Haematology+Oncology_News

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BRCA mutation predicts neoadjuvant therapy benefit but
is not strongly prognostic
BY SUSAN LONDON
Frontline Medical News
In patients with triple-negative
breast cancer, the presence of
a mutation in the breast cancer
susceptibility genes BRCA1 and
BRCA2 appears helpful for iden-
tifying those who will benefit from
neoadjuvant chemotherapy but not
very helpful for estimating progno-
sis, finds a subgroup analysis from
the GeparQuinto trial.
Dr Peter A. Fasching and col-
leagues studied 471 patients with
triple-negative disease who were
treated with neoadjuvant therapy in
the trial, underwent surgery, and did
not receive any postoperative therapy.
Prospectively specified genome-
wide association studies showed
that 17.4% of the patients had a
BRCA1/2 mutation, he reported
at the San Antonio Breast Cancer
Symposium.
The rate of pathologic complete
response (pCR), defined as ypT0/
ypN0 stage, was 50% in the patients
with a mutation, compared with
30.8% in those with wild-type genes
(P = 0.001).
The patients with a mutation also
had better disease-free survival than
their wild-type peers (hazard ratio,
0.64), but this difference missed
statistical significance (P = 0.06).
“BRCA mutation carriers had
a significantly higher pathologic
complete response rate after neo-
adjuvant chemotherapy,” com-
mented Dr Fasching, an oncologist
the University Hospital Erlangen
(Germany), Comprehensive Can-
cer Centre Erlangen-EMN. “And
BRCA mutation carriers had a better
prognosis.”
Attendee Dr George Somlo of
City of Hope, Duarte, California,
wondered if surgical management
played a role in the findings. “Can
you clarify…whether mastectomies
on the ipsilateral side or contralateral
side had any effect on the disease-
free survival, since I assume once
the mutations were known, other in-
terventions might have taken place?”
“Unfortunately, I cannot,” Dr
Fasching replied. “We did not
extend the exploratory analysis to
that subpoint.”
Giving some background to the
analysis, he commented, “Neoadju-
vant studies may serve as a very good
research ground to look for answers
to both questions: whether BRCA
mutation status predicts response to
a chemotherapy and, furthermore,
whether this translates into a prog-
nostic effect.”
All patients with triple-negative
disease in the GeparQuinto ran-
domised phase III trial received neo-
adjuvant chemotherapy (epirubicin,
cyclophosphamide, and docetaxel),
with or without the antiangiogenic
antibody bevacizumab.
Additional findings showed that
among BRCA mutation carriers, a
pCR was not significantly associated
with better disease-free survival. In
contrast, among patients with wild-
type genes, it was associated with a
sharply reduced risk of events (HR,
0.21; P < 0.0001). However, the inter-
action was not statistically significant.
“The prognostic information of pCR
with regard to prognosis appeared to
be somewhat weaker in patients with
a BRCAmutation, compared to wild-
type patients, but you have to keep in
mind the test for interaction in this ex-
ploratory analysis was not significant,”
Dr Fasching commented.
The investigators also performed
exploratory analyses looking at the
impact of achieving a pCR in each
treatment arm.
As far as a rationale, hypoxia
is known to cause DNA damage,
and synthetic lethality has been
described in BRCA mutation carri-
ers, Dr Fasching explained. “There
are some data that show that angio-
genic factors are as a matter of fact
increased in tumours with a BRCA
mutation, compared to wild-type
patients,” he added.
Results here showed that ad-
dition of bevacizumab improved
pCR rate among both BRCA1/2
mutation carriers (65.7% vs 38.3%,
P = 0.025) and patients with wild-
type (35.8% vs 26.2%, P = 0.048).
But addition of bevacizumab did
not significantly improve disease-
free survival in either group.
T-DM1 trial points way to de-escalation of breast cancer therapy
BY BRUCE JANCIN
Frontline Medical News
Twelve weeks of trastuzumab emtasine
as single-agent neoadjuvant therapy in
HER2-positive/hormone receptor-positive
early-stage breast cancer achieved a pathologic
complete response rate of 41%, underscoring the
feasibility of therapeutic de-escalation in that pa-
tient subgroup, according to Dr Nadia Harbeck.
Dr Harbeck, head of the breast centre at the
Technical University of Munich, presented
the final analysis of the phase II, 376-pa-
tient WSG-ADAPT HER2+/HR+ (Women’s
Healthcare Study Group – Adjuvant Dynamic
Marker – Adjusted Personalised Therapy
HER2+/HR+ trial). The primary finding: The
pathologic complete response (pCR) rate in
the breast and lymph nodes after 12 weeks of
neoadjuvant therapy with no systemic chemo-
therapy in this three-armed trial was 41%
with trastuzumab emtasine (T-DM1) alone at
3.6 mg/kg every 3 weeks, 41.5% with T-DM1
plus endocrine therapy, and just 15.1% with
tamoxifen plus endocrine therapy.
Adding in those patients with a near-pCR –
that is, patients who were ypT1a, with very little
remaining tumour burden of dubious clinical
significance – the results looked even stronger:
a pCR/near-pCR rate of 53% with neoadjuvant
T-DM1 alone and 52.9% with T-DM1 and en-
docrine therapy, versus 19.3%with trastuzumab
plus endocrine therapy, Dr Harbeck said at the
San Antonio Breast Cancer Symposium.
Thus, adding endocrine therapy to T-DM1
didn’t improve upon the effectiveness of
T-DM1 alone in this updated and final WSG-
ADAPT analysis. That’s an important differ-
ence from an earlier 130-patient prespecified
interim analysis Dr Harbeck presented at
the 2015 ASCO meeting. At that point it
seemed – incorrectly, as it turned out – that
concurrent endocrine therapy and T-DM1
provided added benefit in premenopausal but
not postmenopausal women.
“Single-agent T-DM1 therapy warrants fur-
ther evaluation in early breast cancer, not just
because of the efficacy, which I think is very
impressive, but also because of the favourable
safety profile,” she said.
Mild to moderate constipation, thrombocy-
topenia, dry mouth, fatigue, arthralgia, head-
ache, and hot flushes were roughly twice as
common in the combined T-DMI and T-DMI
plus endocrine therapy arms, compared with
the trastuzumab plus endocrine therapy arm.
But the only grade 3 adverse event that was
more frequent in the two T-DMI study arms
was an elevation in liver enzymes, which oc-
curred in 4.1% of those patients and none on
trastuzumab and endocrine therapy.
WSG-ADAPT is actually an umbrella trial
that to date has enrolled about 4000 patients.
An important goal of ADAPT is to identify and
validate useful early biomarkers of clinical re-
sponse. WSG-ADAPT HER2+/HR+ assessed
two: a drop in Ki67 of 30% or greater or low
cellularity as defined by fewer than 500 tumour
cells in the biopsy taken at the 3-week point in
neoadjuvant therapy, after one cycle of treat-
ment had been completed. Patients with either
marker of early response proved to be 2.2-fold
more likely to have a pCR than women in whom
the early biomarkers were absent.
Dr Harbeck argued that the ADAPT find-
ings make a cogent case for changing the
current standard of care in treating HER2+
early breast cancer, which is chemotherapy
plus anti-HER2 therapy regardless of the ma-
lignancy’s hormone receptor status.
“We don’t adjust for hormone receptor status
in our standard treatment today, even though
we know hormone receptor-positive disease is
a distinct entity,” she said.
The study was sponsored by Roche. The pre-
senter serves as a consultant to Roche, Celgene,
and Genomic Health.
San Antonio Breast
Cancer Symposium
2015
8–12 December 2015 •
San Antonio, Texas
The 38th Annual San Antonio
Breast Cancer Symposium
presented clinicians with
important clinical information,
including notable results in trials
of adjuvant and neoadjuvant
therapies, promising advances
in immune therapies, and new
findings on predictive factors
such as circulating free DNA
and tumour cells. Go to
for more
reports from SABCS.
© SABCS/Todd Buchanan 2015
Haematology & O ncology News • Vol. 9 • No. 1 • 2016 8
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