n\n\u003cp\u003eA phase 2 trial conducted by Park JW and colleagues evaluated neratinib at 240 mg orally daily versus trastuzumab. Trastuzumab was given at a loading dose of 4 mg\/kg followed by a maintenance dose of 2 mg\/kg intravenously for the first cycle. Then trastuzumab was given at 4 mg\/kg for cycles 2 to 12. The trial included 139 patients with early breast cancer. The pathologic complete response rate was 56% versus 33%.\u003c\/p\u003e\n\n\u003cp\u003eA multinational phase 2 trial conducted by Awada A and colleagues evaluated neratinib at 240 mg orally combined with paclitaxel. Paclitaxel was given at 80 mg\/m2 intravenously on Days 1, 8, and 15 every 28 days. The trial included 479 patients with metastatic HER2-positive breast cancer. This trial was called NEfERT-T. The objective response rate was 74.8% versus 77.6%. The central nervous system recurrence rate was 8.3% versus 17.3%. The median time to central nervous system metastases was 13.4 months versus 12.9 months. The pathologic complete response rate was 38% versus 33%.\u003c\/p\u003e\n\n\u003cp\u003eA multinational phase 2 trial conducted by Jacobs SA and colleagues evaluated three treatment arms in 162 patients with locally advanced HER2-positive breast cancer. Arm 1 received trastuzumab at a loading dose of 4 mg\/kg intravenously followed by 2 mg\/kg weekly for a total of 16 doses, plus paclitaxel at 80 mg\/m2 intravenously on Days 1, 8, and 15 of a 28-day cycle. Arm 2 received paclitaxel at 80 mg\/m2 intravenously on Days 1, 8, and 15 of a 28-day cycle plus neratinib at 240 mg orally daily. Arm 3 received trastuzumab and paclitaxel as given in Arm 1, plus neratinib at 200 mg orally daily. The pathologic complete response rate was 38% versus 33% versus 50%.\u003c\/p\u003e\n\n\u003ch2 id=\"phase3\"\u003ePhase 3 Trials: Comparing Treatments\u003c\/h2\u003e\n\n\u003cp\u003ePhase 3 trials are the most rigorous type of clinical trial. They compare a new treatment to the current standard of care in a large number of patients.\u003c\/p\u003e\n\n\u003cp\u003eThe ExteNET trial was a multinational phase 3 trial conducted by Chan A and colleagues. This trial evaluated neratinib at 240 mg orally once daily versus placebo in 2,840 patients with early-stage HER2-positive breast cancer. The 2-year invasive disease-free survival (iDFS) rate was 93.9% versus 91.6%. The 5-year invasive disease-free survival rate was 90.2% versus 87.7%. The mean progression-free survival was 8.8 months versus 6.6 months.\u003c\/p\u003e\n\n\u003cp\u003eThe NALA trial was a multinational phase 3 trial conducted by Saura C and colleagues. This trial evaluated neratinib at 240 mg orally once daily plus capecitabine at 1,500 mg\/m2 orally twice daily on Days 1 to 14 of a 21-day cycle. This regimen was compared with lapatinib at 1,250 mg orally once daily plus capecitabine at 2,000 mg\/m2 orally twice daily on Days 1 to 14 of a 21-day cycle. The trial included 621 patients with metastatic HER2-positive breast cancer. The median progression-free survival was 5.6 months versus 5.5 months. The mean overall survival was 24.0 months versus 22.2 months. The cumulative incidence of central nervous system intervention was 22.8% versus 29.2%. The objective response rate was 32.8% versus 26.7%. The median duration of response was 8.5 months versus 5.6 months.\u003c\/p\u003e\n\n\u003cp\u003eThe NALA trial also included an analysis of central nervous system disease. The cumulative incidence of central nervous system intervention was 22.8% for neratinib plus capecitabine versus 29.2% for lapatinib plus capecitabine.\u003c\/p\u003e\n\n\u003cp\u003eA phase 3 trial conducted by Geyer CE and colleagues evaluated combination therapy. The combination therapy was lapatinib at 1,250 mg orally once daily plus capecitabine at 2,000 mg\/m2 orally on Days 1 through 14 of a 21-day cycle. This combination was compared with lapatinib alone at 1,500 mg orally daily. It was also compared with capecitabine alone at 2,500 mg\/m2 orally on Days 1 through 14 of a 21-day cycle. The trial included 324 patients with advanced HER2-positive breast cancer. The median time to disease progression was 8.4 months versus 4.4 months.\u003c\/p\u003e\n\n\u003cp\u003eA multinational phase 3 trial conducted by Goss PE and colleagues evaluated lapatinib at 1,500 mg orally daily versus placebo in 3,161 patients with early HER2-positive breast cancer. The pathologic complete response rate was 51.3% versus 29.5%.\u003c\/p\u003e\n\n\u003cp\u003eA multinational phase 3 trial conducted by Baselga J and colleagues, called NeoALTTO, evaluated lapatinib at 1,500 mg orally plus paclitaxel at 80 mg\/m2 weekly. The trial also evaluated trastuzumab at 4 mg\/kg intravenously followed by 2 mg\/kg weekly. The trial also evaluated lapatinib plus trastuzumab. The trial included 455 patients with early HER2-positive breast cancer. The pathologic complete response rate was 51.3% versus 29.5% versus 46.8%.\u003c\/p\u003e\n\n\u003cp\u003eA phase 2 trial conducted by Ma F and colleagues evaluated pyrotinib at 400 mg orally once daily versus lapatinib at 1,250 mg orally once daily. Both drugs were combined with capecitabine at 1,000 mg\/m2 orally twice daily on Days 1 to 14 of a 21-day cycle. The trial included 128 patients with metastatic HER2-positive breast cancer. The median progression-free survival was 18.1 months versus 7.0 months. The median progression-free survival was 11.1 months versus 4.1 months.\u003c\/p\u003e\n\n\u003cp\u003eA phase 3 trial conducted by Yan M and colleagues, called PHENIX, evaluated combination therapy. The combination therapy was pyrotinib at 400 mg orally once daily plus capecitabine at 1,000 mg\/m2 orally twice daily on Days 1 to 14 of a 21-day cycle. This regimen was compared with placebo plus capecitabine. The trial included 279 patients with metastatic HER2-positive breast cancer. The median progression-free survival was 12.5 months versus 6.8 months.\u003c\/p\u003e\n\n\u003cp\u003eA phase 3 trial conducted by Xu B and colleagues, called PHOEBE, evaluated combination therapy. The combination therapy was pyrotinib at 400 mg orally once daily plus capecitabine at 1,000 mg\/m2 orally twice daily on Days 1 to 14 of a 21-day cycle. This regimen was compared with lapatinib at 1,250 mg orally once daily plus capecitabine. The trial included 267 patients with metastatic HER2-positive breast cancer. The median progression-free survival was 12.5 months versus 6.8 months.\u003c\/p\u003e\n\n\u003cp\u003eA phase 2 trial conducted by Kim and colleagues evaluated poziotinib at 12 mg orally once daily on a 14-day on\/7-day off schedule in 106 patients with metastatic HER2-positive breast cancer. The median progression-free survival was 4.04 months. The median overall survival had not been reached.\u003c\/p\u003e\n\n\u003cp\u003eA phase 3 trial conducted by Curigliano and colleagues evaluated combination therapy. The combination therapy was tucatinib at 300 mg orally twice daily plus trastuzumab at 6 mg\/kg every 3 weeks. The combination therapy also included capecitabine at 1,000 mg\/m2 orally twice daily on Days 1 to 14 of a 21-day cycle. This regimen was compared with placebo plus trastuzumab plus capecitabine. The trial included 612 patients with metastatic HER2-positive breast cancer. The 2-year overall survival rate was 51% versus 40%.\u003c\/p\u003e\n\n\u003ch2 id=\"cns\"\u003eNeratinib and Central Nervous System Metastasis\u003c\/h2\u003e\n\n\u003cp\u003eOne of the most promising aspects of neratinib is its potential to treat and prevent cancer that has spread to the central nervous system. This is particularly important for patients with HER2-positive breast cancer, who have a high risk of brain metastases.\u003c\/p\u003e\n\n\u003cp\u003eUnlike monoclonal antibodies such as trastuzumab, which are large molecules that cannot cross the blood-brain barrier, neratinib is a small molecule that can enter the central nervous system. This gives neratinib a potential advantage for treating brain metastases.\u003c\/p\u003e\n\n\u003cp\u003eThe NEfERT-T trial provided important evidence for this. In this trial, patients with metastatic breast cancer who received paclitaxel plus neratinib had lower rates of central nervous system metastases compared to those who received paclitaxel plus trastuzumab. Specifically, the central nervous system recurrence rate was 8.3% for neratinib versus 17.3% for trastuzumab. This suggested that neratinib could be effective in preventing or delaying brain metastases.\u003c\/p\u003e\n\n\u003cp\u003eThe NALA trial also demonstrated the central nervous system activity of neratinib. In this trial, the cumulative incidence of central nervous system intervention was 22.8% for patients receiving neratinib plus capecitabine versus 29.2% for those receiving lapatinib plus capecitabine. This means that fewer patients on the neratinib regimen needed intervention for brain metastases.\u003c\/p\u003e\n\n\u003cp\u003eBased on the results of the NALA study, the FDA approved neratinib plus capecitabine. This approval is for patients with advanced HER2-positive breast cancer who have received more than 2 lines of anti-HER2 therapy. This approval includes both systemic efficacy and intracranial (within the brain) activity.\u003c\/p\u003e\n\n\u003cp\u003eThese findings suggest that neratinib has the potential to effectively control and prevent brain metastasis in patients with advanced breast cancer. This provides a therapeutic strategy specifically for HER2-positive breast cancer with central nervous system involvement.\u003c\/p\u003e\n\n\u003ch2 id=\"her2-negative\"\u003eNeratinib for HER2-Negative and HER2-Mutant Cancers\u003c\/h2\u003e\n\n\u003cp\u003eWhile neratinib is primarily used for HER2-positive breast cancer, researchers have also explored its use in other types of breast cancer.\u003c\/p\u003e\n\n\u003cp\u003eHER2-negative breast cancer does not have overexpression of the HER2 protein. However, some HER2-negative cancers may have mutations in the HER2 gene, which are changes in the DNA that can affect how the gene functions. These are called HER2-mutant cancers.\u003c\/p\u003e\n\n\u003cp\u003eNeratinib has shown some activity in HER2-mutant breast cancers. Because neratinib targets the HER2 receptor, it may be effective even when the receptor is not overexpressed but is mutated.\u003c\/p\u003e\n\n\u003cp\u003eThe authors discussed the potential use of neratinib for HER2-negative and HER2-mutant breast cancers. However, more research is needed to determine the optimal use of neratinib in these settings.\u003c\/p\u003e\n\n\u003ch2 id=\"resistance\"\u003eMechanisms of Resistance to Neratinib\u003c\/h2\u003e\n\n\u003cp\u003eLike all cancer drugs, neratinib can eventually stop working as cancer cells develop resistance. Understanding how resistance occurs is important for developing strategies to overcome it.\u003c\/p\u003e\n\n\u003cp\u003eOne mechanism of resistance involves the internalization of p185 HER2 and the high expression of p95 HER2. This was suggested by the NSABP Foundation Trial FB-10, which evaluated T-DM1 plus neratinib.\u003c\/p\u003e\n\n\u003cp\u003eOther potential mechanisms of resistance include activation of alternative signaling pathways that bypass the blocked HER receptors. Cancer cells may also develop mutations in the target receptors that prevent neratinib from binding effectively.\u003c\/p\u003e\n\n\u003cp\u003eThe authors noted that neratinib has a certain efficacy to reverse drug resistance in patients with breast cancer who have previously developed resistance to HER2 monoclonal antibodies or targeted drugs. This suggests that neratinib may be useful as a later-line treatment for patients whose cancer has stopped responding to other therapies.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSafety and Side Effects\u003c\/h2\u003e\n\n\u003cp\u003eThe most common adverse event associated with neratinib is diarrhea. This was consistently observed across all clinical trials.\u003c\/p\u003e\n\n\u003cp\u003eIn the first-in-human phase 1 trial, diarrhea occurred in 88% of patients. Grade 3 or higher neratinib-related adverse events occurred in 39% of all patients.\u003c\/p\u003e\n\n\u003cp\u003eIn the NSABP Foundation Trial FB-10, all grades of diarrhea occurred in 23 patients (93%), and grade 3 diarrhea occurred in 22% of patients.\u003c\/p\u003e\n\n\u003cp\u003eIn the phase 1\/2 trial of neratinib plus vinorelbine, 26 patients (29%) experienced grade 3 diarrhea. Three patients (3%) discontinued treatment due to diarrhea.\u003c\/p\u003e\n\n\u003cp\u003eImportantly, diarrhea that develops early during treatment can be easily controlled and well managed. Strategies include:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eTemporarily discontinuing the drug\u003c\/li\u003e\n\u003cli\u003eReducing the drug dose\u003c\/li\u003e\n\u003cli\u003eUsing intensive antidiarrheal medications as prophylaxis (preventive treatment)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe anti-diarrheal medication loperamide has been shown to reduce the incidence, severity, and duration of neratinib-related grade 3 diarrhea. This is an important finding because it means that patients can take proactive steps to manage this side effect.\u003c\/p\u003e\n\n\u003cp\u003eOther adverse events reported in clinical trials include:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eAnorexia (loss of appetite)\u003c\/li\u003e\n\u003cli\u003eNausea\u003c\/li\u003e\n\u003cli\u003eFatigue\u003c\/li\u003e\n\u003cli\u003eVomiting\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe safety profile of neratinib was consistent across different patient populations, including Japanese patients. The most common grade 3 neratinib-related adverse events in two or more patients were diarrhea and anorexia.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThe current evidence suggests that neratinib has promising efficacy in patients with breast cancer. The authors noted that neratinib is at least non-inferior compared to previous therapeutic regimens.\u003c\/p\u003e\n\n\u003cp\u003eNeratinib is indicated for the prolonged adjuvant treatment of HER2-positive early breast cancer. Adjuvant treatment means treatment given after the initial treatment, such as surgery, to reduce the risk of cancer returning. The ExteNET trial showed that neratinib improved invasive disease-free survival at 2 years (93.9% versus 91.6%) and at 5 years (90.2% versus 87.7%).\u003c\/p\u003e\n\n\u003cp\u003eNeratinib is also indicated in combination with other drugs, including trastuzumab, capecitabine, and paclitaxel, for the treatment of advanced HER2-positive breast cancer. This is especially relevant for cancers with central nervous system metastasis, where neratinib may reduce the risk of breast cancer recurrence.\u003c\/p\u003e\n\n\u003cp\u003eFor patients with brain metastases, neratinib offers a potential option that can cross the blood-brain barrier. The NEfERT-T trial showed lower rates of central nervous system metastases with neratinib compared to trastuzumab. The NALA trial showed that neratinib plus capecitabine reduced the need for central nervous system intervention compared to lapatinib plus capecitabine.\u003c\/p\u003e\n\n\u003cp\u003eBased on the NALA study results, the FDA approved neratinib plus capecitabine for patients with advanced HER2-positive breast cancer who have received more than 2 lines of anti-HER2 therapy. This approval includes both systemic efficacy and intracranial activity.\u003c\/p\u003e\n\n\u003cp\u003eThe authors emphasized that neratinib has the potential to effectively control and prevent brain metastasis in patients with advanced breast cancer. This provides a therapeutic strategy specifically for HER2-positive breast cancer with central nervous system involvement.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Evidence\u003c\/h2\u003e\n\n\u003cp\u003eWhile the clinical trials of neratinib have shown promising results, there are limitations to consider.\u003c\/p\u003e\n\n\u003cp\u003eMany of the trials were phase 1 or phase 2 studies, which are smaller and less rigorous than phase 3 trials. While these studies provide valuable information about dosing, safety, and preliminary efficacy, they cannot definitively prove that neratinib is superior to other treatments.\u003c\/p\u003e\n\n\u003cp\u003eThe phase 3 trials that have been conducted, such as ExteNET and NALA, provide stronger evidence. However, even these trials have limitations, including the specific patient populations studied and the duration of follow-up.\u003c\/p\u003e\n\n\u003cp\u003eDiarrhea remains a significant side effect that can affect quality of life and lead to treatment discontinuation. While loperamide can help manage this side effect, not all patients tolerate neratinib well.\u003c\/p\u003e\n\n\u003cp\u003eThe optimal dose of neratinib has been debated. The maximum tolerated dose in phase 1 trials was 320 mg per day, but additional clinical experience indicated unacceptable rates of diarrhea at this dose. As monotherapy, the dose of 240 mg per day was used for phase 2 studies.\u003c\/p\u003e\n\n\u003cp\u003eMore research is needed to determine the optimal use of neratinib in different settings, including:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eWhich patients are most likely to benefit from neratinib\u003c\/li\u003e\n\u003cli\u003eThe best dose and schedule for different patient populations\u003c\/li\u003e\n\u003cli\u003eHow to best manage side effects\u003c\/li\u003e\n\u003cli\u003eWhether neratinib should be used alone or in combination with other drugs\u003c\/li\u003e\n\u003cli\u003eThe role of neratinib in HER2-negative and HER2-mutant breast cancers\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Future Directions\u003c\/h2\u003e\n\n\u003cp\u003eBased on the current evidence, neratinib represents a valuable addition to the treatment options for HER2-positive breast cancer. The authors made several key points about its use.\u003c\/p\u003e\n\n\u003cp\u003eFor patients with early-stage HER2-positive breast cancer, neratinib can be used as extended adjuvant therapy after trastuzumab. This means taking neratinib for an extended period after completing initial treatment to reduce the risk of cancer returning.\u003c\/p\u003e\n\n\u003cp\u003eFor patients with advanced HER2-positive breast cancer, neratinib can be used in combination with other drugs such as capecitabine. This is particularly relevant for patients whose cancer has spread to the central nervous system.\u003c\/p\u003e\n\n\u003cp\u003ePatients who are prescribed neratinib should be counseled about the risk of diarrhea and strategies to manage it. Proactive use of loperamide and other antidiarrheal medications can help prevent severe diarrhea and allow patients to continue treatment.\u003c\/p\u003e\n\n\u003cp\u003eThe authors also highlighted the need for further research. Future studies should focus on:\u003c\/p\u003e\n\u003col\u003e\n\u003cli\u003eIdentifying biomarkers that predict which patients will benefit most from neratinib\u003c\/li\u003e\n\u003cli\u003eDeveloping strategies to overcome resistance to neratinib\u003c\/li\u003e\n\u003cli\u003eExploring the use of neratinib in HER2-negative and HER2-mutant breast cancers\u003c\/li\u003e\n\u003cli\u003eOptimizing the dose and schedule of neratinib to minimize side effects while maintaining efficacy\u003c\/li\u003e\n\u003cli\u003eInvestigating combinations of neratinib with other targeted therapies and immunotherapies\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe authors concluded that neratinib has promising efficacy in patients with breast cancer and has the potential to effectively control and prevent brain metastasis. This provides a therapeutic strategy for HER2-positive breast cancer, especially for patients with central nervous system involvement.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is neratinib and who is it approved for?\u003c\/h3\u003e\n\u003cp\u003eNeratinib, sold as Nerlynx, is an oral tyrosine kinase inhibitor approved by the FDA in 2017. It is used for HER2-positive breast cancer. It is indicated as extended adjuvant treatment for early-stage disease and, combined with capecitabine, for advanced HER2-positive breast cancer after more than two lines of anti-HER2 therapy.\u003c\/p\u003e\n\u003ch3\u003eHow does neratinib work against breast cancer?\u003c\/h3\u003e\n\u003cp\u003eNeratinib irreversibly binds to HER1, HER2, and HER4 receptors, blocking signals that drive cancer growth. It also inhibits downstream pathways such as PI3K-AKT-mTOR and RAS-RAF-MEK-ERK. This can slow or stop cancer cell division and promote programmed cell death. As a small molecule, it may also enter the central nervous system.\u003c\/p\u003e\n\u003ch3\u003eWhat is the most common side effect of neratinib?\u003c\/h3\u003e\n\u003cp\u003eDiarrhea is the most common side effect, reported in up to 88% of patients in a phase 1 trial. It can be managed with loperamide, dose reduction, or temporary discontinuation. Other side effects include loss of appetite, nausea, fatigue, and vomiting. Early diarrhea during treatment is often easily controlled with proactive antidiarrheal medication.\u003c\/p\u003e\n\u003ch3\u003eCan neratinib help with breast cancer that has spread to the brain?\u003c\/h3\u003e\n\u003cp\u003eNeratinib is a small molecule that can cross the blood-brain barrier, unlike trastuzumab. In the NEfERT-T trial, central nervous system recurrence was 8.3% with neratinib plus paclitaxel versus 17.3% with trastuzumab plus paclitaxel. In the NALA trial, fewer patients on neratinib plus capecitabine needed central nervous system intervention compared to lapatinib plus capecitabine.\u003c\/p\u003e\n\u003ch3\u003eWhat did the ExteNET trial show for early-stage HER2-positive breast cancer?\u003c\/h3\u003e\n\u003cp\u003eThe ExteNET trial compared neratinib to placebo in 2,840 patients with early-stage HER2-positive breast cancer. The 2-year invasive disease-free survival rate was 93.9% with neratinib versus 91.6% with placebo. At 5 years, it was 90.2% versus 87.7%. This supports neratinib as extended adjuvant therapy after initial treatment.\u003c\/p\u003e\n\u003ch3\u003eIs neratinib effective for HER2-negative or HER2-mutant breast cancer?\u003c\/h3\u003e\n\u003cp\u003eNeratinib has shown some activity in HER2-mutant breast cancers, where the HER2 gene is mutated but not overexpressed. However, more research is needed to determine its optimal use in HER2-negative and HER2-mutant settings. It is not currently approved for these types of breast cancer.\u003c\/p\u003e\n\u003ch3\u003eHow is neratinib taken and what affects its absorption?\u003c\/h3\u003e\n\u003cp\u003eNeratinib is an oral tablet taken at home. It is mainly broken down by the liver enzyme CYP3A4. A high-fat meal increases its absorption, and stomach acidity also affects it. The half-life is 7 to 17 hours, with peak blood levels 2 to 8 hours after taking it. Your doctor will advise how to take it.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with HER2-positive breast cancer that has spread to the brain seek a second opinion?\u003c\/h3\u003e\n\u003cp\u003eA second opinion is worth considering when brain metastases are present, because treatment decisions differ from those for cancer outside the central nervous system. Neratinib is a small molecule that can enter the central nervous system, unlike trastuzumab, and in the NEfERT-T trial the central nervous system recurrence rate was 8.3% with neratinib versus 17.3% with trastuzumab. In the NALA trial, central nervous system intervention was needed in 22.8% versus 29.2%. A second opinion can help clarify whether a neratinib-based regimen fits. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal Article Title:\u003c\/strong\u003e Neratinib for HER2-positive breast cancer with an overlooked option\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Liting Guo, Weiwei Shao, Chenfei Zhou, Hui Yang, Liu Yang, Qu Cai, Junqing Wang, Yan Shi, Lei Huang, and Jun Zhang\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e Molecular Medicine (2023) 29:134\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e https:\/\/doi.org\/10.1186\/s10020-023-00736-0\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor Affiliations:\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eDepartment of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China\u003c\/li\u003e\n\u003cli\u003eDepartment of Pathology, The First People's Hospital of Yancheng City, Yancheng, China\u003c\/li\u003e\n\u003cli\u003eDepartment of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China\u003c\/li\u003e\n\u003cli\u003eDepartment of General Surgery, Shanghai Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China\u003c\/li\u003e\n\u003cli\u003eMedical Center on Aging of Ruijin Hospital, MCARJH, Shanghai Jiao Tong University School of Medicine, Shanghai, China\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eNote:\u003c\/strong\u003e This patient-friendly article is based on peer-reviewed research. The original article is an open-access review published under a Creative Commons Attribution 4.0 International License. This summary is intended for educational purposes and should not replace consultation with a qualified healthcare provider. Patients should discuss their individual treatment options with their medical team.\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47807299977372,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-neratinib-for-her2-positive-breast-cancer-an-overlooked-treatment-option-hero.png?v=1792041701","url":"https:\/\/diagnosticdetectives.com\/ja\/products\/neratinib-for-her2-positive-breast-cancer-an-overlooked-treatment-option","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}