Pharma Disease Insight: Oncology Breast Cancer

DISEASE INSIGHT
BREAST CANCER
BIG PHARMA

4|
Key Findings
Currently approved therapies will continue
to have a meaningful impact on the breast
cancer treatment algorithm and market
sales. Pfizer’s CDK4/6 inhibitor Ibrance will
experience increasing use in the HR-
positive, HER2-negative population,
fueling this agent’s sales to exceed $8.5
billion at its peak.
Roche/Genentech/Chugai’s HER2-
targeted MAb, Perjeta, will continue to
gain traction in the market, with its
forecast adjuvant approval bolstering
sales to exceed $5 billion in 2025.
Despite the patent expiry of several of the
top-selling agents in the breast cancer
market during the forecast period
(Roche/Genentech/Chugai’s Herceptin,
Pfizer’s Ibrance, Novartis’s Afinitor,
AstraZeneca’s Faslodex), the
corresponding sales decline from these
agents will be more than offset by uptake
of novel premium-priced therapies. An
active and diverse late-phase pipeline
means that we anticipate the launch of 16
novel therapies for breast cancer from
eight drug classes over the forecast
period.
The breast cancer therapy market was the
largest in oncology across the major
markets (United States, France, Germany,
Italy, Spain, United Kingdom, and Japan)
in 2015 with sales of $13.8 billion. Sales
are set to soar throughout our forecast
period to $30.5 billion by 2025, driven by
uptake of both current and emerging
agents in multiple treatment settings. Two
drug classes, HER2-targeted agents and
CDK4/6 inhibitors, will account for over
60% of sales in this market in 2025.
This document is a partial preview. Full document download can be found on Flevy:
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INTRODUCTIONANDFORECAST
Breast
Cancer
Introduction
Etiology and
Pathophysiology
Key Pathways and Drug
Targets
MarketOutlook
ETIOLOGY AND
PATHOPHYSIOLOGY 02

10|
We’vegotabiomarkerintheestrogenreceptor,andwe’vegot
HER2,butotherbiomarkershavebeenelusive.FormTOR
inhibitorsforexample,itdoesn’tseemtomatteraboutthelevelof
mTORinthetumor,oranythingelseinthatpathway–Ithinkthe
biologyismorecomplexcomparedtotheHER2pathway.We’re
testingimmunecheckpointsinalltriple-negativepatientsbecause
wedon’tknowifPD-L1istherightbiomarkerfortheseagents–the
problemcouldevenbethatourtestingisn’tsensitiveenough.
Oncologist
“
”
Expert Insight

13|
Disease
Pathophysiology
In breast cancer, the most commonly used staging system is the TNM system. The TNM stage of a
tumor is based on the size of the primary tumor, the extent of lymph node involvement and the
incidence of distant metastases. This has implications for the patient’s prognosis and the selection
of appropriate treatment.
A tumor’s histological grade helps determine the aggressiveness of the tumor and consequent
prognosis and treatment. Three features of the tumor are assessed when assigning a cancer’s
grade: the frequency of cell mitosis, tubule formation, and nuclear pleomorphism. Each of these
features is assigned a score ranging from 1 to 3 (1 indicating slower cell growth and 3 indicating
faster cell growth). The scores of each of the cell’s features are then added together for a final sum
(ranging from 3 to 9). A tumor with a final score of 3, 4, or 5 is considered a grade 1 tumor (well
differentiated). A score of 6 or 7 is considered a grade 2 tumor (moderately differentiated), and a
score of 8 or 9 is a grade 3 tumor (poorly differentiated). Higher-grade tumors are associated with
poorer survival rates; more specifically, five-year survival for grade 3 tumors is at 50% compared
with 75% for grade 2 tumors and 95% for grade 1 tumors.
Staging of Breast Cancer

16|
Disease
Pathophysiology
MammaPrint is a 70-gene microarray
performed on fresh tissue that is
surgically resected from breast cancer
patients aged 61 or younger.
MammaPrint is validated for patients
with node-positive or node-negative
disease with a tumor < 5 cm in diameter.
It is useful only for prognostic purposes
by informing the clinician of the patient’s
gene profile or signature. In its validation
study (NSABP Study B-20), patients with
a good gene signature had a > 90%
survival rate at 12 years, as opposed to
patients with a poor signature (either
node-negative or node-positive), who
had a survival rate of approximately 50%
at 12 years (van de Vijver M, 2002).
MammaPrint
The Quest H:I Ratio Test measures the ratio of HOXB13 and
IL17BR from surgically resected breast tissue. This gene
expression test is used to predict breast cancer recurrence in
treatment-naive estrogen receptor-positive patients (lymph-
node-negative). The H:I ratio is a continuous marker of
recurrence in untreated estrogen receptor-positive, node-
negative patients and is reported as chance of breast cancer
recurrence at five years. A study published in 2006 in Clinical
Cancer Research (Goetz MP, 2006) found that a high H:I
expression ratio is associated with an increased rate of
relapse and mortality in estrogen receptor-positive, lymph
node-negative cancer in patients treated with surgery and
tamoxifen. This result supported a retrospective study in an
852-patient cohort that found that the H:I expression ratio
independently predicted breast cancer recurrence in patients
with estrogen receptor-positive, lymph-node negative
cancer who received tamoxifen therapy as well as in those
who did not (Ma X, 2006).
The Quest H:I RatioTest

19|
Key Pathways and
Drug Targets
DrugTarget Description
PI3K/AKT/mTOR Activation of the PI3K/AKT/mTOR signaling pathwaypromotes cell growth and cell survival. Mechanisms for pathway activation include loss of tumor suppressor PTEN function and
amplification or mutation of PI3K. The PI3K pathwayis the most frequently altered pathwayin cancer,and its activation has been shown to confer resistance to endocrine and HER2-
targeted therapies. Therefore, inhibition of this pathway is an attractive target in breast cancer.
PARP PARPs are a family of nuclear enzymes involved in DNA-damage repair. Activation of PARP-1 is one of the earliest responses to DNA damage, promoting DNA repair. WhenPARP is
inhibited, double strand DNA breaks occurs,whichcan be repaired through homologous recombination, a process mediated through BRCA1 and BRCA2 protein signaling. Therefore, in
BRCA-mutatedbreast cancer,homologous recombination is impaired. Inhibition of PARP in BRCA-mutatedcells is thought to result in “synthetic lethality” and therefore cancer cell death
HER2 HER2 is a transmembrane glycoprotein with intrinsic tyrosine kinase activity. Normally present as inactive monomers on the cell surface membrane,HER2 molecules form homodimers
(pairs of HER2 receptors) or heterodimers with other HER receptors (HER1, for example). This interaction stimulates phosphorylation of the intracellular portion of HER2,strongly
activating multiple intracellular signal-transduction pathways,including the Ras/MAP kinase pathway,and promoting cell proliferation. In healthy cells,binding of the ligand to the
extracellular portion of HER2 is necessary to stabilize the receptor dimers and maximally stimulate signal transduction. In breast cancer,almost 25%of patients overexpress HER2,
causedby the presence of multiple copies of the HER2 gene in 95% of cases.This document is a partial preview. Full document download can be found on Flevy:

INTRODUCTIONANDFORECAST
Breast
Cancer
Introduction
Etiology and
Pathophysiology
Key Pathways and Drug
Targets
MarketOutlook
MARKET OUTLOOK
04

25|
Inthelastyear therehavebeenmoreandmoretreatmentoptions
forpatientswithbreastcancer.Inearly-stagediseaseweuse
neoadjuvanttherapymoreoften.Inthemetastaticsetting,wehave
moredrugoptionstouseandsoweneedtosequencethemto
achievebetterdiseasecontrol— wehavemoreagentsnowforthe
treatmentofHR-positivedisease.
Oncologist
“
”
Expert Insight

28|
What FactorsAre Driving the Market
for Breast Cancer?
Approval and uptake of entinostat, a HDAC inhibitor. Entry of a novel class into the breast cancer
treatment armamentarium—immune checkpoint
inhibitors.
SyndaxPharmaceutical’s entinostat is set to be the first HDAC inhibitor
approvedin breast cancer,and will see uptake in recurrent metastatic
HR-positive/HER2-negative breast cancer. Entinostat’s use will likely be
pushedinto the third- and later-lines by competition from CDK4/6
inhibitors and PI3K inhibitors; however,in these later lines it will capture
a large market share,fueling its sales to approximately $1.2 billion
across the major markets in 2025.
The launch of Merck & Co.’s pembrolizumab and
Roche/Genentech/Chugai’s atezolizumabfor first-line triple-negative
breast cancer will boost the market from the mid point of our forecast.
These agents have seen unprecedentedsuccess in multiple other tumor
types;however,strong competition in the treatment for triple-negative
breast cancer from emerging biomarker-associatedtherapies will limit
their impact in breast cancer, and by 2025we anticipate class sales to
reach $850 million.

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