Exciting Gains in Fighting Breast Cancer Hormone-therapy ...

Exciting Gains in Fighting Breast Cancer Hormone-therapy Resistance
Published on Bioscience Technology (http://www.biosciencetechnology.com)

Exciting Gains in Fighting Breast Cancer Hormone-
therapy Resistance

Cynthia Fox, Science Writer

Guided by breakthrough research on the
Estrogen Receptor 1 (ESR1) gene, many researchers and pharmaceutical companies
are in hot pursuit of the next big anti-resistance breast cancer drug.
In the last year, teams from many institutions—most notably Memorial Sloan
Kettering Cancer Center (MSKCC) and the University of Michigan (U-M)—separately
made an intriguing discovery about relapses in hormone-positive breast cancer.
Many such relapses may be associated with mutations in ESR1 arising after
estrogen deprivation—prompted by prolonged aromatase inhibitor exposure.
“After years of largely unsuccessful attempts to characterize the relevance of
mutations in the estrogen receptor (ER), 2013 brought a number of exciting studies
reporting ESR1 mutations in endocrine-resistant breast cancer,” University of
Pittsburgh Women’s Cancer Research Center Director of Education Steffi
Oesterreich told Bioscience Technology.
“This raised a lot of excitement [1] and hope for improved diagnosis and therapy of
endocrine-resistant disease.”
It is too soon for ESR1 mutation-tailored approaches to hit clinical trial. But new
approaches using old drugs are being considered, and at least one trial of a new
drug may be relevant. That trial is giving a new oral selective estrogen receptor
down-regulator (SERD), ARN810, to patients at MSKCC, Massachusetts General
Hospital and Vanderbilt Ingram Cancer Center, many oncologists told Bioscience

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Exciting Gains in Fighting Breast Cancer Hormone-therapy Resistance
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Technology.

Still, the main benefit right now is an evolving understanding. Several studies are
building on the 2013 work. “We’re extremely excited. I think we’ve been able to put
patients on therapies they wouldn’t have otherwise have had access to and
benefitted from,” MSKCC oncologist Sarat Chandarlapaty told Bioscience
Technology. Chandarlapaty’s 2013 Nature Genetics [2] study was a key ESR1 paper.
“But it is still another step to say that the population as a whole benefits. That will
take time.”

Said Oesterreich, “The finding of ESR1 mutations is one of the most exciting
findings in ER+ (estrogen receptor positive) breast cancer over the last decade. It
holds many promises. But a lot of work has to be done to improve the lives of breast
cancer patients with ER+ disease.”

A run of studies

In December 2013, Nature Genetics
published two studies on ESR1: Chandarlapaty’s, and one led by U-M pathologist
Arul Chinnaiyan [3].

Both studies found “ESR1 mutations are relatively frequent events in advanced ER+
hormone-resistant breast cancer, particularly in metastatic lesions from women who
took estrogen-lowering drugs such as aromatase inhibitors,” Oesterreich wrote in a
Nature Genetics commentary. Chandarlapaty’s study isolated ESR1 mutations in
nine of 36 (25 percent) ER+ metastatic breast tumors, while Chinnaiyan’s study
found ESR1 mutations in six of 11 (55 percent). Chandarlapaty also identified ESR1
mutations in five of 44 (11 percent) ER+ metastatic breast cancers from patients
who worsened on aromatase inhibitors (in the BOLERO-2 clinical trial).

Combined results showed “an estimated frequency of 22 percent (20/91 cases) for
ESR1 mutations in advanced breast cancer.” Both groups also showed ESR1
mutations were lacking pre-therapy. Chinnaiyan’s group saw no ESR1 mutations in
80 breast cancers lacking ER and progesterone receptor (PR) expression.
Chandarlapaty’s group found ESR1 mutations in only 3 percent of 183 pretreatment
BOLERO-2 tumors.

Similarly, an earlier 2012 whole-genome analysis of 46 pretreatment ER+ tumors
identified no ESR1 mutations, Oesterreich wrote. Most of the studies used deep

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Exciting Gains in Fighting Breast Cancer Hormone-therapy Resistance
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sequencing, which enables de novo mutation identification. “Thus, ESR1 mutations
are rare in newly diagnosed, untreated breast cancers but appear to be frequently
acquired during progression to hormone resistance, especially in the context of
estrogen-deprivation therapy,” she wrote.
Significance for drug development
Those studies—alongside complementary work in Cell Reports [4] in September
2013, Cancer Research [5] in December 2013 and Clinical Cancer Research [6] in
January 2014—made an impact.
Chandarlapaty confirmed that “our study was cited in multiple other journals as an
important finding in terms of resistance to hormonal therapy, at meetings as well,
and I think that several pharmaceutical companies have recognized the significance
of this for drug development.”
The work fingers estrogen-deprivation resistance as the culprit, as aromatase
inhibitors prevent estrogen production. But what about other drugs for hormone-
positive cancers, like tamoxifen (a SERM, or selective estrogen receptor modulator)
and fulvestrant (the only FDA-approved SERD)?

“Because tamoxifen and fulvestrant are
direct antagonists, they do still inhibit some of these mutated receptors,” said
Chandarlapaty. Oncologists are considering boosting doses of these two drugs to
see if that might help patients with the ESR1 mutation. “But are they as effective?
That is what is uncertain, especially in the human body.”
U-M Breast Oncology Center Clinical Director Daniel Hayes (a co-author on

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Exciting Gains in Fighting Breast Cancer Hormone-therapy Resistance
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Chinnaiyan’s study) told Bioscience Technology that the “preclinical data suggest
that the ESR1 mutations confer resistance to estrogen depletion, since they induce
ligand (estrogen)–independent ER signaling.” They also “still bind to drugs that work
directly by binding to the ER, SERMS like tamoxifen, and fulvestrant.” But, Hayes
said: “The dose-dependent binding curve is shifted. The drugs still work, but need
higher concentrations.”

Hayes said the field does not know “the effects of increasing SERMs above 20
mg/day.”

One randomized trial of increased dose of tamoxifen to 60—which was done 40 to
50 years ago by people with no knowledge of ESR1 and was very small—was
negative, he said.

Some think that increased doses of fulvestrant could be an answer. “When you
destroy the estrogen receptor, mutations don’t matter. That type of cancer
opportunism goes out the window,” MD Anderson oncologist Craig Jordan told
Bioscience Technology. (Jordan is known as the pioneering “father” of tamoxifen.)

Agreed Hayes: “Fulvestrant is dose-dependent. The original FDA-approved dose was
250 mg/month, but a randomized trial showed 500 is better. Most of us felt we
should go higher.”

But both noted a key problem. Fulvestrant “is very insoluble, not bioavailable by
oral route, so requires intramuscular injection of relatively large volume. Going
above 500 [mg] per month is too painful,” said Hayes.

Agreed Jordan: “It is not patient-friendly to do it for a decade.”

Most researchers contacted by Bioscience Technology noted that many companies
are working on oral SERDs that would be “easier to take, for longer,” Jordan said. As
noted, Seragon’s oral SERD ARN-810 is in trial. That trial doesn’t analyze ESR1
mutations. Still, many will be watching when results are announced at December’s
San Antonio Breast Cancer Symposium.

Significance overall

The ESR1 studies “clearly” represent a “significant finding,” Jordan told Bioscience
Technology. Two decades ago, he discovered a natural mutation that he now sees
possesses similar promise. "About 20 years ago, we found a natural mutation in
experimental tamoxifen-stimulated tumors that enhanced the estrogenic properties
of SERMS at an amino acid critical for the current reported mutations to work,"
Jordan said. "As a result, we put together a position statement to bring the concepts
and pharmacology all together. This is in review."

Many groups have “expanded studies of these mutations, including mechanism of
action, and clinical relevance,” Oesterreich told Bioscience Technology. Two groups
this year detected ESR1 mutations in blood, via circulating tumor [7] cells (CTCs) or
circulating free [8] DNA (cfDNA). Hayes said these have caused “excitement.”

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Exciting Gains in Fighting Breast Cancer Hormone-therapy Resistance
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Oesterreich agreed. ESR1 mutation detection in blood might lead to better therapy.
“It is of great interest to determine whether these mutations can be detected before
metastases develop,” Oesterreich said.

Another question is whether ESR1 mutations can be detected in primary tumors at
low frequency, said Oesterreich. So far, data from The Cancer Genome Atlas
(TCGA) project and Chandarlapaty’s study, “point towards the absence of ESR1
mutations in primary disease. The development of the ESR1 mutations only under
pressure of endocrine treatment is a perfect example for Darwinian-like evolution of
somatic mutations, as elegantly described by Kornelia Polyak [9]. The conclusion
will need to await larger studies using ultrasensitive detection technologies such as
digital droplet PCR (ddPCR).”

Oesterreich noted that studies suggest “the mutations cause conformational
changes, resulting in increased interaction with co-activator proteins, already in the
absence of ligand…The mutations aren’t classical activating mutations, like those
described in mutation-activated ras. We still do not know whether ER mutant
proteins show increased activation of their ‘classical’ target genes, and/or
regulation of novel target genes, potentially driving metastases. It will be important
to generate better in vitro and in vivo models.”

Oesterreich agreed that, as the new data “suggest ESR1-mutant cells retain some
sensitivity to endocrine therapy, higher doses might be required.”

But novel or refurbished drugs will ultimately be needed. Also needed, of course,
Oesterreich concluded, is “published evidence that patients whose tumors express
mutated ESR1 have a worse outcome.”

Source URL (retrieved on 02/12/2016 - 3:53am):
http://www.biosciencetechnology.com/articles/2014/11/exciting-gains-fighting-
breast-cancer-hormone-therapy-resistance

Links:
[1] http://www.ncbi.nlm.nih.gov/pubmed/24487689
[2] http://www.nature.com/ng/journal/v45/n12/full/ng.2822.html
[3] http://www.nature.com/ng/journal/v45/n12/full/ng.2823.html#affil-auth
[4] http://www.cell.com/cell-reports/abstract/S2211-1247(13)00463-4?_returnURL=h
ttp%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124713004634
%3Fshowall%3Dtrue
[5] http://www.ncbi.nlm.nih.gov/pubmed/24217577
[6] http://clincancerres.aacrjournals.org/content/early/2014/03/19/1078-0432.CCR-1
3-2332
[7] http://www.sciencemag.org/content/345/6193/216.figures-only
[8] http://www.ncbi.nlm.nih.gov/pubmed/25009010
[9] http://www.nature.com/nm/journal/v20/n4/full/nm.3518.html

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