tratamientos para el mieloma multiple WHAT IS MM? Multiple myeloma (MM) is the second most common cancer of the blood formed by malignant plasma cells. Normal plasma cells are found in the bone marrow and are an important part of the immune system. Despite recent advances, remains incurable in the vast majority of patients.
In the United States, there will be an estimated 24,050 new cases of MM in 2014 and >60,000 individuals living with the disease. Worldwide, ~86,000 patients are diagnosed each year with myeloma, while ~63,000 patients die every year from disease-related complications.
WHERE DOES EVERYTHING START? Everything start in plasma cells which are mainly found in bone marrow. Bone marrow is the soft tissue inside some hollow bones.
WHAT HAPPENS? When plasma cells become cancerous and grow out of control, they can produce a tumor called a plasmacytoma. These tumors generally develop in a bone, if someone has more than one plasmacytoma, they have multiple myeloma. (Isolated (or solitary) plasmacytoma si es uno solo).
The growth of this tumor, weakens the bones and also makes it harder the formation of healthy blood cells and platelets. According to this…
WHAT CAN WE EXPECT TO FOUND? As we know, the bone marrow produces blood cells, if a tumor in the bone occurs, we see:
• decreases the number of red blood cells: which leads to have an anemia
• Decreases the number of white blood cells: which favors infections cause, plasma cells make the antibodies (also called immunoglobulins) that help the body attack and kill germs. (leucopenia)
• diminishes the number of platelets: that can be evidenced with unusual bleeding (trombocitopenia)
We can also found b
It is important to note that standard cancer treatments (surgery, chemo/radiation) can always be optimized and improved and many examples exist of life enhancing advancements for almost every type of cancer.
tratamientos para el mieloma multiple WHAT IS MM? Multiple myeloma (MM) is the second most common cancer of the blood formed by malignant plasma cells. Normal plasma cells are found in the bone marrow and are an important part of the immune system. Despite recent advances, remains incurable in the vast majority of patients.
In the United States, there will be an estimated 24,050 new cases of MM in 2014 and >60,000 individuals living with the disease. Worldwide, ~86,000 patients are diagnosed each year with myeloma, while ~63,000 patients die every year from disease-related complications.
WHERE DOES EVERYTHING START? Everything start in plasma cells which are mainly found in bone marrow. Bone marrow is the soft tissue inside some hollow bones.
WHAT HAPPENS? When plasma cells become cancerous and grow out of control, they can produce a tumor called a plasmacytoma. These tumors generally develop in a bone, if someone has more than one plasmacytoma, they have multiple myeloma. (Isolated (or solitary) plasmacytoma si es uno solo).
The growth of this tumor, weakens the bones and also makes it harder the formation of healthy blood cells and platelets. According to this…
WHAT CAN WE EXPECT TO FOUND? As we know, the bone marrow produces blood cells, if a tumor in the bone occurs, we see:
• decreases the number of red blood cells: which leads to have an anemia
• Decreases the number of white blood cells: which favors infections cause, plasma cells make the antibodies (also called immunoglobulins) that help the body attack and kill germs. (leucopenia)
• diminishes the number of platelets: that can be evidenced with unusual bleeding (trombocitopenia)
We can also found b
It is important to note that standard cancer treatments (surgery, chemo/radiation) can always be optimized and improved and many examples exist of life enhancing advancements for almost every type of cancer.
Potential of Targeting Bone Metastases with Immunotherapies_Crimson PublishersCrimsonpublishersCancer
Cancer-related bone metastases are incurable and cause high mortality in patients. Immunotherapies have been evaluated in large-scale clinical trials with advanced cancer patients, but effects on bone metastases have not been specified. This mini review introduces case reports where patients with bone metastases have been treated with immunotherapies and local effects on tumor growth have been assessed. Potential skeletal-related adverse effects of immunotherapies are also discussed.
Triple-Negative Breast Cancer: 2018 Status UpdateZeena Nackerdien
Up to 20% of all invasive female breast cancer diagnoses are defined by the clinically significant absence of three hormone receptors i.e., ER, PR and HER2. This group of highly heterogeneous tumors exhibit aggressive growth patterns and are known as TNBCs. Although most TNBCs are ductal carcinomas (no special types), the identification of specific histologic/molecular subtypes potentially open up further modes of treatment for a disease that has thus far mainly been treated with cytotoxic chemotherapies. Biologic features in tumor subsets that carry such implications include BRCA pathway inhibition, increased tumor infiltrating lymphocytes (TILs), detection of other biomarkers paving the way for immunotherapies such as elevated PD-L1 expression and AR expression. Here, is some of the relevant information about TNBCs.
Disclaimer: This deck is meant to provide a springboard to interested readers who wish to look for materials to discuss with a doctor and is not a substitute for expert advice. Information was culled from the Internet and sources cited in the deck.
Potential of Targeting Bone Metastases with Immunotherapies_Crimson PublishersCrimsonpublishersCancer
Cancer-related bone metastases are incurable and cause high mortality in patients. Immunotherapies have been evaluated in large-scale clinical trials with advanced cancer patients, but effects on bone metastases have not been specified. This mini review introduces case reports where patients with bone metastases have been treated with immunotherapies and local effects on tumor growth have been assessed. Potential skeletal-related adverse effects of immunotherapies are also discussed.
Triple-Negative Breast Cancer: 2018 Status UpdateZeena Nackerdien
Up to 20% of all invasive female breast cancer diagnoses are defined by the clinically significant absence of three hormone receptors i.e., ER, PR and HER2. This group of highly heterogeneous tumors exhibit aggressive growth patterns and are known as TNBCs. Although most TNBCs are ductal carcinomas (no special types), the identification of specific histologic/molecular subtypes potentially open up further modes of treatment for a disease that has thus far mainly been treated with cytotoxic chemotherapies. Biologic features in tumor subsets that carry such implications include BRCA pathway inhibition, increased tumor infiltrating lymphocytes (TILs), detection of other biomarkers paving the way for immunotherapies such as elevated PD-L1 expression and AR expression. Here, is some of the relevant information about TNBCs.
Disclaimer: This deck is meant to provide a springboard to interested readers who wish to look for materials to discuss with a doctor and is not a substitute for expert advice. Information was culled from the Internet and sources cited in the deck.
Unfortunately several cancers are not predictable with simple tests .pdfaquastore223
Unfortunately several cancers are not predictable with simple tests rather required much
intensive diagnosis. The whole genome sequence in determining the entire DNA in normal cells
as well as in tumor cells provide the facility to compare and pin point the mutations occurring in
the oncogenes or tumor suppressor genes responsible for causing the cancer seems to be a better
approach. But such approaches are highly expensive and require expertise.
Though, the whole genome sequencing is carried out pin pointing of specific driver mutations
responsible for cancer phenotype would be a question. Some critical mutations can be identified
in some cancer genome sequences while others are hard to find among the thousands of
possibilities. The mutations like missense, nonsense frameshift, rearrangements may alter the
coding sequences of any gene must be checked. The regulatory mutations that increase the
transcription of oncogenes or decrease that of tumor suppressor genes are potentially important
but are very difficult to find in a whole genome sequence.
The catalogs of regulatory elements in human genomes provide list of certain potential
sequences to be targeted. But the catalogs are rudimentary or incomplete. Therefore, the whole
genome sequencing is not a panacea that will lead to immediate cures of all cancers. Recent
studies have shown that the whole genome sequences of cells derived from different regions of
same tumor have suggested an important reason for cancer reference. Certain cancers are
heterogenous and cells within the tumor have different genomes. Certain mutations in oncogens
or tumor suppressor genes are common to all cells in the tumor but some are not.
These findings make a sense that accumulation of mutations in clone of cells cause cancer.
Therefore, designing drug targeting specific cells protecting adult stem cells cannot be
accomplished. Thus, effective cancer treatments would be directed against the common
mutations but is difficult to identify the specific mutations without sequencing of genomes of
many cells throughout the tumor. Cancer landscape is a large scale cancer genome sequencing
project (cancer genome atlas) funded by National Institute of Health (NIH). In this project the
whole genomes or exomex of several hundreds of cancer are being characterized. The recurrent
patterns of mutations are subdivided cancers in to groups with probable clinical relevance.
For example, 4 groups of breast cancers have been identified. Almost 178 lung squamous cell
carcinoma’s genomes have been characterized and matched with DNA of normal cells from
same patients. Mutations in certain tumor suppressor genes like p53 and certain oncogenes have
shown relatively high frequencies among these cancers. The mutations of certain cancers
resemble cancers in some other organs. For example, pattern of mutation in breast cancer
resembles many ovarian cancers more than other types of breast cancers. These findings may
help in designing the drugs .
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...JohnJulie1
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...EditorSara
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...NainaAnon
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...EditorSara
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Breast cancer is the most common female malignancy and is
responsible for about 14% of cancer-related deaths in women
[1]. Triple-negative breast cancer (TNBC), characterized by the
absence of expression of Estrogen Receptor (ER), Progesterone
Receptor (PR), and human epidermal growth factor receptor 2
(HER2), is the most aggressive and deadly subtype of breast cancer
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...daranisaha
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...eshaasini
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...semualkaira
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...semualkaira
: Prolyl 4-hydroxylase, beta polypeptide (P4HB)
and Glucose‑regulated protein 78 (GRP78) represent for poor
prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...
Gluck-Clin Breast Cancer-2016
1. Review
Consequences of the Convergence of Multiple
Alternate Pathways on the Estrogen Receptor in
the Treatment of Metastatic Breast Cancer
Stefan Glück
Abstract
Endocrine therapy is the usual first-line therapy for patients with hormone receptor-positive metastatic breast cancer.
However, resistance to hormone therapies frequently occurs during the course of treatment. Growing understanding
of the signal cascade of estrogen receptors and the signaling pathways that interact with estrogen receptors has
revealed the complex role of these receptors in cell growth and proliferation, and on the mechanism in development of
resistance. These insights have led to the development of targeted therapies that may prove to be effective options for
the treatment of breast cancer and may overcome hormone therapy resistance. This article reviews current under-
standing of the cellular receptor signaling pathways that interact with estrogen receptors. It also reviews data from
recent ongoing clinical trials that examine the effects of targeted therapies, which might interfere with estrogen re-
ceptor pathways and might reduce or reverse resistance to traditional, sequential, single-agent endocrine therapy.
Clinical Breast Cancer, Vol. -, No. -, --- ª 2016 The Author. Published by Elsevier Inc. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Cyclin-dependent kinases, Endocrine therapy, Hormone receptor-positive, PI3K/Akt/mTOR pathway, Programmed
cell death inhibitor
Introduction
Breast cancer is the most common malignancy and the second
leading cause of cancer-related death among women in the United
States according to 2016 estimates.1
Approximately 6% of cases are
advanced or metastatic breast cancer (MBC) at diagnosis, and, for
those diagnosed at early stages, recurrence to distant sites occurs in
20% to 30%.2-4
Of patients with breast cancer, approximately 75%
have hormone receptor-positive (HRþ
) tumors.5
Therapies for MBC are aimed at palliation of symptoms with
improvement or conservation of quality of life and, potentially, pro-
longation of survival; unfortunately, prolonged survival is observed in
only a small percentage of patients.6,7
Both hormone receptor status
(eg, estrogen receptor [ER] and progesterone receptor [PgR]) and
human epidermal growth factor 2 (HER2) status are important pre-
dictive markers for treatment efficacy.7,8
Patients with HRþ
MBC are
candidates for initial endocrine therapy (ET).9
In premenopausal
women with MBC, various endocrine treatments are employed,
including ovarian suppression or oophorectomy, selective ER mod-
ulators such as tamoxifen, aromatase inhibitors (AIs) in conjunction
with ovarian suppression, and the selective ER downregulator, ful-
vestrant, all of which have different mechanisms of action. These
mechanisms have been reviewed extensively, demonstrating the
diversity of approaches that ultimately antagonize the growth-
promoting effects of estrogen on breast cancer cells. These mecha-
nistic differences are also linked to dissimilarities in resistance
mechanisms and thus influence treatment selection, particularly in the
context of sequencing and the use of combination regimens.10-17
In
the setting of postmenopausal HRþ
MBC, ET has a better tolerability
profile and longer time to progression (TTP) than chemotherapy.18,19
In clinical trials of AIs employed for first- or second-line treatment of
postmenopausal patients with MBC, AIs have greater efficacy than
either tamoxifen or megestrol acetate.20
Resistance to ET in HRþ
MBC is common, and given sufficient
time, most patients are faced with disease progression.21,22
The
mechanisms underlying disease progression and the development of
resistance to endocrine treatment are complex and not fully un-
derstood. Nevertheless, over the past several years, insights into
several pathways of resistance have grown and have led to increased
understanding of the clinical value of sequential lines of therapy and
co-targeting strategies. While receiving ET, up to 20% of patients
Department of Medicine, Division of Hematology Oncology, Sylvester Comprehensive
Cancer Center, Miami, FL
Submitted: Jun 17, 2016; Revised: Aug 1, 2016; Accepted: Aug 14, 2016
Address for correspondence: Stefan Glück, MD, PhD, FRCPC, Sylvester Professor of
Medicine, Department of Medicine, Division of Hematology Oncology, Sylvester
Comprehensive Cancer Center, Miami, FL 33136
E-mail contact: sgluck1@mac.com
1526-8209/ª 2016 The Author. Published by Elsevier Inc. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.clbc.2016.08.004 Clinical Breast Cancer Month 2016 - 1
2. experience a loss of ERs with concomitant loss of response to es-
trogen.23
Amplified expression of HER2 may reduce ER levels and
serve as an alternative pathway for tumor cell survival.23,24
Cellular
signaling of growth-factor receptors interacts with ER nuclear and
nonnuclear pathways and may contribute to resistance through
posttranslational modifications of ER and/or coregulators.25-27
Mutations and/or aberrant forms of ER and their coregulators
may also be a primary cause or contribute to the development of
resistance to ET.21,22,25
The aim of this review is to describe emerging information on
cellular pathways that interact with ER and impact cell proliferation
and development of resistance to ET. We will discuss the biologic
rationale for combining ET with agents that target these pathways
and review the current status of clinical trials that are investigating
the effects of combination treatments (Table 1). We also illustrate
the cellular receptors and intracellular signaling pathways that
interact with ER (Figure 1).
Estrogen-Receptor Signaling
ER functions through 2 separate but interrelated pathways: nu-
clear (genomic) and nonnuclear (nongenomic) pathways. The nu-
clear pathway mediates the effects of ER on genomic activity,
thereby altering expression of many genes involved in physiologic
cell function and in abnormal cell proliferation, resulting in
tumorigenesis.28
The ER nuclear pathway is activated by estrogen
binding, receptor dimerization and translocation to the nucleus,
interaction with coregulator proteins (both coactivators and co-
repressors), and through estrogen response elements modulation of
gene transcription.29
ER coregulators have been implicated in the
pathogenesis of breast cancer. Most notable is amplified in breast
cancer 1, which, as its name implies, is overexpressed in breast
cancers. Moreover, amplified in breast cancer 1 overexpression may
play a role in resistance to ET.30
The nonnuclear pathway of ER
function (originating in cellular cytoplasm) is mediated by estrogen-
bound ER acting outside the cell nucleus through interaction with
multiple cellular signaling pathways, tyrosine kinases, and
membrane-bound growth factor-receptor pathways, including
HER2, insulin-like growth factor-1 receptor (IGF1R), and fibro-
blast growth factor receptor (FGFR).31,32
Multiple levels of inter-
action or crosstalk between ER and growth factor and tyrosine
kinase pathways may contribute to ER actions. These interactions
include modulation of ER activity, upregulation of competing
pathways and development of resistance to ET, and alternative or
escape pathways for cellular proliferation and tumorigenesis.
Estrogen can modify the activity of growth factor pathways by
increasing levels of growth factors such as transforming growth factor-
a and IGF1R and, alternatively, by altering the expression of
epidermal growth factor receptors (EGFR).27,32,33
Conversely, acti-
vation of growth factor-receptor signaling pathways may down-
regulate expression of ER, resulting in decreased estrogen effects.34,35
This crosstalk, which can up- or downregulate competing pathways
between ER and growth factor-receptor signaling, is recognized as a
major mechanism of ET resistance, and implies that ER-positive
(ERþ
)/HER2-positive (HER2þ
) breast cancer should be treated
with a combination of ET and HER2 inhibitors or antagonists.36
In addition to ER and HER2 status, assessment of PgR status is also
typically used to characterize MBC and shape treatment decisions. In
normal breast tissue, ER and PgR appear to be expressed in different
epithelial populations and regulate distinct pathways; estrogen is
involved in extracellular signaling and progesterone is associated with
cell growth.8
This independent activity is altered in breast cancer cells
where ER and PgR expression become correlated and converge on
pathways that promote tumor growth and metastasis, and both PgR
and ER become regulated by estrogen.8
Although PgR in ERþ
patients with MBC has been used as a predictor of response to ET, it is
controversial and not as well-accepted as the role of ER.37
Data indicate that ERþ
/PgR-negative (PgRÀ
) breast tumors are
not as responsive to selective ER modulator therapy as ERþ
/PgR-
positive (PgRþ
) tumors. One proposed mechanism for this anties-
trogen resistance involves aberrant growth factor signaling (a marker
for loss of PgR), but other unknown contributory mechanisms are
also likely to play a role. Further research is needed to identify such
mechanisms and thereby refine therapeutic strategies.38
In a recent study of MBC, PgR was found to associate with ER in
the presence of agonist ligands, and the ER-PgR ligand-activated
complex acted to modify chromatin-binding events and gene tran-
scription, leading to an antitumorigenic effect.39
Stimulation with
progesterone in an estrogen-rich context induced interactions be-
tween known ER cofactors and PgR, but did not alter the association
of those cofactors with ER, yielding an ER-PgR binding complex that
promoted cell death, apoptosis, and differentiation pathways.39
This
finding, coupled with the association between PgR gene (PgR) copy
number loss and poorer clinical outcome possibly owing to a reduc-
tion in ER-PgR binding complex formation, suggests a more intricate
relationship beyond PgR as a simple marker for ER pathway function
in the MBC setting.39
Although this contrasts with hormone
replacement studies in which synthetic progesterone (medrox-
yprogesterone) was associated with an increased breast cancer risk, it
was found that natural progesterone did not have the same effect,
which suggests different mechanisms of action for synthetic ago-
nists.40,41
Interestingly, semi-synthetic progestin, megestrol acetate,
provided clinical benefit to ERþ
patients with MBC who experienced
disease progression after estrogen suppression with a nonsteroidal
AI.42
Molecular subtyping of tumors may offer additional insight into
treatment of early-stage and locally advanced breast cancer. In a study
that evaluated molecular subtype and diagnostic classification of the
154 patients classified as Luminal type B (high risk), a group that is
typically sensitive to chemotherapy, 145 were ERþ
and 99 were PgRþ
tumors.43
Among the Luminal B patients, pathologic complete
response was 85%, suggesting a possible association between ER/PgR
status and the benefit of chemotherapy.43
Clearly the complex rela-
tionship between ER and PgR depends on many factors, including
genomic alteration, interaction of cofactors at a transcriptional level,
relative levels of estrogen and progesterone in the tumor cell envi-
ronment, and possibly variations in conformational changes related to
the form of the agonist.
Growth-Factor Receptors
Growth-factor receptors, particularly receptor tyrosine kinases,
play an integral role in growth promotion, cellular proliferation, and
tumorigenesis. Growth-factor pathways may act as ER-independent
drivers of tumor growth and survival, contributing to resistance to
all types of ET. HER2, IGF1R, and FGFR have been implicated in
resistance.26,44,45
2 - Clinical Breast Cancer Month 2016
Alternate Pathways on Estrogen Receptor in Metastatic Breast Cancer
3. Table 1 Clinical Trials Investigating the Effects of Combination Treatments in Breast Cancer (Available at https://clinicaltrials.gov/)
NCT Identifier (Acronym)
Study Agents Phase Study Design Selected Clinical Outcomes
Start Date/Estimated
Completion
Growth-factor receptor TK
inhibitors
NCT00634634
Sorafenib/letrozole
I/II Open-label, single-arm
Postmenopausal, HRþ advanced/MBC
Phase I
Primary: RPTD
Phase II
Primary: CBR
Phase I/II
Secondary: TTP, OS, safety
August 2008/December 2015
NCT00752986 (ZACFAST)
Vandetanib/fulvestrant
Placebo/fulvestrant
II Randomized, double-blind
Placebo-controlled
Postmenopausal/advanced BC
Primary: Event-free survival
Secondary: TTP, PFS, OS, safety
December 2008/September 2013
NCT01528345
Dovitinib/fulvestrant
Placebo/fulvestrant
II Randomized, double-blind
Placebo-controlled
Postmenopausal/HRþ
/HER2À
advanced/MBC
Primary: PFS
Secondary: ORR, DOR, OS, safety, ECOG performance
April 2012/October 2015
NCT02053636 (FINESSE)
Lucitanib
II Open-label, single-arm
HRþ
MBC
Primary: ORR December 2013/July 2016
NCT00305825
Bevacizumab/letrozole
II Open-label, single-arm
Postmenopausal/HRþ
Unresectable advanced/MBC
Primary: Safety
Secondary: ORR, CBR
August 2004/November 2017
NCT00390455
Fulvestrant/lapatinib
Fulvestrant/placebo
III Randomized, double-blind
Placebo-controlled
Postmenopausal/HRþ
advanced/MBC
Primary: PFS
Secondary: OS, ORR, DOR, OS, safety, QOL
September 2006/July 2014
NCT01160211
AI/trastuzumab/lapatinib
AI/trastuzumab AI/lapatinib
III Randomized, open-label, multiple-arm
Postmenopausal/HRþ
/HER2þ
, advanced/MBC; prior trastuzumab and ET
Primary: OS
Secondary: PFS, ORR, CBR, OS, safety, QOL, TTP, DOR
May 2011/December 2017
PI3K/Akt/mTOR inhibitors
NCT01248494
BEZ235/letrozole
BKM120/letrozole
BKM120 (intermittent)/letrozole
Ib Open-label, multiple-arm
Postmenopausal, HRþ
MBC
Primary: MTD BEZ235 or BKM120
Secondary: PFS, ORR
November 2010/October 2013
NCT01344031
MK-2206/anastrozole
MK-2206/fulvestrant
MK-2206/anastrozole/
fulvestrant
I Open-label, multiple-arm
Postmenopausal, HRþ
advanced/MBC
Primary: MTD MK-2206, RPTD for all agents
Secondary: Safety, CBR
April 2011/October 2013
NCT01339442
BKM120/fulvestrant
I Open-label, multiple-arm
Postmenopausal, HRþ
advanced/MBC
Primary: MTD BKM120 safety
Secondary: ORR, PK
November 2011/December 2014
NCT01791478
Letrozole/BYL719
Ib Open-label, single-arm
Postmenopausal HRþ
MBC
Primary: MTD BYL719
Secondary: CBR, PFS, ORR, Safety
April 2013/March 2016
NCT01797120
Fulvestrant/everolimus
Fulvestrant/placebo
II Randomized, double-blind, placebo-controlled
Postmenopausal HRþ MBC, AI refractory
Primary: PFS
Secondary: Safety, ORR, TTP, OS
May 2013/November 2015
StefanGlück
ClinicalBreastCancerMonth2016-3
4. Table 1 Continued
NCT Identifier (Acronym)
Study Agents Phase Study Design Selected Clinical Outcomes
Start Date/Estimated
Completion
NCT02049957
Exemestane/MLN0128
Fulvestrant/MLN0128
IIb/II Open-label, multiple-arm
Postmenopausal HRþ
/HER2À
, advanced/MBC, everolimus refractory
Primary: Safety, CBR
Secondary: ORR, tumor size, PK-PD, PFS, OS
February 2014/June 2016
NCT01992952 (FAKTION)
Fulvestrant/AZD5363
Fulvestrant/placebo
Ib/II Randomized, double-blind, placebo-controlled
Postmenopausal HRþ
, advanced/MBC
Phase Ib Primary: MTD AZD5363
Phase II Primary: PFS
Phase Ib/II Secondary: Safety, ORR, OS
May 2014/August 2016
NCT01698918 (BOLERO-4)
Letrozole/everolimus (1st line)
Exemestane/everolimus (2nd line)
II Open-label, single-arm
Postmenopausal HRþ
/HER2À
, advanced/MBC
Primary: PFS after 1st line
Secondary: ORR, OS, CBR, safety, PFS after 2nd line
March 2013/October 2016
NCT01296555
GDC0032 only
Letrozole/GDC0032
Fulvestrant/GDC0032
I/II Open-label, multiple-arm
Phase I advanced/metastatic solid tumors
Phase II: Postmenopausal/HRþ
advanced/MBC
Phase I Primary: Safety
Phase II: Fulvestrant/GDC0032
Secondary: ORR, DOR, PFS
Phase II Primary: CBR, ORR
Secondary: DOR, PFS, OS
March 2011/July 2017
NCT01437566
Fulvestrant/GDC0941
Fulvestrant/GDC0980
Fulvestrant/placebo
II Randomized, double-blind, placebo-controlled
Postmenopausal HRþ
, MBC, AI refractory
Primary: PFS, safety
Secondary: ORR, CBR, DOR, PK
October 2011/November 2015
NCT02035813 (DETECT IV)
Everolimus/standard ET
II Open-label, single-arm
Postmenopausal HRþ
/HER2À
, advanced/MBC
Primary: PFS
Secondary: ORR, DCR, OS
January 2014/December 2019
NCT01610284 (BELLE-2)
Fulvestrant/BKM120
Fulvestrant/placebo
III Randomized, double-blind, placebo-controlled
Postmenopausal HRþ
, MBC, AI refractory
Primary: PFS
Secondary: OS, ORR, CBR, safety, PK
August 2012/March 2017
NCT01633060 (BELLE-3)
Fulvestrant/BKM120
Fulvestrant/placebo
III Randomized, double-blind, placebo-controlled
Postmenopausal HRþ
/HER2À
, advanced/MBC, AI treated, progressed
on/after mTOR
Primary: PFS
Secondary: OS, ORR, CBR, safety, PK
October 2012/March 2017
Src inhibitors
NCT00696072
Letrozole/dasatinib
Letrozole only
II Open-label, multiple-arm
Postmenopausal HRþ
/HER2À
, advanced/MBC
Primary: CBR
Secondary: ORR, PFS, TTF, safety
August 2008/February 2015
CDK 4/6 Inhibitors
NCT01857193
Exemestane
Everolimus/LEE011 (palbociclib)
Exemestane/everolimus
Exemestane/LEE011 (palbociclib)
Ib/II Open-label, multiple arm
Postmenopausal, HRþ
/HER2À
advanced/MBC
Phase I Primary: Safety
Phase II Primary: PFS
Phase Ib/II Secondary: Safety, PK, ORR, DOR, OS, DCR
September 2013/July 2016
NCT00721409
Letrozole/palbociclib
Letrozole only
I/II Open-label, multiple-arm
Postmenopausal HRþ
/HER2À
, advanced/MBC
Phase I Primary: Safety
Phase I Secondary: PK, QTc, antitumor activity
Phase II Primary: PFS
Phase II Secondary: Antitumor activity, OS, safety
September 2008/July 2018
AlternatePathwaysonEstrogenReceptorinMetastaticBreastCancer
4-ClinicalBreastCancerMonth2016
5. Table 1 Continued
NCT Identifier (Acronym)
Study Agents Phase Study Design Selected Clinical Outcomes
Start Date/Estimated
Completion
NCT02088684
LEE011/BKM120/
Fulvestrant LEE011/BYL719/
Fulvestrant LEE011/fulvestrant
IIb/II Open-label, multiple-arm
Postmenopausal HRþ
/HER2À
, advanced/MBC
Phase Ib Primary: Dose-limiting toxicity
Phase II Primary: PFS
Phase Ib/II Secondary: Safety, PK, ORR, DOR, PFS (Phase I
only), OS (Phase II only)
May 2014/February 2019
NCT01723774
Postmenopausal: Anastrozole/
palbociclib
Premenopausal: Goserelin/
palbociclib
II Neoadjuvant, open-label, single-arm
Pre/postmenopausal HRþ
/HER2À
, Stage 2/3 BC
Primary: Complete cell cycle arrest (Ki672.7%)
Secondary: PEPi 0 score, response- clinical, radiological,
Ki67 level, pCR rate, PK, safety
June 2013/August 2015
NCT02040857
Palbociclib/standard ET
II Open-label, single-arm
Pre/postmenopausal HRþ
/HER2À
, Stage 2/3 BC
Primary: Treatment DC rate January 2014/June 2019
NCT01942135 (PALOMA-3)
Fulvestrant/palbociclib
Fulvestrant/placebo
III Randomized, double-blind, placebo-controlled
Postmenopausal HRþ
/HER2À
, MBC, ET refractory
Primary: PFS
Secondary: OS, ORR, DOR, CBR, QOL, TTD
September 2013/January 2017
NCT01958021 (MONALEESA-2)
Letrozole/LEE011
Letrozole/placebo
III Randomized, double-blind, placebo-controlled
Postmenopausal HRþ
/HER2À
, advanced/MBC, therapy-naive
Primary: PFS
Secondary: OS, ORR, CBR, safety, QOL, QTc
December 2013/January 2017
PD-1 inhibitors
NCT02129556 (PANACEA)
MK-3475/trastuzumab
I/II Open-label, single-arm
HER2þ
, advanced/MBC, trastuzumab refractory
Primary: Dose-limiting toxicity, RPTD
Secondary: Safety, CBR, DOR, TTP, PFS, OS
July 2014/July 2023
Proteasome inhibitors
NCT01142401
Fulvestrant/bortezomib
Fulvestrant only
II Randomized, double-blind
Postmenopausal HRþ
, advanced/MBC
Primary: PFS
Secondary: CBR, OS, safety
May 2010/June 2014
Epigenetic modifiers
NCT02374099
Oral azacitidine/fulvestrant
Fulvestrant only
II Randomized, open-label
Postmenopausal ERþ
, HER2À
MBC who progressed on an AI
Primary: PFS
Secondary: ORR, CBR, OS, DOR, safety
March 2015/February 2018
NCT00676663 (ENCORE301)
Exemestane/entinostat
Exemestane only
II Randomized, double-blind
Postmenopausal ERþ
, locally recurrent or MBC who progressed on an AI
Primary: PFS
Secondary: ORR, CBR, safety
May 2008/October 2012
NCT01349959
Azacitidine/entinostat
II Randomized, open-label
TNBC or HRþ
/HER2À
, advanced/MBC
Primary: Confirmed response rate by RECIST
Secondary: CBR, OS, PFS, Safety
April 2011/March 2014
NCT01194908
Decitabine/panobinostat/tamoxifen
I/II Randomized, open-label
TNBC, MBC or locally advanced
Primary: MTD
Secondary: Safety
July 2010/January 2014
Abbreviations: AI ¼ aromatase inhibitor; BC ¼ breast cancer; CBR ¼ clinical benefit rate; DC ¼ discontinuation rate; DOR ¼ duration of response; ECOG ¼ Eastern Cooperative Oncology Group; ET ¼ endocrine therapy; HER2þ
/HER2À
¼ human epidermal growth factor
receptor-2 positive/negative; HRþ
¼ hormone receptor-positive; MBC ¼ metastatic breast cancer; MTD ¼ maximum tolerated dose; mTOR ¼ mammalian target of rapamycin inhibitor; ORR ¼ overall response rate; OS ¼ overall survival; pCR ¼ pathologic complete response;
PD ¼ pharmacodynamics; PD-1 ¼ programmed cell death protein 1; PFS ¼ progression-free survival; PK ¼ pharmacokinetics; QOL ¼ quality of life; QTc ¼ corrected QT interval; RPTD ¼ recommended phase II dose; TK ¼ tyrosine kinase; TNBC ¼ triple negative breast
cancer; TTD ¼ time to deterioration; TTF ¼ time to treatment failure; TTP ¼ time to progression.
StefanGlück
ClinicalBreastCancerMonth2016-5
6. In breast cancer, HER2, a member of the EGFR family, is an
important independent pathway for cell proliferation.46
HER2 is
constitutively in an active conformation that allows dimerization with
itself (homodimerization) or other members of the EGFR family
(heterodimerization). When HER2 is overexpressed, as it is in w15%
to 20% of all breast cancers, it mediates cell growth and survival
through activation of its downstream mediators, PI3K/Akt/mTOR
and Ras/Raf/MEK/MAP kinase.47
Overexpression of HER2
(HER2þ
) is an independent prognostic (and predictive for sensitivity
to its antagonists/inhibitors) factor indicating a more aggressive form
of cancer with a higher recurrence rate and higher mortality.46,48
Approximately 10% of patients with HRþ
MBC are also HER2þ
and, conversely, approximately 50% of HER2þ
breast cancers are also
HRþ
. Women with HRþ
and HER2þ
disease may not respond to ET
as well as women with HRþ
and HER2-negative (HER2À
) MBC.7,49
Reversing resistance to antiestrogen therapy in MBC is an important
tactic to avoid and delay the use of cytotoxic compounds. The
mammalian target of rapamycin (mTOR) has been associated with
in vitro reversal of drug resistance, including tamoxifen resistance.50
A number of compounds that interfere with HER2 are either
approvedfortherapyofHER2þ
breastcancerorareunderinvestigation
as treatments for HER2þ
MBC and HRþ
HER2þ
MBC. Trastuzu-
mab is a humanized monoclonal antibody directed against the extra-
cellular domain-2 of HER2, which prevents ligand-independent
signaling.51,52
Trastuzumab has been widely studied for treatment of
HER2þ
breast cancer and is approved by the US Food and Drug
Administration (FDA) for first-line treatment of HER2þ
MBC as well
as a component of adjuvant systemic therapy for HER2þ
breast can-
cer.53
Two large phase III trials have demonstrated the benefit of
trastuzumab treatment with ET in patients with HRþ
and HER2þ
MBC. In the Trastuzumab and Anastrozole Directed Against
ER-Positive HER2-Positive Mammary Carcinoma (TAnDEM) trial,
median progression-free survival (PFS) was significantly improved in
patients with HRþ
and HER2þ
MBC who received anastrozole and
trastuzumab (n ¼ 103) compared with anastrozole (n ¼ 104) alone
(4.8 vs. 2.4 months, respectively; P ¼ .0016).54
In the Efficacy of
letrozole in combination with trastuzumab compared to letrozole
monotherapy (eLEcTRA) trial, median time to progression was
numerically longer in HRþ
and HER2þ
MBC patients receiving
letrozoleandtrastuzumab(n¼26)versusletrozole(n¼ 31)alone(14.1
vs. 3.3 months, respectively; P ¼ .23). The failure to achieve statistical
significance was attributed to the small sample of patients evaluated.55
Another FDA-approved agent, lapatinib, is a dual EGFR/ErbB2
reversible tyrosine kinase inhibitor that competes with ATP for its
binding site on the tyrosine kinase domain. It blocks PI3K/Akt/
mTOR and Ras/Raf/MEK/MAP kinase pathways downstream of
HER2.56
Lapatinib is FDA-approved for systemic treatment of
HER2þ
advanced or MBC with systemic chemotherapy as second-
line treatment or in first-line combination with letrozole for HRþ
and HER2þ
MBC.57
In the EGF30008 trial, addition of lapatinib to
letrozole significantly reduced the risk of disease progression versus
letrozole plus placebo; median PFS was 8.2 versus 3.0 months,
respectively, (P ¼ .019) in patients with ERþ
and HER2þ
early breast
cancer. The clinical benefit rate was significantly greater for lapatinib-
letrozole versus letrozole-placebo (48% vs. 29%, respectively;
P ¼ .003).58,59
These findings led to FDA approval of first-line MBC
therapy in ERþ
and HER2þ
disease. Phase III trials of lapatinib for
postmenopausal advanced HRþ
MBC are also underway. For
example, one study is examining lapatinib plus fulvestrant compared
with lapatinib and placebo (NCT00390455). Another study is
comparing 3 arms: lapatinib plus trastuzumab plus an AI, trastuzu-
mab plus an AI, and lapatinib plus an AI (NCT01160211).
Combined targeting of HER2 with lapatinib and trastuzumab may
improve outcomes compared with single-agent targeting. Dual inhibi-
tion with these agents may also provide a regimen with greater tolera-
bility compared with alternative treatments that involve the use of
cytotoxic agents.60
A phase III trial demonstrated that lapatinib plus
trastuzumabsignificantlyimprovedPFSandoverallsurvival(OS)versus
lapatinib monotherapy in patients with HER2þ
MBC whose disease
had progressed during prior trastuzumab therapy.61
The ALTERNA-
TIVE (Safety and efficacy of lapatinib [L], trastuzumab [T], or both in
combination with an aromatase inhibitor [AI]) study is an ongoing
phase III, randomized, open-label, multicenter trial in HRþ
HERþ
MBC examining the safety and efficacy of lapatinib plus trastuzumab
plus AI versus trastuzumab plus AI.62
The rationale for this trial is to
evaluate dual anti-HER2 therapy with an AI compared with single anti-
HER2 therapy and an AI because HER2þ
MBC is associated with a
poor prognosis and increased resistance to ET in patients who are HRþ
.
Pertuzumab is a monoclonal antibody to the extracellular domain
4 of HER2 that blocks heterodimerization between HER2 and
HER3 as well as other HER family members, thereby inhibiting
signal transduction via MAPK and PI3K pathways, which can lead
to cell growth arrest and apoptosis.63
In a phase II trial, pertuzumab
plus trastuzumab showed some improvements in patients with
HER2þ
MBC with progression on trastuzumab.64
A phase III trial
of pertuzumab plus trastuzumab plus cytotoxic chemotherapy with
docetaxel as first-line treatment in HER2þ
MBC demonstrated
improved PFS compared with trastuzumab plus docetaxel alone,
and resulted in the FDA approval of this combination.65
IGF1R is a tyrosine kinase growth factor receptor that has been
shown to promote the growth of breast cancer cells.66
Similar to the
HER2/EGFR family of receptors, growth-promoting effects of
IGF1R are mediated by PI3K and Ras/Raf/Mek/MAPkinase intra-
cellular signaling. Inhibition of IGF1R function blocks the growth-
promoting effects of IGF1 on breast cancer.67,68
Early preclinical
studies were promising; however, trials with the monoclonal anti-
bodies figitumumab, AVE1642, ganitumab, and dalotuzumab tar-
geting IGF1R with ET in HRþ
MBC have not shown advantage over
ET alone.66
A potential reason for this lack of benefit may be related
to findings that breast cancer cells, which are resistant to tamoxifen,
are also refractory to IGF1R antibody treatment.69
Inhibition of
IGF1R function at different stages of HRþ
MBC or in combination
with inhibitors of other pathways may prove more effective.
GrowthfactorreceptorpathwayssuchasHER2,IGF1R,andFGFR,
which are independent of ER signaling, can subvert ET and lead to
tumor cell growth and proliferation in MBC. Combination strategies,
which include monoclonal antibodies that block growth factor re-
ceptors, coupled with tyrosine kinase inhibitors or other agents that act
to disrupt signaling of multiple downstream effector molecules may be
an effective approach to optimize treatment for the patient with MBC.
Intracellular Signaling Cascades
PI3K/Akt/mTOR Pathway. The PI3K signaling pathway plays a
vital role in cell proliferation, differentiation, and cell survival.70
The
Alternate Pathways on Estrogen Receptor in Metastatic Breast Cancer
6 - Clinical Breast Cancer Month 2016
7. cell cycle is often dysregulated in cancer cells, resulting in reduced
growth-factor dependency and increased replicative potential.
Approximately 8% of breast cancers have mutations in PI3K; gain-
of-function mutations in the PI3K alpha catalytic subunit
(PIK3CA) occur in approximately 30% of ERþ
breast cancers and
are a common genomic alteration in this subtype of breast can-
cer.71,72
PI3K is activated by growth-factor receptor tyrosine ki-
nases, HER2, EGFR, IGF1R, and FGFR, and through a series of
steps, activation of PI3K stimulates the downstream mediators Akt
and mTOR.73
The PI3K pathway interacts with ER directly and
indirectly in that PI3K and Akt can phosphorylate and thereby
activate ER in the absence of estrogen.74,75
This interaction of the
PI3K pathway with ER confers ET resistance.74,76
A phase II
clinical trial that studied the combination of ET with everolimus, an
inhibitor of mTOR, tested the rationale that inhibition of the PI3K
pathway might amplify response or reverse resistance to ET. In
patients with HRþ
breast cancer, the combination of everolimus
and letrozole resulted in increased clinical response and suppression
of tumor cell proliferation compared with letrozole and placebo.77
The Tamoxifen Plus Everolimus (TAMRAD) study in patients
with HRþ
HER2À
MBC who had progressed on an AI found that
the addition of everolimus to tamoxifen improved clinical benefit
rate, TTP, and OS compared with tamoxifen alone.78
The phase III
Combination of everolimus with trastuzumab plus paclitaxel as fi
rst-line treatment for patients with HER2-positive advanced breast
cancer (BOLERO-2) trial showed that treatment with everolimus
plus exemestane demonstrated a median TTP of 10.6 months
compared with 4.1 months with exemestane alone in post-
menopausal HRþ
MBC that recurred or progressed on previous
ET.79,80
However, in the phase III Placebo-controlled trial of
letrozole plus oral temsirolimus (HORIZON) trial, the addition of
the mTOR inhibitor temsirolimus to letrozole did not lead to
improvement in PFS in AI-naive advanced breast cancer.81
Several
differences between these trials may contribute to the varied results.
Figure 1 Cellular Signaling Pathways in Breast Cancer and Resistance to Endocrine Therapy. Estrogen Activates Cytoplasmic and
Nuclear ER. Cytoplasmic ER Binds to Growth Factor Signaling Components Such as PI3K, Activating Key Signaling Molecules
Such as Akt and RAS, and Downstream Molecules Such as mTOR, Raf, and MAPK, Which Promote Cell Proliferation and
Survival. In Addition, Many of These Signal-Transduction Molecules Can Phosphorylate and Activate ER and its Co-
Regulators to Enhance Nuclear Genomic ER-Mediated Responses. Src Can Also Interact With ER and Mediate Nongenomic
ER Activation of Signaling Pathways and Gene Transcription. Src May Be a Key Signaling Molecule in the Development of
Resistance to ET. ER Degradation by the 26S Proteasome is Depicted by the Schematic Model. Src Activation and ER
Proteolysis Support a Model Whereby Crosstalk Between Ligand-Bound ER and Src Drives ER Transcriptional Activity and
Targets ER for Ubiquitin-Dependent Proteolysis. Src Activation May Promote Not Only Proliferation, but Also Estrogen-
Activated ER Loss Through Proteolysis. Cyclin E1-CDK2 and Cyclin E2-CDK2 Are Activated During Estrogen-Mediated
Proliferation. Estrogen, via ER, Upregulates Cyclin D1. Cyclin D1 Upregulates E2F Transcription Factors, Leading to Active
Cyclin E2-CDK2 Complexes. Mitogenic Signals Converge at the Level of Cyclin D1 Upregulation and CDK4/6 Association,
Localization, and Kinase Activity
Abbreviations: AI ¼ Aromatase inhibitor; CDK ¼ Cyclin-dependent kinases; EGFR ¼ epidermal growth factor receptor; ER ¼ estrogen receptor; ERE ¼ estrogen response elements; FGFR ¼ fibroblast
growth factor receptor; HER2 ¼ human epidermal growth factor; IGF ¼ insulin-like growth factor; MAPK ¼ mitogen-activated protein kinases; mTOR ¼ mammalian target of rapamycin inhibitor; p ¼
phosphorylation sites; PI3K ¼ phosphatidylinositol 3-kinase; RTK ¼ receptor tyrosine kinase; Ub ¼ ubiquitin; TF ¼ transcription factor.
Stefan Glück
Clinical Breast Cancer Month 2016 - 7
8. First, patient populations differed, with AI-resistant patients in the
TAMRAD and BOLERO-2 trials, but AI-naive patients in the
HORIZON trial. With both mTOR inhibitors subject to meta-
bolism by the same CYP enzyme (CYP3A), population differences
in its expression might have resulted in variable metabolism across
diverse ethnic groups. Genotypic and phenotypic variation across
populations may have also accounted for variable response. Finally,
relative differences in drug effectiveness between everolimus and
temsirolimus cannot be ruled out.82
Ongoing studies of fulvestrant
with everolimus and standard ET with everolimus will provide
additional perspective on the potential combined benefit of mTOR
and ER inhibition (NCT01797120, NCT02035813).
Inhibitors of PI3K in preclinical and clinical trials for breast
cancer include BKM120, LY294002, GDC0941, BYL719, and
GDC0032.83
Additionally, combination PI3K/mTOR inhibitors,
GDC0980 and BEZ235, are also being studied. In preclinical
studies, GDC0980, GDC0032, and GDC0941, given in combi-
nation, enhanced activity of fulvestrant in MCF-7 xenografts,
resulting in tumor regression and tumor growth delay.84
A com-
bination of tamoxifen, everolimus, and LY294002 produced
increased antitumor effects compared with tamoxifen alone or
tamoxifen and everolimus in a breast cancer cell line.85
In addition,
treating breast cancer cells with BEZ235 induced apoptosis when
combined with estrogen deprivation, suggesting potential activity in
HRþ
breast cancer.86
In an initial phase I/II study, patients with
trastuzumab-resistant locally advanced or metastatic HER2þ
breast
cancer were treated with BKM120 (buparlisib) and trastuzumab.
Two patients (17%) had partial responses, and 7 (58%) had stable
disease (! 6 weeks) with a disease-control rate of 75%.87
Buparlisib
in combination with letrozole has also been used to treat ERþ
HER2À
MBC, and provided clinical benefit in both patients with
PI3K-wild type and mutant tumors, but patients with coexisting
PI3K and MAP3K mutations derived the greatest clinical benefit
from this regimen.88
The Akt inhibitor MK2206 is also being
studied in breast cancer. In MCF-7 cells, overexpression of consti-
tutively active Akt1 induced resistance to anastrozole; addition of
the Akt inhibitor MK2206 restored sensitivity to this AI.89
Taken together, the preclinical and clinical data suggest that ER
and PI3K pathways counter-regulate each other with low PI3K
activation resulting in high ER levels, and hyperactivation of
PI3K causing a reduction in ER levels.90
Further validation of this
notion comes from studies showing that inhibition of HER2 with the
antibody trastuzumab or the tyrosine kinase inhibitor lapatinib
restores or upregulates ER levels or transcriptional activity in breast
cancer cells and patient tumors.91,92
Also, AIs or fulvestrant inhibit
the growth of HER2þ
tumors that have progressed on trastuzumab or
lapatinib.92
Numerous ongoing phase I to III studies are examining
the effects of AIs or fulvestrant in combination with PI3K and
Akt inhibitors (NCT01610284, NCT01633060, NCT01791478,
NCT02088684, NCT01248494, NCT01339442, NCT01437566,
NCT01296555, and NCT01344031).
Src kinases, intracellular tyrosine kinases that contribute to
control of cell proliferation, have been implicated in oncogenic
activity in breast cancer, particularly HRþ
breast cancer.93
Dasatinib
is a small-molecule inhibitor of several Src family kinases approved
for use in chronic myelogenous leukemia.94
A recent phase II trial of
dasatinib in women with MBC showed modest activity with disease
control rates (ie, complete response, partial response, or stable dis-
ease for at least 16 weeks) for 8.3% of patients with HER2þ
MBC
and 15.6% of those with HRþ
MBC.95
Early results of a trial of
dasatinib in combination with fulvestrant as second-line treatment
of HRþ
MBC in postmenopausal women did not find improved
efficacy with the addition of dasatinib.96
With the variety of agents available that target the PI3K/Akt/
mTOR pathway, the challenge remains to identify which subset of
targets, and therefore, which combination of agents may be the
most impactful to maximize clinical benefit and adapt to ET
resistance in individual patients.
Cell Cycle Control and Proliferation
Cellular pathways involved in cell proliferation are targets for new
drugs that interfere with development of resistance to ET and that
treat HRþ
MBC. Cyclin-dependent kinases (CDKs) are a subgroup
of serine/threonine kinases that play a key role in regulating cell
cycle progression.97
The cell cycle G1 to S-phase transit is
controlled by CDK4 and CDK6, which are activated upon binding
to D-type cyclins leading to expression of genes required for S-phase
entry.98
Several studies have identified alterations of cell cycle reg-
ulators in human breast cancer and provide a rationale for the po-
tential therapeutic role for CDK4/6 inhibition in breast tumors.
Cyclin D1 is a direct transcriptional target of ER.99,100
Treatment
with antiestrogens induces growth arrest of HRþ
breast cancer cells
and decreases cyclin D1 expression.101
Conversely, microinjection
of antibodies into cyclin D1 inhibits estrogen-induced S-phase en-
try.102,103
Endocrine resistance is associated with persistent cyclin
D1 expression and Rb phosphorylation.104
Compared with other
subtypes of breast cancer, HRþ
breast cancer is commonly associ-
ated with hyperactivation of cyclin D1-CDK4/6.105
CDK4/6 inhibitors, including palbociclib, abemaciclib, and ribo-
ciclib, are being investigated in both the preclinical and clinical settings;
some are becoming available for treatment of HRþ
MBC. In 2015,
palbociclib, a highly selective inhibitor of CDK4/6 kinase, was
approved by the FDA in combination with letrozole for the treatment
of postmenopausal women with ERþ
HER2À
advanced breast cancer
as initial endocrine-based therapy for their metastatic disease.106,107
Approval for this indication was accelerated based on PFS data.
Continued approval for this indication may be contingent upon veri-
fication and description of clinical benefit in a confirmatory trial. In
preclinical studies, palbociclib inhibited growth of HRþ
cancer cells,
including those that are resistant to antiestrogen.105
Additionally, a
synergistic antitumor effect was observed when palbociclib was com-
bined with tamoxifen in both tamoxifen-sensitive and tamoxifen-
resistant cell lines. Palbociclib in combination with letrozole versus
letrozole alone (PALOMA-1), a randomized phase II study of the AI
letrozole with or without palbociclib as first-line therapy for ERþ
,
HER2À
MBC(n¼ 165),reportedastrikingimprovementinPFSfrom
7.5 to 26.2 months (hazard ratio [HR], 0.32; 95% confidence interval
[CI], 0.19-0.56; P .001) without additional safety concerns.108
In
the final results analysis, the median PFS was 20.2 months with
letrozole plus palbociclib compared with 10.2 months for letrozole
alone (HR, 0.488; 95% CI, 0.319-0.748; 1-sided P ¼ .0004), and the
combination demonstrated significant clinical benefit as first-line
treatment in this patient population.109
Several phase I, II, and III
studies of palbociclib in combination with fulvestrant and AIs (eg,
Alternate Pathways on Estrogen Receptor in Metastatic Breast Cancer
8 - Clinical Breast Cancer Month 2016
9. PALOMA-2 and PALOMA-3) in HRþ
MBC are currently underway
or have recently concluded.110,111
Most recently, treatment with the
combination of palbociclib and fulvestrant in patients with advanced
HRþ
HER2À
breast cancer who had relapsed or progressed during
prior endocrine therapy, received FDA approval based on the findings
of the phase III study, PALOMA-3.110
The study demonstrated that
the combination of palbociclib and fulvestrant resulted in significantly
longer median PFS (9.5months [95%CI, 9.2-11.0 months] compared
with 4.6 months [95% CI, 3.5-5.6 months]) for fulvestrant alone (HR,
0.46; 95% CI, 0.36-0.59; P .001).110
Other CDK inhibitors are in various stages of clinical develop-
ment (NCT00721409, NCT01723774, NCT01942135,
NCT02040857). Additionally, another CDK inhibitor, LEE001,
ribociclib, is being used in addition to everolimus and exemestane in
patients with advanced HRþ
, HER2À
breast cancer who have
anastrozole- or letrozole-resistant disease (NCT01857193). Interim
results from the phase Ib/II study showed a 70.9% disease control
rate.112
This agent is also being examined in combination with
fulvestrant and PI3K inhibitors (NCT02088684).
The CDK pathway regulates the cell cycle, with CDK4 and 6
directly controlling the gap phase 1 of mitosis (G1). Dysregulation of
these components may occur through multiple mechanisms
contributing to tumor growth and metastatic potential, and is a
common feature in many cancers, including breast cancer. Therefore,
therapeutic inhibition of CDK is a relevant treatment strategy, and a
number of agents are currently under investigation in clinical tri-
als.98,105
Ongoing clinical trials that combine CDK inhibitors with
inhibitors of other dysregulated pathways commonly found in breast
cancer may improve outcomes and act to overcome ET resistance.
Immune Response Modulation
Antitumor immunity in human cancer is often ineffective owing
to the tight regulation associated with the maintenance of immune
homeostasis. Previous attempts to develop effective immunother-
apies for cancer have been unsuccessful because there are significant
barriers that have been difficult to overcome. However, blockade of
the programmed death receptor (PD-1), which may play a role in
the tumor’s ability to bypass immune modulation and is overex-
pressed in certain tumors such as melanoma, has been proven
effective for treatment.113-115
Additionally, a monoclonal antibody
targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), an immune
checkpoint molecule that downregulates pathways of T-cell activa-
tion, has also been proven effective for treatment of melanoma.116
The place of PD-1 and CTLA-4 inhibition in the treatment of
HRþ
MBC is not as clearly defined.
The extent of mutations and aberrant protein expression associ-
ated with cancer cells may also dictate the potential for efficacy of
immunotherapy.117
Foreign antigens expressed on the surface of
pathogens trigger the body’s immune system to target and eliminate
these invaders. However, tumor cells are often undetected by im-
mune surveillance owing to identification of tumor cells as “self.”
Although tumor cells may over express tumor-associated antigens,
these same antigens are expressed at low levels on normal cells,
leading to immune tolerance. In contrast, neoantigens that arise due
to mutations in a tumor cell, which are not expressed on any other
normal cells, represent prime targets for Tecell-mediated elimina-
tion with no risk to normal tissues.117
This has led to the hypothesis
that tumors with high mutation rates have increased neoepitopes,
and use of checkpoint blockade therapies (PD-1, PD-L1, and
CTLA-4) can reactivate tumor-infiltrating T cells in these cases,
leading to tumor regression.117
The heterogeneous nature of breast cancer has led to studies that
seek to identify biomarkers associated with drug response. Triple-
negative breast cancer (TNBC) lacks the molecular targets for
many treatment options and is associated with high genetic alter-
ation rates. In particular, one study of 2111 patients with TNBC
(ERÀ
/PgRÀ
/HER2À
) found that 91% of patients showed dimin-
ished androgen receptor expression and/or mutations in PI3KCA/
PTEN/AKT1, or loss of PTEN.118
In addition, expression of PD-L1
is more prevalent in TNBC, and this coupled with increased PD-
L1-mediated T-cell reactivation suggests that PD-L1 inhibitors may
be effective in this patient population.117,119
In fact, a preliminary
study that targeted PD-L1 showed promising objective clinical ac-
tivity in TNBC patients (NCT01375842).119
Estrogen-Receptor Degradation and Proteasome
Inhibitors (PIs)
Proteasomes are multicatalytic protease complexes in the cell,
involved in the non-lysosomal recycling of intracellular proteins. Pro-
teasomes play a critical role in regulation of cell division in both normal
and cancer cells.120-123
In cancer cells, this homeostatic function is
deregulated, leading to the hyperactivation of the proteasomes. PIs
interfere with the ubiquitin proteasome pathway and lead to the
accumulation of proteins engaged in cell cycle progression. They ulti-
mately put a halt to cancer cell division and induce apoptosis. Cell cycle
proteins are regulatory proteins whose temporal activity is tightly
controlled and are thus important targets of proteasome degradation.
Major proteins related to the cell cycle process are cyclins, CDKs, CDK
inhibitors (CKIs), and some transcription factors. Cyclin proteins are
found to be highly upregulated in cases of aberrant cell division in
cancer cells,particularly cyclins D and E.124,125
The precise mechanism
ofactionofPIs incancertreatment isnot well-understood.Intreatment
of breast cancer, 2 potential mechanisms have been described: the PI,
bortezomib, may inhibit cell proliferation and may decrease levels of
ER.126,127
Results from early preclinical and clinical trials have been
mixed, with 1 small study showing no effect of treatment with borte-
zomib and another showing enhanced MCF-7 tumor suppression with
bortezomib and trastuzumab.128
Data in MCF-7 breast cancer cells
suggest that fulvestrant’s antiestrogenic effects of induction of protea-
somal degradation of ER may involve c-SRC, a cellular kinase proto-
oncogene. In light of this potential interaction, a phase II study of
fulvestrant and bortezomib in women with locally advanced or MBC is
underway (NCT01142401).
Epigenetic Modifiers
In addition to genetic alterations such as the mutations and de-
letions that alter the composition of genomic DNA, epigenetic
changes including DNA methylation, histone modifications, and
chromatin remodeling can reversibly alter gene expression and play
a key role in tumorigenicity and metastatic potential of breast cancer
cells.129
Therapeutic interventions that target epigenetic modifica-
tions have been used to partially or completely revert the altered
gene expression, and several epigenetic agents that are approved for
use in other settings have potential as breast cancer therapies.
Stefan Glück
Clinical Breast Cancer Month 2016 - 9
10. Several clinical trials of these epigenetic agents are planned or
underway in the breast cancer setting. Azacitidine and decitabine are
hypomethylating agents that inhibit DNA methyltransferase,
thereby halting tumor cell growth and division through epigenetic
manipulation.130,131
Both agents have been approved for use in
myelodysplastic syndrome and are currently being investigated for
breast cancer treatment.130,131
In combination with fulvestrant,
azacitidine is being evaluated in a phase II trial in patients with
ERþ
, HER2À
MBC who have progressed on an AI
(NCT02374099). In addition, a class I HDAC inhibitor, entino-
stat, was assessed in a phase II trial (NCT00676663) with or
without the AI exemestane in patients with ERþ
breast cancer who
have progressed on an AI, and the combination was found to not
only improve PFS and OS, but restore sensitivity to hormone
therapy.132
Entinostat is currently being studied in combination
with azacitidine in a phase II trial of patients with either TNBC or
HRþ
HER2À
breast cancer (NCT01349959). Decitabine in
combination with the HDAC inhibitor panobinostat (LBH589)
was also being investigated in TNBC in an attempt to re-express
ER; however, the study was closed due to slow accrual
(NCT01194908).
Conclusions
ER-targeted therapy is important for many women with breast
cancer, but resistance to therapy inevitably occurs. The ER
signaling pathway is a complex network of extensive crosstalk with
growth-factor signaling pathways, cell cycle control pathways, and
protein degradation pathways. These pathways provide many
alternative targets for agents that may be useful in combination
with ET to decrease resistance to treatment and to extend benefit
to patients who do not achieve optimal benefit from ET alone. As
effective treatments are identified, an important area of focus must
be on the factors that determine optimal combination treatments
in subtypes of breast cancer. Such factors comprise not only the
responsiveness of the cells of a particular subgroup of tumors, but
also the characteristics of different treatment combinations with
respect to the temporal profile of effects, relative tolerability of
different combinations, and the compatibility of routes of
administration. Several therapies that are discussed in this review,
among them everolimus (mTOR inhibitor), palbociclib (CDK4/6
inhibitor), and MK-3475 (PD-1 inhibitor), are already proving to
be effective treatments for MBC and useful in reversing or pre-
venting the development of resistance to ET. Through inhibition
of central components of pathways for growth factor-promoted
cellular proliferation, cell cycle-mediated cellular proliferation,
and immunosuppressive programs that initiate and sustain tumor
growth, these agents are effective options that may extend survival
and maintain quality of life for women with MBC who have
relapsed on endocrine therapies.
Acknowledgments
Medical writing and editorial services were provided by SCI
Scientific Communications Information, Parsippany, NJ, and
The Lockwood Group, Stamford, CT (funded by AstraZeneca LP).
Disclosure
This article was supported by AstraZeneca LP. Dr Glück has
received grant support and consulting fees from Agendia, Celgene,
Dara, Eisai, Genentech/Roche, GHI, Mylan, and Onyx/Amgen. At
the time of the initiation of manuscript development, Dr Glück was
the Sylvester Professor of Medicine, Department of Medicine, Di-
vision of Hematology Oncology, Sylvester Comprehensive Cancer
Center, Miami, FL. Dr Glück is a current employee and shareholder
of Celgene Corporation, Summit, NJ.
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Alternate Pathways on Estrogen Receptor in Metastatic Breast Cancer
12 - Clinical Breast Cancer Month 2016
![Review
Consequences of the Convergence of Multiple
Alternate Pathways on the Estrogen Receptor in
the Treatment of Metastatic Breast Cancer
Stefan Glück
Abstract
Endocrine therapy is the usual first-line therapy for patients with hormone receptor-positive metastatic breast cancer.
However, resistance to hormone therapies frequently occurs during the course of treatment. Growing understanding
of the signal cascade of estrogen receptors and the signaling pathways that interact with estrogen receptors has
revealed the complex role of these receptors in cell growth and proliferation, and on the mechanism in development of
resistance. These insights have led to the development of targeted therapies that may prove to be effective options for
the treatment of breast cancer and may overcome hormone therapy resistance. This article reviews current under-
standing of the cellular receptor signaling pathways that interact with estrogen receptors. It also reviews data from
recent ongoing clinical trials that examine the effects of targeted therapies, which might interfere with estrogen re-
ceptor pathways and might reduce or reverse resistance to traditional, sequential, single-agent endocrine therapy.
Clinical Breast Cancer, Vol. -, No. -, --- ª 2016 The Author. Published by Elsevier Inc. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Cyclin-dependent kinases, Endocrine therapy, Hormone receptor-positive, PI3K/Akt/mTOR pathway, Programmed
cell death inhibitor
Introduction
Breast cancer is the most common malignancy and the second
leading cause of cancer-related death among women in the United
States according to 2016 estimates.1
Approximately 6% of cases are
advanced or metastatic breast cancer (MBC) at diagnosis, and, for
those diagnosed at early stages, recurrence to distant sites occurs in
20% to 30%.2-4
Of patients with breast cancer, approximately 75%
have hormone receptor-positive (HRþ
) tumors.5
Therapies for MBC are aimed at palliation of symptoms with
improvement or conservation of quality of life and, potentially, pro-
longation of survival; unfortunately, prolonged survival is observed in
only a small percentage of patients.6,7
Both hormone receptor status
(eg, estrogen receptor [ER] and progesterone receptor [PgR]) and
human epidermal growth factor 2 (HER2) status are important pre-
dictive markers for treatment efficacy.7,8
Patients with HRþ
MBC are
candidates for initial endocrine therapy (ET).9
In premenopausal
women with MBC, various endocrine treatments are employed,
including ovarian suppression or oophorectomy, selective ER mod-
ulators such as tamoxifen, aromatase inhibitors (AIs) in conjunction
with ovarian suppression, and the selective ER downregulator, ful-
vestrant, all of which have different mechanisms of action. These
mechanisms have been reviewed extensively, demonstrating the
diversity of approaches that ultimately antagonize the growth-
promoting effects of estrogen on breast cancer cells. These mecha-
nistic differences are also linked to dissimilarities in resistance
mechanisms and thus influence treatment selection, particularly in the
context of sequencing and the use of combination regimens.10-17
In
the setting of postmenopausal HRþ
MBC, ET has a better tolerability
profile and longer time to progression (TTP) than chemotherapy.18,19
In clinical trials of AIs employed for first- or second-line treatment of
postmenopausal patients with MBC, AIs have greater efficacy than
either tamoxifen or megestrol acetate.20
Resistance to ET in HRþ
MBC is common, and given sufficient
time, most patients are faced with disease progression.21,22
The
mechanisms underlying disease progression and the development of
resistance to endocrine treatment are complex and not fully un-
derstood. Nevertheless, over the past several years, insights into
several pathways of resistance have grown and have led to increased
understanding of the clinical value of sequential lines of therapy and
co-targeting strategies. While receiving ET, up to 20% of patients
Department of Medicine, Division of Hematology Oncology, Sylvester Comprehensive
Cancer Center, Miami, FL
Submitted: Jun 17, 2016; Revised: Aug 1, 2016; Accepted: Aug 14, 2016
Address for correspondence: Stefan Glück, MD, PhD, FRCPC, Sylvester Professor of
Medicine, Department of Medicine, Division of Hematology Oncology, Sylvester
Comprehensive Cancer Center, Miami, FL 33136
E-mail contact: sgluck1@mac.com
1526-8209/ª 2016 The Author. Published by Elsevier Inc. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.clbc.2016.08.004 Clinical Breast Cancer Month 2016 - 1](https://image.slidesharecdn.com/357d126c-e71f-4b6b-b18c-23b6b1df0b58-161108164247/85/Gluck-Clin-Breast-Cancer-2016-1-320.jpg)
