[Debbie L.]

This is a report on the same study, but with a much more understandable (to me) explanation of why it's important. And if this idea panned out, what a different way of looking at (and perhaps dealing with) endocrine resistance in ER+HER2+ cancer. Apologies for the funky formatting - there's a lot of extra graphic stuff when copy/pasting from MedPage, even from a print page.
http://www.medpagetoday.com/MeetingCoverage/IMPAKT/19995

IMPAKT: Breast CA Receptor Tug-of-War May Impact Therapy
By Crystal Phend, Senior Staff Writer, MedPage Today May 07, 2010
MedPage Today Action Points Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Review BRUSSELS -- Breast tumors' estrogen receptors may interact with their HER2 receptors in a way that has implications for treatment of both, researchers found. Tumors that were positive for both ER and HER2 preferentially activated a different set of biologic pathways compared with ER-/HER2+ cancers, found Sherene Loi, MD, PhD, of the Jules Bordet Institute in Brussels, and colleagues. Greater activation of the PI3K/AKT pathway was seen in double-positive tumors, whereas ER-/HER2+ tumors favored EGFR/RAS/MAPK signaling, they reported here at the IMPAKT Breast Cancer Conference. Loi speculated that one implication could be that HER2-targeted agents may work better without the hormonal therapy typically given to women who are ER+ and overexpress HER2. Giving antiestrogen therapy would essentially switch them from ER+ to ER- by destroying the cells that rely on estrogen and thus switch the tumor's dominant pathway away from the PI3K/AKT pathway upon which trastuzumab (Herceptin) works, explained co-author Christos Sotiriou, MD, PhD, also of Jules Bordet Institute and conference co-chair. "It's known that HER2 confers resistance to endocrine therapy, but this is now the opposite," he said in an interview. "The ER pathway may confer resistance to anti-HER2 therapy." He cautioned that the results should be considered hypothesis generating, but suggested that it may be possible to optimize therapy for these patients by combining trastuzumab and lapatinib (Tykerb), which blocks both pathways. ER-/HER2+ patients might be better suited to lapatinib rather than trastuzumab, Sotiriou added. Regardless, anti-HER2 therapy now needs to be studied in ER+/HER2+ and ER-/HER2+ patients as distinct entities, conference co-chair Angelo Di Leo, MD, PhD, of the Hospital of Prato, Italy, said at a press conference. Clifford A. Hudis, MD, of Memorial Sloan-Kettering Cancer Center in New York City and chair of the session, agreed that this should be marching orders for preclinical and clinical trials. "We haven't quite done the experiment, but this would have really big implications," he told MedPage Today. "If it showed what they predicted, it would be really, really provocative." Trastuzumab often overlaps with hormonal therapy in the postoperative adjuvant setting for these double-positive women, which might not be the right thing to do based on the results, he said. He noted, though, that there is a range of ER positivity. "The HER2s are going to be at the low end of ER positive," he said in an interview. "They're over the threshold to call positive, but they're really not the same positivity as a Luminal A." Thus, the HER2 group "may be even more finely dividable than that," he added. "All of this represents a challenge. . . . We may be dividing these beyond the point of clinical practicality." The researchers meta-analyzed data from 12 cohorts of patients for a total of 1,150 with gene expression data on ER status and 822 with HER2 status, about a quarter overall being HER2+. Because 1,072 of these patients had been treated in the era before systemic therapies became available, the researchers examined their outcomes across breast cancer subtypes to approximate a natural history of the disease. Among them, ER+/HER2+ had the worst relapse-free survival rates followed by ER+/HER2 Luminal B (P=0.06), triple negative (P=0.02), ER+/HER2 Luminal A (P=0.001), and ER-/HER2+ (P=0.01) cancers. "While obviously these data likely represent a highly selected population, it's already begun to tell us that there seem to be significant biological differences by estrogen receptor status," Loi said at the conference. Gene expression analyses showed that 24% of the whole genome differed in probe sets by ER status in HER2+ tumors while copy number differences were seen in 10% of the genome. The level of HER2 mRNA expression was actually higher when ER status was negative (P=0.002), as was the epidermal growth factor receptor (EGFR) mRNA expression (P<0.001). With regard to the functional impact of these differences on downstream pathway activation, ER positivity was associated with PIK3CAmt (as described by Loi) and AKT1 gene signaling, whereas there was a negative correlation with RAS (as described by Bild) and MAPK (as described by Creighton) gene signaling in HER+ breast cancer. Among HER2+ cell lines, ER- cells showed reduced response compared with ER+ cells to both trastuzumab and lapatinib (both P<0.001). ER-/HER2+ status was also associated with little response to AKT inhibition (P=0.001), unlike the dramatic sensitivity of ER+/HER2+ cell lines (P<0.001). Loi reported that when the ER+/HER2+ cell lines were exposed to endocrine therapy (fulvestrant, Faslodex) -- a standard treatment for patients with this receptor status combination -- the addition of AKT inhibition blunted its impact on the disease (P<0.0001). Altogether, these differences may yield different "pathway output dependency," which Loi said has different clinical implications. "ER signaling may antagonize EGFR/RAS/MAPK signaling, leading to increased PI3K/AKT output in the double positives," Loi's group explained in the study abstract. The researchers reported no conflicts of interest. Hudis and Di Leo reported no conflicts of interest. Primary source: IMPAKT Breast Cancer Conference Source reference: Loi S, et al "Molecular and clinically distinct phenotypes in HER2-overexpressing breast cancer (HER2+ BC) correspond to estrogen receptor status (ER) status" IMPAKT 2010; Abstract 970.