Controversy: IS HER2-positive breast cancer a misnome?

HER2, Chinese the human epidermal growth factor receptor 2, is one of the most widely recognized cancer genesBut there is growing evidence that HER2 may not be the main driver of breast cancer, and that "HER2-positive breast cancer" may be a misnousscientists have questioned whether the study by several HER2 drug makers, including Genentech, has derailed current guidelines for the classification and treatment of breast cancerThe new classification scheme should better identify patients who are more likely to benefit from anti-HER2 treatment, or point to more effective treatments1980s, scientists discovered HER2 breast cancerToo much copy of the HER2 gene or excessive expression of her2 proteins seem to make breast cancer particularly aggressiveBy the end of the 1990s, the first HER2-targeted drug, herceptin ,quoctal monitahlon, was approved by the FDAAs Harold Burstein, an oncologist at the Dana-Farber Cancer Institute in the United States, said a few years ago, HER2 breast cancer, once the most feared type of breast cancer, is no longer a headache for doctors, thanks largely to Heseltineabout 14% of breast cancers are HER2 positiveThe American Society of Clinical Oncology (ASCO) recommends Herceptin as a first-line treatment for HER2-positive breast cancerIn the United States, thousands of patients receive Herceptin each yearHowever, researchers, including scientists from Genentech, have recently begun to rethink the HER2-positive subtypein the HER2-centric breast cancer model, highly dysfunctional HER2 signaling drives cells out of controlHER2-positive breast cancer carries up to 50 copies of the HER2 gene, compared with only two in non-cancer cells, and the gene is highly expressed, resulting in a 40-100-fold higher LEVEL of HER2 protein than normalBut after analyzing several published genome datasets, Genetek researchers reported in 2018 that there was no evidence that HER2 gene amplification represented a subtype of breast cancerHER2 amplification appears to have little effect on the expression of HER2-mediated genesInstead, it is associated with an increase in the gene that controls the signal of the androgen receptor (androgen receptor, AR) AR signals coordinate the effects of testosterone and related hormones, which are usually enhanced in breast cancer This link between HER2 amplification and AR signals suggests that AR may play a greater role in the disease than previously known other researchers also used transcription maps to re-evaluate breast cancer, which looks at gene expression across the genome rather than on individual genes that are considered to have a significant impact "The whole process of subdividing and classifying breast cancer is changing, and we're in the molecular age, so I think we know more." "Memorial Sloan Kettering Cancer Center oncologist Larry Norton, who played a key role in clinical trials that made HER2-positive breast cancer a subtype and herceptin as the first drug to treat this type of breast cancer, said the traditional view of rethinking her2 breast cancer subtype her2 breast cancer, which guides current clinical practice, has been under pressure for some time While most researchers still believe THAT HER2 is a significant driver of some breast cancers, Herceptin itself has struggled to knock down HER2-positive tumors in early clinical trials "It was the synergy with the chemotherapy drug, yewol, that really made the drug so well known," Norton said If we had treated Herceptin as a single drug, it would have been abandoned long ago Norton led a published trial that included 469 patients between June 1995 and March 1997 (below), pushing the FDA to approve Herceptin for advanced breast cancer in 1998 However, the trial did not really prove that herseltin and yew alcohol were better than single yew alcohols in improving survival rates Only when the data were combined with a separate trial to detect non-cyanosis-free chemotherapy, did the researchers find a statistically significant difference in survival rates Photo Source: NEJM In addition, two trials that pushed Hercetin for early breast cancer in 2006 later raised doubts about HER2 as a biomarker for drug responses A 2007 reanalysis of one of the trials found no statistical interaction between the patient's HER2 status and whether he benefited from Heceptin A similar analysis of the second trial confirmed the results, the researchers wrote in their report: "The benefits of Herceptin do not appear to be related to her2 amplification 2000, a team at Stanford University School of Medicine used state-of-the-art microarray technology to propose molecular subtypes of breast cancer based on the expression of more than 8,000 genes in 42 patientbiotic tissues This new subtype, later known by the research team as HER2 Enrichment (HER2E), breaks the CLASSIFICATION of HER2: according to the classic classification method may be A HER2-positive tumor, the transcription level does not show THE signal activity of HER2 mediated In fact, only 47% of HER2 amplification tumors are HER2E Margaret Gatti-Mays of the National Cancer Institute estimates that 30 to 40 percent of HER2E tumors are clinically not CLINICALly positive in a 2005 paper, Richard Iggo, who was working at the Swiss Institute of Experimental Cancer, and his colleagues conducted a molecular subtype similar to that proposed by researchers at Stanford University in 2000 Iggo's team found that the previously discovered HER2 group did not appear to be defined by HER2, but by genes that appeared to be associated with androgen signals Similarly, anneleen Daemen and Gerard Manning found that AR activity is key to the HER2E subtype in Genetek's 2018 study "In essence, HER2E is not her2-driven, but androgen signaling," said Daeman, head of translational medicine at ORIC Pharmaceuticals "This may be because AR can act as an estrogen receptor (estrogen receptor, ER) that drives tumor growth in the most common form of breast cancer," explains Gerard Tarulli, an endocrinology researcher at the University of Melbourne at In HER2E tumors, AR signals are considered to be the driving factors for replacing ER, and AR almost physiologically replaces the presence of ER." Iggo and his colleagues called for the HER2E subtype to be renamed "molecular apocrine" to reflect a pathology that, unlike HER2 central disease, involves signaling of AR and other pathways "I'm a little disappointed that the name hasn't changed," Iggo said The Stanford team, known only as HER2E, continues the idea of HER2 amplification to define a biological subtype Daemen agrees "When they first defined these subtypes, they shouldn't use the word 'HER2E' because it's misleading," she said The name is now so ingrained in breast cancer research that people really stick to it These subtypes are not questioned throughout the study." According to Daemen, her research has been closely watched by clinicians and biomarker scientists who are conducting breast and stomach cancer trials "I was working closely with Genetek's clinical team to see if we could explain why some of the patients in our trial did not respond to HER2 drugs, for example, because of AR expression." however, Daemen left Genentech last fall "As far as I know, the company doesn't do any additional research on this," she said Kayla Bruneau, a spokeswoman for Genentech, said the company does not currently have any researchers to discuss Daemen's and Manning's papers the clinical road ahead
at present, clinical practice still strictly follows the classic definition of THEHER2 positive subtype Gatti-Mays said in a statement that her2 receptor overdose or HER2 amplification has been shown to be a biomarker of HER2-targeted therapeutic therapy But the diversity of subtypes produced by recent molecular analysis has attracted interest her2E is being supported as a possible subtype for eventual clinical application According to a meta-analysis published earlier this year, HER2E patients showed stronger clinical benefits from anti-HER2 treatment than other molecular subtypes Tarulli said: "It is significant that HER2E is included in future clinical trials of anti-HER2 therapies, as we now have a better understanding of the mechanisms behind HER2's work he says researchers can make more informed decisions once clinical trial data starts to be updated "If you can demonstrate that adding HER2E analysis to clinical decision-making can improve patient prognosis, then this classification is needed Tarulli added: "For PATIENTs with HER2E, inhibition of AR and HER2 is significant and may increase the effect of both." in a clinical trial, Daeman did not agree to use HER2E to determine which patients receive anti-HER2 treatment because it may have heart-related side effects "The decision to treat the disease based on the HER2E marker of the tumor could cause harm to patients who lack HER2 amplification," she said Margaret Gatti-Mays of the National Cancer Institute agrees that HER2E is an "interesting subtype", but more information about the long-term clinical outcomes of these HER2E patients remains to be known Reference: Benefits from Herceptin and Other Anti-HER2 Cancer Therapies? (Source: The Scientist)