Breast Cancer
ASCO 2016: Breast Cancer
By Cynthia X. Ma, MD, PhD
T he ASCO 2016 Annual Meeting marks another year of
progress in clinical cancer research. For breast cancer pa-
tients, pressing clinical issues such as the use of extended
adjuvant hormonal therapy beyond 5 years, the role of an-
thracycline in the adjuvant setting for HER2-negative disease, utility
of pertuzumab post progression on trastuzumab containing regimens
and the potential of trastuzumab biosimilars for HER2-positive meta-
static disease, and data further supporting the benefit of CDK4/6 inhi-
bition and the prognostic and predictive value of ESR1 mutations in
estrogen receptor positive (ER+) breast cancer were addressed at the
meeting to better inform our decisions in the clinic.
In addition, novel therapeutic targets such as HER2 mutation in
HER2 non-amplified breast cancer and glutaminase in triple negative
breast cancer (TNBC) have shown promising results in early phase
trials that warrant further investigation.
Abstract 505: Persistent risk of recurrence post 5 years of adjuvant
endocrine therapy
EBCTCG meta-analysis that included 46,000 women with early stage
ER+ breast cancer post 5 years of tamoxifen or aromatase inhibi-
tor (AI) demonstrated that the risk of distant recurrence persists in
subsequent years. Without extended
endocrine therapy, distant recurrence
risk in years 5-20 was approximately
14 percent for stage 1 disease and
much greater for higher stage or node
positive disease.
Abstract LBA1: Extending adjuvant AI
beyond 5 years
MA 17.R was a double-blind, placebo-
controlled phase III trial evaluating
the efficacy of preventing breast can-
cer recurrence with 5 additional years
Thinkstock
of letrozole versus placebo in post-
menopausal women with early stage
ER+ breast cancer who already com-
pleted 5 years of adjuvant letrozole following 0-5 years of tamoxifen.
The primary endpoint was disease-free survival (DFS). The study
enrolled 1,918 women (median follow-up: 6.3 years). Compared to
placebo, letrozole led to 4 percent absolute improvement in 5-year DFS
(95% vs 91%; HR 0.66; p=0.01), including 1.1 percent absolute risk
reduction in distant recurrence rate (4.4% vs 5.5%), without substan-
tive difference in quality of life assessed by MENQOL and SF-36. The
benefit was independent of nodal status, prior adjuvant chemotherapy,
time since the last dose of AI, and duration of prior tamoxifen. A large
effect was observed in contralateral breast cancer incidence (1.4% vs
3.2%; HR 0.42, p=0.007). No difference in 5-year overall survival was
observed (93% in the letrozole arm and 94% in the placebo arm; HR
of 0.97 (p=0.83)). Letrozole was associated with increased incidence
of bone fracture (14% vs 9%; p=0.001).
This data supports the use of extended AI therapy beyond 5 years
in postmenopausal women in the adjuvant setting to reduce the risk of
recurrence and preventing new primary breast cancer, with the caveats
of increased bone fracture and the lack of overall survival benefit in
unselected patient population. Tailored assessment of individual risk of
recurrence is needed.
Abstract 507: Phase III confirmation of palbociclib benefit in combi-
nation with letrozole in postmenopausal women with ER+/HER2- ad-
vanced breast cancer
14 Oncology Times
Cynthia X. Ma, MD, PhD, Associate
Professor of Medicine, Washington University
School of Medicine, St. Louis, Mo.
PALOMA 3 randomized 666 patients with advanced ER+/HER2-
breast cancer to received either palbociclib/letrozole (n=444) or pla-
cebo/letrozole (n=222) as first line hormonal therapy. The addition of
palbociclib led to a significant improvement in progression free sur-
vival (PFS): 24.8 (22.1-NR) months in the palbociclib/letrozole arm
vs 14.5 (12.9-17.1) months in the placebo/letrozole arm, HR 0.58;
p<0.000001. All subgroups derived benefit. Palbociclib was associated
with an improved response rate (42% vs 35%, p=0.03) and clinical
benefit rate (85% vs 70%, p<0.0001). The study provided confirma-
tory support for the indication of palbociclib plus letrozole as first line
therapy for metastatic ER+HER2- breast cancer.
Abstract 510: Abemaciclib, a CDK4 and CDK6 inhibitor, as monother-
apy, demonstrated benefit for heavily pretreated advanced ER+HER2-
breast cancer
MONARCH 1 is a single arm phase II trial of abemaciclib 200mg Q12h in
patients with metastatic HR+HER2- breast cancer progressed on or after
prior endocrine therapy and at least two chemotherapy regimens (at least
1 taxane regimen and 1 regimen in the metastatic setting). One hundred
thirty two patients, a median of three prior systemic regimens for metastatic
disease, enrolled to the study. The clinical benefit rate of 42.4 percent and
overall response rate of 19.7 percent were observed, clearly indicating its
activity in ER+ breast cancer. Most common adverse events were diarrhea
(90.2%) (grade 1: 41.7%, grade 2: 28.8%, grade 3: 19.7%). Neutropenia
(87.7%) (grade 1, 17.7%, grade 2: 43.1%, grade 3: 22.3%, grade 4: 4.6%)
was less severe than other CDK4/6 inhibitors. The preferential effect on
CDK4, daily dosing schedule, and the toxicity profile differentiate abe-
maciclib from other CDK4/6 inhibitors. Abemaciclib in combination with
nonsteroidal AI as first line (MONARCH 3) and in combination with ful-
vestrant in endocrine pre-treated setting (MONARCH 2) are ongoing.
Abstracts 511 and 512: ESR1 mutation by ctDNA in MBC
In a retrospective study of ctDNA ESR1 mutation (D538G, Y537S/
N/C) by digital droplet PCR at disease progression after first-line AI in
patients with metastatic breast cancer, ESR1 mutation was detected in
44/144 (30.6%) patients and was a strong and independent prognostic
factor for PFS to subsequent therapy and OS.
In the SoFEA study, ESR1 mutation was associated with worse
PFS while on exemestane compared to fulvestrant, consistent with
the preclinical data indicating that these mutations lead to estrogen
independent ER activation. In the PALOMA-3 study, ctDNA ESR1
mutation was detected in 27 percent baseline samples by BEAMing
digital PCR. Benefit of palbociclib was observed in both ESR1 mu-
tated versus wild type cohorts.
Abstract 518: Efficacy of pan-HER inhibitor neratinib in HER2 mutated
non-amplified MBC
Approximately 2 percent of HER2 non-amplified breast cancers har-
bor recurrent mutations in HER2. Results of a multi-center phase II
trial of neratinib in HER2 mutated non-amplified metastatic breast
cancer (MBC) were reported. 14 patients with activating HER2
Continued on page 16
August 10, 2016

Breast Cancer
continued from page 14
mutations were enrolled, 5/14 (36%, 90% CI: 15-61%) achieved
clinical benefit, including one complete response, one partial re-
sponse, and three stable disease for at least 6 months. The trial met
its primary endpoint. The data provided proof of concept regarding
HER2 mutation as a therapeutic target in non-amplified breast can-
cer. Accrual is ongoing for neratinib plus fulvestrant in ER+, HER2
mutated, non-amplified MBC. (ClinicalTrials.gov: NCT01670877)
LBA503: Trastuzumab Biosimilar MYL-14010 demonstrated equiva-
lency to trastuzumab for treating HER2+ MBC
Heritage study is a phase III double blind study that compared MYL-
14010 versus trastuzumab when combined with taxanes as first line
treatment for HER2 positive MBC and demonstrated equivalency in
efficacy, side effect profile, immunogenicity and population pharma-
cokinetics of the two agents. MYL-1401O has the potential to provide
an affordable trastuzumab biosimilar for patients with HER2 positive
breast cancer.
Abstract 504: Pertuzumab in HER2 positive breast cancer progressed on
prior trastuzumab regimen
PHEREXA trial is a phase III study evaluating the benefit of add-
ing pertuzumab to trastuzumab plus capecitabine in HER2+ MBC
progressed on previous trastuzumab regimens. The median PFS was
9.0 months in the trastuzumab/capecitabine arm vs 11.1 months in
Lung Cancer Screening
continued from page 8
• While LDCT radiation is a fairly low dose, “it is still a con-
cern,” especially over time with repeated screenings, said Barnett
Kramer, MD, MPH, Director of the Division of Cancer Prevention
at NCI and a member of the NCPF workshop planning commit-
tee. Radiating the chest means radiating the breast, he noted. Otis
Brawley, MD, Chief Medical Officer and Executive Vice President
of the ACS and a member of the NCPF, agreed. He cautioned
that screening “is not a slam dunk,” and said radiation-induced
harm to the lung and breast is “information that very few people
appreciate.”
• Although shared decision-making is the goal, cancer screen-
ing discussions often fail to adequately inform and engage patients,
said Richard M. Hoffman, MD, MPH, Professor of Internal Medicine
and Epidemiology and Director of the Division of General Internal
Medicine at the University of Iowa’s Carver College of Medicine, Iowa
City. Hoffman said “there are a lot of misconceptions about smoking,”
with some people believing that screening can be protective against
lung cancer. Furthermore, he said, some people may not want to un-
dergo lung cancer surgery if the screening detects cancer and surgery
is recommended.
• Whether high-quality smoking cessation programs are ad-
equately linked to lung cancer screening programs, since stopping
smoking should be the goal of every high-risk screening candidate
who still smokes. Screening alone does not seem to change smoking
behavior.
• Whether there is adequate insurance coverage for LDCT, espe-
cially for younger patients who are not Medicare eligible. Will they
incur out-of-pocket costs if they have the screening?
• Whether there is adequate insurance coverage for follow-
up tests and procedures, should the screening show an abnormal
finding.
• What to do about incidental abnormal findings that might not
ever cause harm during the person’s lifetime. “Just because we find
something doesn’t mean we need to do something about it,” said
16 Oncology Times
the trastuzumab/capecitabine/pertuzumab arm, HR (95% CI) 0.82
(0.65-1.02), p=0.07, without statistically significant difference be-
tween the two arms. At this time, there is insufficient data to recom-
mend pertuzumab in later lines of treatment.
Abstract 1011: Glutaminase as a novel therapeutic target for TNBC
Cancer cells have altered glucose metabolism and dependency on
glutamine cell growth and survival. TNBC has increased expression
of glutaminase which converts glutamine to glutamate and sensi-
tivity to glutaminase inhibition in preclinical studies. A phase I
study of CB-839, an oral small molecule inhibitor of glutaminase
in combination with paclitaxel in TNBC was presented and dem-
onstrated promising activity. Partial response was observed in three
of 15 patients (20%), two of whom were heavily pretreated and
with prior disease progression on paclitaxel in the metastatic set-
ting. Additional clinical development is warranted.
Abstract 1000: Anthracycline remains an important component of adju-
vant regimens for HER2- breast cancer
The ABC adjuvant trials (B-49, B-46-I/USOR 07132) were conducted
to determine if TC (docetaxel and cyclophosphamide) for 6 cycles is
non-inferior to combination regimens of doxorubicin/cyclophospha-
mide with docetaxel or paclitaxel (TaxAC) in women with resected
high-risk, HER2-negative breast cancer. The primary endpoint of
the study was invasive disease free survival (iDFS). With 399 iDFS
events, 4 year iDFS is 88.2 percent for TC versus 90.7 percent for
TaxAC. HR=1.23, 95 percent CI (1.01-1.5), p=0.04. TC was inferior
to TaxAC. Longer follow-up should clarify the clinical utility of these
initial findings.  OT
Douglas E. Wood, MD, Professor and Interim Chair of the Department
of Surgery and Chief of the Division of Cardiothoracic Surgery at the
University of Washington. Specifically, he said, some lung nodules can
be managed with careful surveillance, and do not need to be immedi-
ately removed.
Developing LDCT Centers
Brawley told Oncology Times he also is concerned about the potential
commercialization of LDCT centers and about hospitals that decide
to offer and advertise such screening as a business decision because of
the revenue it will generate—not just from the screening itself but also
from downstream testing and procedures. In that case, he warned, the
shared decision-making visits between provider and screening candi-
date may be merely perfunctory, not a substantive effort to inform and
educate the person and to determine his/her individual values, wishes,
and preferences.
When it comes to starting an LDCT screening program, “the costs
should be justified in the business plan,” said Christopher S. Lathan,
MD, MS, MPH, a medical oncologist in the Lowe Center for Thoracic
Oncology at Dana Farber Cancer Institute, founding faculty Director
of the Cancer Care Equity Program at Dana-Farber, Assistant Professor
of Medicine at Harvard Medical School and a member of the work-
shop planning committee.
He told Oncology Times he is not overly worried about the
overbuilding of LDCT centers because right now “the uptake is
quite low.” He added, “It’s expensive to start such a screening
program.” Lathan stressed the benefits of LDCT: “I see patients
with metastatic lung cancer. If we can prevent that, we should
do it.”
While it is important to implement LDCT screening judiciously
now, there may come a time fairly soon when it becomes outdated
by new technology, cautioned Fabrice Smieliauskas, PhD, Assistant
Professor in the Department of Public Health Sciences and Co-Chair
of the Cancer Policy and Outcomes Workgroup in the Comprehensive
Cancer Center at the University of Chicago. New blood-based DNA
lung cancer screening tests may be imminent, he said, which would
reduce the capacity need for LDCT centers.  OT
Peggy Eastman is a contributing writer.
August 10, 2016