Download Highlights from the San Antonio Breast Cancer Symposium

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Volume 3, Number 3, 03.09
Reports and Insight for Community-Based Oncologists
Highlights from the San Antonio
Breast Cancer Symposium
CellSearch Test
Predicts Outcomes
Better than Levels
of PSA
I
Gonzalez-Angulo: Photo Courtesy © SABCS/Todd Buchanan 2008; CTC: Courtetsy Veridex LLC.
Ana M. Gonzalez-Angulo, MD, speaking at this year's SABCS. Page 18
n a February article in Lancet Oncology, researchers from Sloan
Kettering Cancer Center in New
York said that CellSearch, a device
that measures circulating tumor cells
(CTCs), is an effective way to track
the response of castration-resistant
prostate tumors to chemotherapy.
CellSearch is manufactured by Veridex LLC, a Johnson & Johnson subsidiary, and it recently headed the
Cleveland Clinic’s list of top medical innovations for 2009 (Oncology
& Biotech News, Jan., p. 31). In
2008, the FDA expanded approval of
CellSearch to include monitoring of
patients with metastatic prostate
cancer, adding to its earlier approvals
for patients with metastatic breast or
colorectal cancers.
(Continued on page 16)
With a Special Report on Aromatase Inhibitors
T
he 31st Annual CTRC-AACR San
Antonio Breast Cancer Symposium
(SABCS) took place December 1014, 2008, in Texas. Research teams from
around the globe presented more than
6000 abstracts and posters. Attendees
received updated data from several major studies, including the BIG (Breast
International Group) 1-98, NOAH (Neoadjuvant Herceptin), ZO-FAST (ZometaFemara Adjuvant Synergy Trial), and
TEAM (Tamoxifen Exemestane Adjuvant
Multicenter) trials. The symposium
featured important research on novel
and existing breast cancer treatments,
innovative diagnostic techniques, and
newly discovered biomarkers. The following summary highlights some of the
more significant research presented at
the conference. Additional coverage
can be found on pages 8-15 and in our
regular departments.
Women with Dense Breast Tissue
Face Higher Cancer Risks
Dense breast tissue as measured by
mammography is the primary risk
factor for breast cancer development,
next to age. Nearly 10% of women have
dense breasts, and studies suggest
that women with highly dense breasts
(≥60%-75% dense tissue) are 6 times
more likely to develop breast cancer
than women whose breasts consist
— by Christin Melton
primarily of fatty tissue. Researchers
continue to investigate the association
between breast density and cancer and
look for ways of mitigating cancer risk
in these women.
Study analyzes breast tissue composition
A group of Mayo Clinic researchers evaluated samples of breast tissue from 60
volunteers, aged 40-85 years. Inclusion
criteria included no symptoms of breast
cancer, a normal mammogram within 6
months of study onset, and no personal
history of breast cancer. Women receiving endocrine therapy or those who had
breast-related symptoms or bleeding
tendencies were excluded.
Investigators used ultrasonographyguided core-needle biopsy to obtain tissue samples from dense and non-dense
areas of the breast from each participant.
Next, they determined the percentage of
epithelium tissue, stroma (connective
tissue), and fat content in each sample.
The authors said their study was the
first to analyze both types of tissue taken from the same breast. Karthik Ghosh,
MD, breast cancer researcher and physician with the Mayo Clinic, led the research team. Dr. Ghosh said they “found
Inside:
8 S ABCS Special Report:
Aromatase Inhibitors
16 In the News
18 Clinical Trial Reports
20 R eimbursement and
a dramatic difference in tissue composition between dense and non-dense tissue in the breast.”
Consistent with earlier studies, preliminary results from 34 patients showed
that dense tissue contained much higher concentrations of epithelium and
stroma but less fat than tissue samples
from less-dense areas of the breast.
“This shows us that both the epithelium and stroma contribute to density
and suggests that the large difference
in stroma content in dense breast tissue may play a significant role in breast
cancer risk,” Dr. Ghosh explained.
Area
Sampled
Epithelium, Stroma,
%
%
Fat,
%
Dense
6
64
30
Non-dense
1
20
80
Researchers also noted more lobular
involution in non-dense tissue. Lobular involution refers to a decrease in
the size and number of milk ducts.
This lobular regression typically accelerates with age and is associated
with a reduced risk of breast cancer.
(Continued on page 12)
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Cancer
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Oncology & Biotech News
|
03.09
INTHENEWS
Zoledronic Acid Improves Response in Breast Tumors
juvant therapy with zoledronic acid plus stanZoledronic acid (Zometa) and other bisphosdard chemotherapy shrinks malignant tumors.
phonates are generally used in cancer therapy
This could help some women avoid mastectomy
to mitigate the likelihood of bone problems,
and opt for less radical surgical procedures.
such as loss of bone mineral density and fracThe multinational trial enrolled 3360 pre- and
tures. Two recent studies have determined
postmenopausal women from 7 countries with
that adding zoledronic acid to some existing
early stage breast cancer. The retrospective analbreast cancer regimens may improve diseaseysis looked at a subset of 205 patients who refree survival.
ceived standard chemotherapy alone (n = 104) or
The Austrian Breast and Colorectal Cancer
combined with zoledronic acid 4 mg IV every 3 to
Study Group (ABCSG)-12 enrolled 1803 pre4 weeks for 6 months (n = 101) prior to surgery.
menopausal women with ER+ early breast
Patients’ baseline characteristics were similar becancer. Following surgery, patients were rantween the cohorts, and both groups underwent the
domized to receive goserelin (Zoladex) 3.6 mg
same median number of chemotherapy cycles.
subcutaneously every 28 days along with oral
Adjusted mean tumor size after treatment
tamoxifen 20 mg per day or anastrozole (Arimiwas 28.2 mm in the zoledronic acid group and
dex) 1 mg per day for 3 years. A subset of pa42.4 mm in the chemotherapy group. Researchtients also received zoledronic acid 4 mg intraers classified this 33% reduction as “significant.”
venous (IV) every 6 months.
Pathological complete response was seen in
In the February issue of New England Journal of
10.9% of women in the zoledronic acid group
Medicine, investigators reported that the group
compared with 5.8% in the chemotherapy group
receiving adjuvant therapy with zoledronic acid
(P = .033). Investigators said the addition of zoleand anastrozole had a 36% reduced risk of disdronic acid to standard
ease progression comchemotherapy allowed
pared with endocrine
16% of women in this
monotherapy (P = .01)
“These results support a potential
group to forego masand a 35% reduction in
risk of recurrence (P =
anti-tumor benefit of combining Zometa tectomy for less radi.02). Michael Gnant,
with chemotherapy in the neoadjuvant cal procedures; the
mastectomy rates were
MD, Medical Univertreatment of breast cancer.”
65.3% in the zoledronic
sity of Vienna, Austria,
acid group compared
and colleagues said
–Matthew Winter, MD
with 77.9% for the chethe combined regimen
motherapy arm.
produced no benefit in
Lead author Matthew Winter, MBChB, MSc,
overall survival, and toxicities were consistent
clinical research fellow, University of Sheffield,
with the agents’ known safety profiles. ResearchUK, said, “These results support a potential
ers quantified the number needed to treat with
anti-tumor benefit of combining Zometa with
zoledronic acid to prevent progression as 31,
chemotherapy in the neoadjuvant treatment
which they indicated was “consistent with the
of breast cancer.” AZURE investigators hope
number needed to treat for cancer therapies
to present final results from the trial in 2 to
that in the past have caused a shift in treatment
3 years. Robert E. Coleman, MD, also of Unistandards.”
versity of Sheffield, cautioned that this was a
Preclinical and earlier-phase studies found
“hypothesis-generating study,” not a “practicethat zoledronic acid acts directly on tumor
changing” one.
cells. It inhibits cell adhesion, spread, and proBoth trials were funded in part by Novartis,
liferation; induces apoptosis; acts synergistithe manufacturer of Zometa. Dr. Coleman precally with chemotherapy; and exerts antiangiodicted that if the preliminary findings from the
genic effects.
AZURE trial hold up, Novartis will likely file for
The second study, a retrospective analysis of
a new indication for the drug.
data from the AZURE (Adjuvant Zoledronic Acid
to Reduce Recurrence) trial, showed that neoad–Christin Melton
News Capsules
Cases of melanoma, the deadliest form of skin cancer,
rose 3.1% annually from 1992-2004 in the United
States. (Journal of Investigative Dermatology, Jan. 2009)
Radiotherapy before tumor excision reduced rectal
cancer recurrence by 5.6%. (Lancet, Mar. 2009)
Meta-analysis finds 2 alcoholic drinks a day may boost
pancreatic cancer risk by 22%. (Cancer Epidemiology,
Biomarkers, and Prevention, Mar. 2009)
Breast-Specific Gamma Imaging is more sensitive than
mammography at detecting invasive lobular breast
carcinoma. (American Journal of Roentgenology, Feb. 2009)
FLT PET scanning, which uses radioactive fluorothymidine
tracer, may indicate a patient’s response to chemotherapy
as early as the day after treatment. (University of Wisconsin
Madison, Mar. 2009)
HPV 16 and HPV 18 are the most prevalent genotypes of
human papillomavirus associated with invasive cervical
cancer, accounting for 70% of cases. (International Journal
of Cancer, Feb. 2009)
Almost all patients with epidermolysis bullosa (subtype
Hallopeau-Siemens) will develop squamous cell
carcinoma by age 55. (Journal of the American Academy of
Dermatology, Feb. 2009)
CellSearch Predicts Outcomes
(Continued from cover)
In the initial stages of advancing prostate cancer,
patients are treated with hormonal therapies and oncologists measure PSA levels to evaluate response.
An increasing PSA level typically correlates to tumor
growth or spread. Other factors can influence PSA
levels, however, including commonly used medications like statins and aspirin (Oncology & Biotech
News, Jan., p. 24), compromising the reliability of
PSA testing. Once a patient with castration-resistant
prostate cancer initiates chemotherapy, PSA levels
become even less reliable at indicating progression,
making it hard to identify which patients are benefitting from therapy.
Enter CellSearch. A sample of the patient’s blood
is treated with CTC-seeking antibodies fused to
microscopic iron balls. The fused particles affix
themselves to CTCs, which are then drawn from
the sample using a powerful magnet. The CTCs are
stained to enhance identification, analyzed, and tallied. CellSearch makers say the system can identify
a single cancer cell out of 40 billion blood cells in
a 7.5 mL blood sample. Several studies have concluded that serial monitoring of CTCs in cancer patients effectively predicts PFS and overall survival.
Sloan Kettering researchers enrolled 164 men
with prostate cancer who were beginning first-line
chemotherapy. They used CellSearch to ascertain
CTC numbers before and after treatment. They
also documented PSA and lactate dehydrogenase
(LDH) levels at baseline and measured PSA levels
during treatment. The risk of death was greater for
patients with high baseline CTC counts or PSA
levels. Tests at 4, 8, and 12 weeks after starting
treatment found that the CTC count continued to
correlate strongly with mortality risk but the PSA
level became less reliable.
Investigators concluded that a baseline CTC
count accurately predicts survival for patients with
prostate cancer just starting chemotherapy and effectively indicates response to treatment. They said
CellSearch was a more reliable indicator of response
than PSA both pre- and posttreatment. They noted,
however, that the most accurate model at predicting survival included baseline CTC count and LDH
levels in conjunction with treatment-related changes
in CTC count. Researchers are accruing more than
1100 men with prostate cancer for a larger study to
confirm these findings.
The study adds support to results from a Nevada
Cancer Institute trial published last year that found a
decrease in CTCs was “most often associated with
patients successfully responding to therapy.” Data
from this trial found that a baseline measurement <5
CTCs correlated significantly to better survival rates
versus >5 CTCs in patients with prostate cancer.
–Christin Melton
Courtetsy Veridex LLC
16
03.09
Earlier research found that a high ratio of
HOXB13 to IL17BR gene expression (HOXB13:
IL17BR) is strongly associated with poorer
disease-free survival in women with ER+
breast cancer treated with adjuvant tamoxifen. High expression of HOXB13:IL17BR may
indicate impaired ER signaling, associated
with tamoxifen resistance. A team of investigators from Sweden recently determined that
HOXB13 protein expression alone is a significant predictor of response to tamoxifen and
presented their findings at SABCS.
They randomized 912 postmenopausal
women with node-negative breast cancer to
receive 2 years of tamoxifen monotherapy
or no treatment. The subset of patients who
remained recurrence-free after 2 years were
then randomized to 3 years of tamoxifen
monotherapy or no treatment. Investigators
used the Theros Breast Cancer Index by bioTheranostics, a molecular testing firm in San
Diego, California, to assess HOXB13 protein
levels and determine the 2-gene ratio.
Data on HOXB13 protein expression were
available for 866 patients. The majority of
women were negative or low expressors. In
this group, those treated with tamoxifen experienced a longer time to distant recurrence
than untreated patients. The nearly one-third
of patients with high or intermediate HOXB13
expression had similar rates of distant recurrence-free survival (RFS) regardless of whether
they received tamoxifen therapy.
No. of Patients
(N = 866)
Percentage
Negative
291
33.6
Low
317
36.6
Intermediate
212
24.5
High
46
www.hcplive.com/obtnlive
PharmaFocus
HOXB13 Gene Predicts
Tamoxifen Response
HOXB13
Expression
l
5.3
The researchers concluded that HOXB13 expression alone constituted a statistically significant indicator of which patients would benefit
from tamoxifen, with high expressors deriving little to no benefit. The level of HOXB13
protein was not predictive of RFS in untreated
patients.
A second study, led by Matthew Goetz, MD,
Mayo Clinic, Rochester, Minnesota, in collaboration with bioTheranostics, sought to identify
prognostic markers of distant breast cancer
recurrence. Using the Theros Breast Cancer
Index, investigators found that 25% of tumors
had high expression of HOXB13:IL17BR and
a 5-gene molecular grade index. This overexpression was associated with 3 times the likelihood of distant metastases compared with
patients with low-risk genetic markers.
Dr. Goetz said using the Theros Breast Cancer Index to evaluate both molecular biomarkers might help identify patients with early
stage breast cancer at high risk of distant metastases if treated with tamoxifen. These patients might benefit from treatment with other
therapies, such as aromatase inhibitors.
–Christin Melton
Avastin (Bevacizumab)
Avastin is a recombinant humanized monoclonal antibody specific for VEGF. It is the first FDA-approved biologic agent
designed to slow or halt tumor growth through the initiation of angiogenesis. Avastin binds to VEGF, preventing VEGF
receptor binding and subsequently disrupting VEGF activity. It is used in treating a variety of solid tumors and off-label
in select noncancerous ocular diseases. Avastin is administered intravenously, in conjunction with a prescribed chemotherapy regimen. Although Avastin is generally well tolerated by most patients, it is associated with an increased
risk of hypertension, proteinuria (protein in the urine), gastrointestinal perforation, and delayed wound healing.
Currently more than 450 clinical trials worldwide are investigating Avastin in at least 30 types of solid tumors.
Current Indications
• C
ombined with IFL chemotherapy in first-line
metastatic colorectal cancer—2004
• Combined with IFL chemotherapy in second-line
metastatic colorectal cancer—2006
• Combined with carboplatin and paclitaxel in first-line
non–small cell lung cancer (NSCLC)—2006
• Accelerated approval in combination with paclitaxel
as a treatment for first-line HER2- metastatic breast
cancer (mBC)—2008
Pending FDA Approval
Metastatic renal cell carcinoma—In the third
quarter of 2008, Genentech Inc filed a supplemental
Biologics License Application (sBLA) with the
FDA requesting approval for Avastin as a first-line
treatment for metastatic renal cell carcinoma in
combination with interferon alfa 2-a. A decision is
expected in August 2009.
Persistent or recurrent cervical cancer—A phase
II study by Monk, et al, published in the March 2009
issue of Journal of Clinical Oncology concluded that
Avastin was “well tolerated and active” as a secondor third-line treatment in women with previously treated
squamous cell carcinoma of the cervix. Investigators
recommended proceeding with a phase III study of
Avastin for this indication.
Glioblastoma multiforme—Genentech based its
sBLA for Avastin in glioblastoma on the results of
a phase II trial involving patients with recurrent,
treatment–refractory glioblastoma. This tumor has a
high rate of VEGF expression, and patients have few
options for treatment. A regimen combining Avastin
with irinotecan produced PFS ≥6 months in more than
half of patients. Surprisingly, patients who received
Avastin monotherapy had greater overall survival—a
median of 9.2 months versus 8.7 for the combination
arm. The trial is now in phase III.
Glioblastoma—In November 2008, the FDA granted
Priority Review to Genentech’s sBLA for Avastin
in patients with previously treated glioblastoma.
Glioblastoma is a particularly aggressive brain cancer;
patients with this diagnosis have a poor prognosis, with
median survival averaging 3 to 6 months. Priority Review
is granted to agents expected to provide “significant
improvement compared to (already) marketed products.”
A decision is expected in May 2009.
NSCLC—In February, Genentech reported that
Avastin combined with erlotinib (Tarceva) was effective
maintenance therapy in previously treated patients with
recurrent NSCLC who had achieved stable disease on
a regimen of Avastin and chemotherapy. The phase III
trial was halted early after a monitoring board found
the drug duo significantly extended PFS versus Avastin
monotherapy.
Trial News
Latest News
HER2- locally recurrent or mBC—Three phase III
studies (AVADO, E2100, and RIBBON-1) established
that Avastin, in combination with various approved
agents, enhances treatment in women with this
disease. When Avastin was added to the agents used
in each study, patients in the Avastin-containing arms
experienced significantly longer PFS, greater tumor
shrinkage, and acceptable toxicity.
Genentech says it will use data from the AVADO
and RIBBON-1 studies to petition the FDA this year
to convert its accelerated approval of Avastin as a
first-line treatment for HER2- mBC into full approval.
Canada approved this indication in February 2009.
In addition, the company plans to discuss data
from the ATLAS study with the FDA to determine
its next steps.
Recent Avastin Trials
Trial
Indication
Treatment
Results
ATLAS
(N = 1157)
Maintenance therapy for
advanced NSCLC
Avastin + erlotinib
vs Avastin alone
Patients in the combination arm had significantly longer PFS
and no new safety signals.
AVADO
(N = 736)
Inoperable HER2- locally
recurrent or mBC
Avastin 7.5 or 15 mg/kg +
docetaxel vs docetaxel alone
Avastin regimen significantly improved PFS and response rate.
BRAIN
(N = 167)
Previously treated
glioblastoma multiforme
Avastin + irinotecan
vs Avastin alone
Both regimens showed high rates of response and PFS ≥6
months; OS was superior with Avastin monotherapy.
GOG Study
(N = 46)
Persistent or recurrent
cervical cancer
Avastin 15 mg/kg every 21 days
Primary end points: PFS at 6 months, toxicity. Median response
was 6.21 months, and 11 patients had PFS ≥6 months.
E2100 (N = 772)
Untreated locally
recurrent or mBC
Avastin + paclitaxel
vs paclitaxel alone
Independent review of results found patients in the combination
group had a 52% reduction in risk of progression or death.
RIBBON-1
(N = 1237)
First-line metastatic
HER2- mBC
Avastin + taxane/anthracycline/
capecitabine vs taxane/
anthracycline/capecitabine alone
Study met its end point of significantly increasing PFS in all
Avastin arms vs placebo.
GOG indicates Gynecologic Oncology Group; NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression-free survival.
17