new target identified for her2+ breast cancers resistant to dual targeting with

[Lani]

herceptin+ lapatinib as well as pertuzumab+herceptin--and it may be possible with testing, to predict which tumors will respond/not respond to the combinations in order to preempt resistance, by blocking "the puppy's means of escape"

Study Identifies Potential New Approach to Overcome Breast Cancer Resistance to HER2-targeted Therapies

April 8, 2014


SAN DIEGO — Resistance to a combination of HER2-targeted therapies, trastuzumab and lapatinib, was associated with elevated activation of a group of proteins called fibroblast growth factor receptors (FGFRs), which are the target of a number of drugs currently being developed, according to preclinical results presented here at the AACR Annual Meeting 2014, April 5-9.
Joan T. Garrett, Ph.D.
About 20 percent of breast cancers have elevated levels of the protein HER2 and are said to be HER2-positive. Drugs that target HER2 have improved outcomes for patients with HER2-positive breast cancer, but most tumors eventually become resistant to the effects of these drugs.

“A number of clinical trials have shown that treatment with a combination of two HER2-targeted therapies is superior to treatment with either alone,” said Joan T. Garrett, Ph.D., research instructor at Vanderbilt University Medical Center in Nashville, Tenn. “However, resistance to this dual blockade of HER2 eventually arises.

“The goal of this study was to identify how HER2-positive tumors develop resistance to dual blockade of HER2 with trastuzumab and lapatinib,” she continued. “Our finding that amplification of FGF3, 4, and 19 is associated with resistance to this drug combination is significant because it opens up an avenue of research that could provide the basis for clinical testing of FGFR inhibitors, if all the results are consistent with what we have seen so far.”

Garrett and colleagues started the study by treating mice bearing tumors comprising a human HER2-positive breast cancer cell line with trastuzumab and lapatinib. The tumors disappeared and treatment was stopped. In some mice, however, the tumors recurred and would not respond to further treatment with trastuzumab and lapatinib. More than 90 percent of these tumors also failed to respond to a second combination of HER2-targeted therapies, trastuzumab and pertuzumab.

One approach the researchers used to understand the molecular mechanisms of resistance to trastuzumab and lapatinib was next-generation genome sequencing. Analysis of five tumors resistant to trastuzumab and lapatinib and five tumors sensitive to the drug combination showed that one of the resistant tumors had extra copies of the genes FGF3, FGF4, and FGF19. According to Garrett, these genes produce proteins that attach to FGFRs, triggering cell growth.

Garrett and colleagues found that tumor cells with extra copies of the genes FGF3, FGF4, and FGF19 showed signs of elevated FGFR activation, as measured by levels of phosphorylated FGFR.

“This suggests that amplification of FGFR signaling could be a mechanism of acquired resistance to dual blockade of HER2,” said Garrett. “We are in the early stages of experiments designed to test whether drugs that block FGFRs, FGFR inhibitors, are effective in mice whose tumors have become resistant to the combination of trastuzumab and lapatinib.

“If we observe tumor shrinkage or elimination in this setting and can show that FGFR signaling is amplified in HER2-positive breast tumors from patients treated with dual blockade of HER2, we will have a good rationale for considering clinical trials,” she added.

This study was funded by the National Institutes of Health and the National Cancer Institute. Garrett declares no conflicts of interest.

[Lani]

from a poster presentation at the aacr annual meeting that I attended 2 weeks ago


Abstract Number: LB-212
Presentation Title: HER2-overexpressing breast cancer xenografts amplify FGFR signaling upon acquisition of resistance to dual blockade with trastuzumab and lapatinib
Presentation Time: Tuesday, Apr 08, 2014, 8:00 AM -12:00 PM
Location: Hall A-E, Poster Section 42
Author Block: Joan T. Garrett, Jennifer Becker, Mónica Valeria Estrada, Carlos L. Arteaga. Vanderbilt Univ., Nashville, TN
Abstract Body:
We sought to discover mechanisms of acquired resistance to the combination of the HER2 inhibitors trastuzumab and lapatinib in HER2 gene amplified BT474 xenografts. The combination of lapatinib and trastuzumab completely eliminated BT474 tumors established in nude mice after <3 weeks of treatment. However, some tumors recurred as early as 9 weeks after the combination was stopped. Three recurrent tumors did not respond to retreatment with the combination of lapatinib and trastuzumab. More than 90% of tumors derived from these recurrent tumors did not respond to lapatinib/trastuzumab or the combination of trastuzumab and pertuzumab. Both the parental drug-sensitive xenografts and the lapatinib/trastuzumab-resistant (LTR) tumors exhibited 5 to 6-fold HER2 gene amplification as measured by FISH using probes for HER2 and chromosome 17. The LTR cancers maintained levels of P-HER2, P-AKT and P-ERK in the presence of lapatinib and trastuzumab as measured by IHC of tumor sections whereas treatment of parental BT474 xenografts reduced P-HER2 levels. LTR tumors exhibited markedly reduced in situ levels of lapatinib compared to BT474 sensitive tumors (2.157 µg lapatinib/gm tissue versus 4.701 µg lapatinib/gm tissue, p=0.02) as assessed by liquid chromatography-mass spectrometry (LC-MS). Quantitative site-specific mass spectrometric analysis of tyrosine phosphorylation from tumor lysates revealed enriched P-Y877 HER2 in LTR compared to parental BT474 xenografts. We next performed next generation sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes. There were no mutations in HER2 but we observed amplification of FGF3, FGF4, and FGF19 genes in LTR xenografts. Consistent with increased autocrine activation of FGFR, we observed markedly elevated levels of P-FGFR in LTR xenografts compared to parental xenografts as assessed by IHC. We speculate that ligand-induced FGFR signaling may induce resistance to dual HER2 blockade by 1) a tumor cell autonomous mechanism resulting in transactivation of HER2 and, 2) an alteration in the tumor microenvironment that reduces lapatinib uptake and/or retention by the LTR tumors. In conclusion, we show amplification of FGFR signaling upon acquired resistance to combinations of HER2-targeted agents. Studies with FGFR tyrosine kinase inhibitors to reverse drug resistance are in progress.

[suzan w]

This might seem like a silly question...if, in my case, the tumor was small and removed via bilateral mastectomy, with no node involvement...is there any "puppy" left to escape??

[Lani]

breast cancer is a disease that metastasizes early--even before a lump can be detected.

According to the stem cell "theory" of breast cancer (the cancer stem cells have been identified, and I for one, no longer consider it a theory as the facts seem to support it) those cells sit quiescently,dormantly, not dividing in the bone marrow and once "re-awakened" are the source of recurrence/distant metastasis.

[suzan w]

I wonder if there is anything else I should be doing..I want the be pro-active. My oncologist in Seattle basically told me I was "done". Now I have relocated to Naples Florida and do not want to leave any stone unturned. The idea of stem cells lurking around, just waiting to sprout scares me.

[linn65]

Lani,

So the puppies name is, "Escape"??? I can read what you just wrote, and I know we have all these brainiacs on this board, but I still am clueless what you are talking about. Trastuzumab is herceptin and lapatinib is what????

You need to write one post on medical findings for whoever is on your level of intelligence. Then if you could so kindly re-write it for the everyday, average, I don't have a clue what you mean when you write stuff, dummy it down or whatever for me and surely I am not alone!! I know what you research, research, and read and read so I want to know what the heck you are talking about!!

Thank you in advance!!!

p.s. Good thing Escape is a puppy or I would have him put to sleep.

[suzan w]

Lapatinib is tykerb...trastuzumab is herceptin.