Posted article on page 4:
IBC: Identifying factors that impact survival among women with inflammatory breast cancer.
Dawood S, Ueno NT, Valero V, Woodward WA, Buchholz TA, Hortobagyi GN, Gonzalez-Angulo AM, Cristofanilli M. (2012 article)
http://www.ncbi.nlm.nih.gov/pubmed/21765048
As usual, I was looking for something and found something else. Hence, the following:
Posted the following on page 4:
Slides from a presentation: Update on TNBC by Lisa Carey MD, UNC on TNBC.
Not sure of the date. One of her slides had a reference of 2011, so it was from 2011 or 2012.
http://whcenter.org/documents/cme/4-Carey.pdf
St Gallen International Breast Cancer Conference.
Internatlonal Breast Cancer Conference held every 2 years in St. Gallen, Switzerland.
Here's the link with the program for the St Gallen (Switzerland) conference for 2013;
http://www.oncoconferences.ch/dynasite.cfm?dsmid=111795 A summary of the consensus from the 2011 St Gallen Breast Cancer Conference at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100376/ Note: There may have been some changes in consensus since 2011.
As usual, discuss with your physician if your plan is/was different than conference
consensus and you have questions.
Cancer Legal Resource Center.
Contact the CLRC (Cancer Legal Resource Center)
http://www.lls.edu/academics/candp/clrc.html https://www.disabilityrightslegalcenter.org/about/cancerlegalresource.cfm The CLRC has a national, toll-free Telephone Assistance Line (866-THE-CLRC) where callers can receive free and confidential information about relevant laws and resources for their particular situation. Members of the CLRC's Professional Panel of attorneys, insurance agents, and accountants can provide additional assistance. That phone number is 866-843-2572)
So far, trials in prostate cancer only but studies in mouse model for breast cancer suggests efficacy: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth http://www.ncbi.nlm.nih.gov/pubmed/21926191
Cabozantinib has been shown to be effective in pre-clinical studies of several different cancers.
This paper describes the use of mTor inhibitors in breast and
ovarian cancer models, and is relevant because of ongoing (or canceled?)
clinical trials using an mTor inhibitor in breast cancer (not sure if
TN was broken out). The paper essentially concludes that they get the
best effect when they use a combination of an mTor inhibitor and a Bcl2
inhibitor.
I
brought up this paper on a previous thread about lymphovascular
invasion, since it essentially claims that using pericyte coverage is an
important prognostic indicator of systemic recurrence. It is also
important because it suggests that use of single agent tyrosine kinase
inhibitors can paradoxically shrink the primary tumor, while promoting
metastasis by upregulating hypoxia in the primary tumor, thereby driving
EMT by upregulating cMet expression. Again, I think there have been
several clinical trials (that may be suspended) using various tyrosine
kinase inhibitors for breast cancer (but maybe only in the metastatic
setting?).
A
related paper suggesting similarly that antiangiogenic therapies such
as sunitinib (tyrosine kinase inhibitor) or bevacizumab (VEGF antibody)
increase hypoxia thereby upregulating cancer stem cells comes to similar
conclusions, in that drugs targeting specific kinases be used in
combination therapy, rather than monotherapy.
3-19-12 entry Myc pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition http://jem.rupress.org/content/early/2012/03/13/jem.20111512 -- results from the original ISPY trial. 33 out of 36 TNBC tumors had a high-intermediate Myc gene signature score, correlating with worse outcome : diminished disease-free survival in patients whose tumors exhibited poor response to neoadjuvant treatment. Increased Myc expression makes tumor cells more sensitive to CDK inhibition. CDK = cyclin dependent kinase consists of a group of kinases that function in the cell cycle. They tested 2 CDK inhibitors, one dinaciclib is in phase 2 trial for different cancers.
3-29-12 entry
Drug candidates derailed in case of mistaken identity
PARP inhibitor that wasn't highlights widespread flaws in preclinical studies.
Found this article on Tyrosine Kinase Inhibitors and thought it could be added to the discussion above.
New class of proteins allows breast cancer cells to evade Tyrosine Kinase Inhibitors
Aberrant regulation of cell growth pathways is required for normal cells to become cancerous, and in many types of cancer, cell growth is driven by a group of enzymes known as receptor tyrosine kinases (RTKs). The RTK epidermal growth factor receptor (EGFR) is overexpressed in over 30% of breast cancers; however, drugs that target RTKs, known as tyrosine kinase inhibitors (TKIs) have not been effective in treating breast cancer. Researchers believe that the cancer cells escape TKIs by circumventing the RTKs and utilizing other enzymes that are not TKI-sensitive.
In the current issue of the Journal of Clinical Investigation, two groups identify a pair of related oncogenes, FAM83A and B, which allow breast cancer cells to survive TKI treatment. Researchers led by Mina Bissell at the Lawrence Berkeley National Laboratory in Berkeley, CA performed a screen of human breast cancer cell lines to identify genes that make cancer cells resistant to EGFR TKIs. Bissell and colleagues determined that increased expression of FAM83A increases proliferation and invasion, while decreased expression delays tumor growth in mice and renders cancer cells sensitive to TKIs. At Case Western Reserve Medical School in Cleveland, OH, Mark Jackson and colleagues identified FAM83B as a gene that allows normal human mammary cells to become malignant. Further, expression of FAM83A and B in human tumors was correlated with decreased overall survival. Taken together, these studies identify two genes that may serve as novel therapeutic targets. In a companion piece, Steven Grant of the Medical College of Virginia discusses the impact of this research on the development of strategies to overcome resistance to currently available TKIs.
TITLE: FAM83B mediates EGFR- and RAS-driven oncogenic transformation
Tips and tricks in triple-negative breast cancer: how to manage patients in real-life practice?
M Piccart, G Viale, P Ellis, M Abramowicz, and L Carey
Ecancermedicalscience. 2011; 5: 217.
Published online 2011 July 19. doi: 10.3332/ecancer.2011.217
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223951/
Triple-negative breast cancer in focus: From biology to novel therapeutics
In "Annals of Oncology" Volume 23 suppl 6 August 2012:
http://annonc.oxfordjournals.org/content/23/suppl_6.toc Using the above link, all below articles have free full text.
Articles are research articles and mostly European authors.
P. Boyle
Triple-negative breast cancer: epidemiological considerations and recommendations
Ann Oncol (2012) 23(suppl 6): vi7-vi12 doi:10.1093/annonc/mds187
C. Criscitiello, H. A. Azim, Jr, P. C. Schouten, S. C. Linn, and C. Sotiriou
Understanding the biology of triple-negative breast cancer
Ann Oncol (2012) 23(suppl 6): vi13-vi18 doi:10.1093/annonc/mds188
F. Penault-Llorca and G. Viale
Pathological and molecular diagnosis of triple-negative breast cancer: a clinical perspective
Ann Oncol (2012) 23(suppl 6): vi19-vi22 doi:10.1093/annonc/mds190
B. E. Dogan and L. W. Turnbull
Imaging of triple-negative breast cancer
Ann Oncol (2012) 23(suppl 6): vi23-vi29 doi:10.1093/annonc/mds191
W. Eiermann and K. A. Vallis
Locoregional treatments for triple-negative breast cancer
Ann Oncol (2012) 23(suppl 6): vi30-vi34 doi:10.1093/annonc/mds192
G. von Minckwitz and M. Martin
Neoadjuvant treatments for triple-negative breast cancer (TNBC)
Ann Oncol (2012) 23(suppl 6): vi35-vi39 doi:10.1093/annonc/mds193
H. Joensuu and J. Gligorov
Adjuvant treatments for triple-negative breast cancers
Ann Oncol (2012) 23(suppl 6): vi40-vi45 doi:10.1093/annonc/mds194
F. André and C. C. Zielinski
Optimal strategies for the treatment of metastatic triple-negative breast cancer with currently approved agents
Ann Oncol (2012) 23(suppl 6): vi46-vi51 doi:10.1093/annonc/mds195
M. Aapro and H. Wildiers
Triple-negative breast cancer in the older population
Ann Oncol (2012) 23(suppl 6): vi52-vi55 doi:10.1093/annonc/mds189
J. Crown, J. O'Shaughnessy, and G. Gullo
Emerging targeted therapies in triple-negative breast cancer
Ann Oncol (2012) 23(suppl 6): vi56-vi65 doi:10.1093/annonc/mds196
Alfred
I. Neugut, Wei Yann Tsai, Judith S. Jacobson, and Dawn L. Hershman,
College of Physicians and Surgeons, Columbia University;
Alfred I. Neugut, Grace Clarke Hillyer,
Nicole Leoce, Wei Yann Tsai, Judith S. Jacobson, and Dawn L. Hershman,
Mailman School
of Public Health, Columbia University, New
York; Christine B. Ambrosone, Roswell Park Cancer Institute, Buffalo;
Carol Magai,
Long Island University, Brooklyn, NY;
Lawrence H. Kushi, Kaiser Permanente of Northern California, Oakland,
CA; Lois Lamerato
and S. David Nathanson, Henry Ford Health
System, Detroit, MI; Dana H. Bovbjerg, University of Pittsburgh and the
University
of Pittsburgh Cancer Institute, Pittsburgh,
PA; and Jeanne S. Mandelblatt, Georgetown University Medical Center,
Washington,
DC.
Corresponding author: Alfred I. Neugut, MD, PhD, Division of Medical Oncology, Columbia University Medical Center, 722 W 168th
St, Room 725, New York, NY 10032; e-mail: ain1@columbia.edu.
Abstract
Purpose For some
women, adjuvant chemotherapy for nonmetastatic breast cancer decreases
recurrences and increases survival; however,
patient-physician decisions regarding
chemotherapy receipt can be influenced by medical and nonmedical
factors.
Patients and Methods
We used a prospective cohort design and multivariate modeling to
investigate factors related to noninitiation of chemotherapy
among women with newly diagnosed breast cancer
recruited from three US sites. We interviewed patients at baseline and
during
treatment on sociodemographic, tumor, and
treatment decision-making factors. Patients were categorized according
to National
Comprehensive Cancer Network guidelines as those
for whom chemotherapy was definitely indicated, clinically
discretionary,
or discretionary based on age greater than 70
years.
Results Of 1,145
patients recruited, chemotherapy was clinically indicated for 392
patients, clinically discretionary for 459 patients,
discretionary because of age for 169 patients,
and not indicated for 93 patients; data were insufficient for 32
patients.
Chemotherapy rates were 90% for those in whom
chemotherapy was clinically indicated, 36% for those in whom it was
discretionary
because of clinical factors, and 19% for those
in whom it was discretionary based on age greater than 70 years.
Nonreceipt
of chemotherapy was associated with older age,
more negative beliefs about treatment efficacy, less positive beliefs
about
chemotherapy, and more concern about adverse
effects. In the two discretionary groups, clinical predictors of worse
outcome
(greater tumor size, positive nodes, worse
grade, and estrogen receptor– and progesterone receptor–negative status)
were associated
with increased chemotherapy initiation.
Conclusion Utilization
of adjuvant chemotherapy was most common among patients who, based on
clinical criteria, would most likely benefit
from it, patients with more positive than
negative beliefs regarding treatment efficacy, and patients with few
concerns about
adverse effects.
New treatment option possible for triple-negative breast cancers
11/12/2012
– The simultaneous inhibition of two separate and seemingly unrelated
pathways could potentially provide an effective treatment for women with
triple-negative breast cancer, according to results of two studies
published in the November issue of Cancer Discovery, a journal of the
American Association for Cancer Research.
Triple-negative
breast cancers do not express three common targets of breast cancer
treatments: the estrogen receptor, progesterone receptor and HER2/neu.
As a result, women with triple-negative breast cancer have few treatment
options. In early-phase clinical studies, those women with
triple-negative breast cancer with BRCA1 gene mutations had some
clinical benefit from treatments with poly-ADP-ribose-polymerase (PARP)
inhibitors. However, the activity of the PARP inhibitors is short-lived.
“We
are in desperate need of new therapies for triple-negative breast
cancer, which is a type of breast cancer that is very aggressive and
occurs mostly in young females,” said José Baselga, M.D., Ph.D., chief
of the division of hematology and oncology at Massachusetts General
Hospital Cancer Center in Boston.
In their study, Baselga; Yasir
Ibrahim, Ph.D., a postdoctoral fellow at Vall D’Hebron Institute of
Oncology in Barcelona, Spain; and Maurizio Scaltriti, Ph.D., faculty
assistant and lab coordinator at Massachusetts General Hospital Cancer
Center, hypothesized that inhibiting PI3-kinase, a key component of a
signaling pathway frequently activated inappropriately in
triple-negative breast cancer, would replicate the conditions present in
BRCA-mutated breast cancers, thereby increasing sensitivity to PARP
inhibitors.
They found that if PI3-kinase function was blocked in a
BRCA-proficient triple-negative breast cancer cell line, DNA damage
would occur due to BRCA protein downregulation, and that this resulted
in activation of PARP to repair the damage.
“In a way, with
PI3-kinase inhibitors, we are converting BRCA-proficient triple-negative
breast cancer into BRCA-deficient breast cancer and, therefore, these
cells become sensitive to PARP inhibition,” Baselga said.
In the
second study, Lewis C. Cantley, Ph.D.; Gerburg Wulf, M.D., Ph.D.; and
colleagues used an endogenous mouse model of BRCA1-deficient breast
cancer. They observed that mice with a BRCA1 mutation also had molecular
indicators of strong activation of the PI3-kinase pathway, suggesting
that the tumors might be vulnerable to PI3-kinase inhibitors.
When
the mice were treated with a PI3-kinase inhibitor, tumor doubling was
delayed from five to 26 days. Given that BRCA-mutated tumors are also
known to respond to PARP inhibitors, the researchers combined the two
medications and found that this delayed tumor doubling to more than 70
days.
“We saw in vivo synergy that led to dramatic prolongation of
progression-free survival in these mice of more than two to three
months, which in the life of a mouse is very long,” said Wulf, staff
physician in the division of hematology and oncology at Beth Israel
Deaconess Medical Center. “This is an unusual observation that makes us
hopeful that it is worthwhile to explore in an early-phase clinical
trial.”
Both studies received funding from Stand Up To Cancer Dream Team Translational Research Grants.
Cantley,
who conducted the research while director of the cancer center at Beth
Israel Deaconess Medical Center in Boston, and his colleagues have
worked with Novartis and AstraZeneca, the two companies that manufacture
the PI3-kinase inhibitor (BKM120) and the PARP inhibitor (Olaparib) to
initiate a clinical trial combining the two drugs in humans.
Cantley
said it is extremely unusual for two unapproved drugs to be combined in
a cancer clinical trial, especially when the two drugs are produced by
separate companies. Yet the preclinical results were sufficiently
compelling to accelerate the initiation of this trial. The trial, led by
Ursula Matulonis, M.D., director of medical gynecologic oncology at the
Dana-Farber Cancer Institute in Boston, is now open and starting to
enroll patients with triple-negative breast or ovarian cancer.
“This
is truly an amazing story where essentially the same week that the
paper is coming out showing an observation, the clinical trial is
starting,” Cantley said. “This type of bench-to-bedside process
typically takes five to 10 years but was dramatically accelerated by the
collaborative efforts of the Stand Up To Cancer-funded PI3-Kinase Dream
Team.”
REVIEW ARTICLE
New Insights and Emerging Therapies for Breast Cancer Brain Metastases
By Elgene Lim, MD, PhD, Nancy U. Lin, MD | July 12, 2012
Women’s Cancers Program, Dana-Farber Cancer Institute, Boston, Massachusetts
"How Do I Treat a Patient with Chemotherapy-Induced Nausea and Vomiting?"
By RUDOLPH M. NAVARI, MD, PHD, FACP
Indiana University School of Medicine South Bend; Clinical Director, Harper Cancer Research Institute
Enrollment took place
between June 11, 1997 and June 3, 1999; 745 patients were assigned to
receive TAC and 746 patients were assigned to receive FAC. After a
median follow-up of 124 months (IQR 90–126), disease-free survival was
62% (95% CI 58–65) for patients in the TAC group and 55% (51–59) for
patients in the FAC group (hazard ratio
0·80, 95% CI 0·68–0·93;
log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72–79) for
patients in the TAC group and 69% (65–72) for patients in the FAC group
(HR 0·74, 0·61–0·90; log-rank p=0·0020). TAC improved disease-free
survival relative to FAC irrespective of nodal, hormone receptor, and
HER2 status, although not all differences were significant in these
subgroup analyses. Grade 3–4 heart failure occurred in 26 (3%) patients
in the TAC group and 17 (2%) patients in the FAC group, and caused death
in two patients in the TAC group and four patients in the FAC group. A
substantial decrease in left ventricular ejection fraction (defined as a
relative decrease from baseline of 20% or more) was seen in 58 (17%)
patients who received TAC and 41 (15%) patients who received FAC. Six
patients who received TAC developed leukaemia or myelodysplasia, as did
three patients who received FAC.
Interpretation
Our
results provide evidence that the initial therapeutic outcomes seen at
the 5-year follow-up with a docetaxel-containing adjuvant regimen are
maintained at 10 years. However, a substantial percentage of patients
had a decrease in left ventricular ejection fraction, probably caused by
anthracycline therapy, which warrants further investigation.
TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer.
J. Clin. Invest. ePub Feb. 8, 2013
After an initial response to chemotherapy, many patients with
triple-negative breast cancer (TNBC) have recurrence of drug-resistant
metastatic disease. Studies with TNBC cells suggest that
chemotherapy-resistant populations of cancer stem-like cells (CSCs) with
self-renewing and tumor-initiating capacities are responsible for these
relapses. TGF-β has been shown to increase stem-like properties in
human breast cancer cells. We analyzed RNA expression in matched pairs
of primary breast cancer biopsies before and after chemotherapy.
Biopsies after chemotherapy displayed increased RNA transcripts of genes
associated with CSCs and TGF-β signaling. In TNBC cell lines and mouse
xenografts, the chemotherapeutic drug paclitaxel increased autocrine
TGF-β signaling and IL-8 expression and enriched for CSCs, as indicated
by mammosphere formation and CSC markers. The TGF-β type I receptor
kinase inhibitor LY2157299, a neutralizing TGF-β type II receptor
antibody, and SMAD4 siRNA all blocked paclitaxel-induced IL8
transcription and CSC expansion. Moreover, treatment of TNBC xenografts
with LY2157299 prevented reestablishment of tumors after paclitaxel
treatment. These data suggest that chemotherapy-induced TGF-β signaling
enhances tumor recurrence through IL-8–dependent expansion of CSCs and
that TGF-β pathway inhibitors prevent the development of drug-resistant
CSCs. These findings support testing a combination of TGF-β inhibitors
and anticancer chemotherapy in patients with TNBC.
Further subclassification of breast cancer tumors needed to help identify new biomarkers
DURHAM, NC — Breast cancers that are typically
classified as triple-negative are in fact biologically heterogeneous and
should be further classified into distinct molecular
subtypes, according to a comprehensive study of breast cancer datasets.
The study, which will be published in the February issue of The Oncologist, was conducted by a team of scientists from the University of North Carolina at Chapel Hill and the Vall d’Hebron Institute
of Oncology in Barcelona, Spain.
Previous research had identified four main subtypes
of breast cancer: luminal A, luminal B, HER2-enriched and basal-like.
Basal-like cancer has become more commonly known as
triple-negative breast cancer to define breast cancers that lack
expression
of hormone receptors and overexpression and/or
amplification of HER2 – even though up to 30 percent of tumors
identified as
triple-negative do not actually fall into the
basal-like subtype category.
The study examined more than 1,700 samples from 12
publicly available datasets, and highlighted the following findings:
Triple-negative and basal-like definitions
should not be considered synonymous because considerable discordance
exists.
Triple-negative disease is a heterogeneous
clinical entity composed of all the intrinsic molecular subtypes, with
the
basal-like tumors being the most frequent (70%).
Triple-negative tumors that are identified as
non-basal-like (such as HER2-enriched or luminal A/B) show nearly
undistinguishable
global gene expression patterns versus
non-triple-negative tumors that are HER2-enriched or luminal A/B.
Basal-like tumors that are non-triple-negative
show similar genomic features, and an association with young age at
diagnosis,
as do basal-like tumors that are triple-negative.
Previously described triple-negative
heterogeneity in part reflects known intrinsic subtype biology and
microenvironmental
heterogeneity.
“Our findings have very important implications for
clinical trials focused on triple-negative breast cancers,” said
corresponding
author Dr. Charles Perou, Ph.D., of the Lineberger
Comprehensive Cancer Center at the University of North Carolina at
Chapel
Hill. “Future clinical trials focused on
triple-negative breast cancers should consider stratifying patients
based on basal-like
versus non-basal-like gene expression profiles, which
appear to be the main biological difference seen in patients with
triple-negative
breast cancer. In addition, our findings argue for
very rigorous hormone receptor and HER2 testing due to the known
reproducibility
issues associated with these pathology-based
biomarkers.”
Perou and his colleagues suggest that recognizing
the molecular diversity of triple-negative tumors and subclassifying
them as separate entities could support efforts to
identify new biomarkers, which might possibly result in tests for
subtype
specific responses to different treatments, and
conduct more targeted research on the clinical importance of the various
molecular
subtypes.
"The last decade has seen an increasing emphasis on
subtyping of common cancers such as breast cancer. Multiple assays
have been devised that help oncologists determine
prognosis of particular subsets. However, as we move into routine
clinical
use of these assays, the current study reminds us that
there is more work to do in this complex field especially if we are
to use molecular assays to help change therapy and
predict outcomes," said Shelley Earp, M.D., Director of the UNC
Lineberger
Comprehensive Cancer Center.
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