NcXHF

CONTROVERSIES IN BREAST CANCER NEOADJUVANT THERAPY
select the most promising agents to take forward to confırmatory
trials. First, all chemotherapy should be given before
surgery. Second, pathologic assessment of residual diseae at
surgery must use the FDA-recommended defınition of elimination
of all invasive cancer in the breast and axillary lymph
nodes. Third, the neoadjuvant trial and subsequent adjuvant
trial must have identical chemotherapy treatment plans and
minimal differences in variability in postoperative treatments
such as radiation. Finally, the subsequent confırmatory
phase III trial should be suffıciently powered for the EFS
HR that would be predicted by the improvement in pCR.
The FDA has proposed such a strategy in its guidance allowing
pCR to be considered an endpoint for accelerated approval of
drugs before completion of confırmatory trials. 13
INTEGRATING FINDINGS FROM NEOADJUVANT
CLINICAL TRIALS INTO STANDARD SYSTEMIC
THERAPY
The neoadjuvant setting is used to test both new agents on the
path to regulatory approval and previously approved agents
that could provide benefıt in this setting. In addition to improving
EFS, such trials may show other important clinical
benefıts of new neoadjuvant approaches for patients. These
include improving the likelihood of resectability or breast
conservation or reducing the need for full axillary dissection.
These are tangible benefıts to patients that are demonstrable
at the time of initial report of pCR fındings, and they do not
require waiting for reductions in locoregional/distant recurrence
or survival.
When should the practicing physician implement new
neoadjuvant strategies with existing drugs for these outcomes?
In this situation, toxicity plays a key role in determining
whether the potential benefıt is worth the risk for the
individual patient. An example of this conundrum is whether
to add carboplatin or bevacizumab to anthracycline/taxanebased
neoadjuvant chemotherapy in patients with triplenegative
(ER-/PR-/HER2-) breast cancer. pCR rates in triplenegative
disease with standard therapy are typically in the
35% to 40% range, and patients without a pCR have an abysmal
prognosis, with a median survival of 3 years. 5 Platinum
analogs have been demonstrated to be highly active in
BRCA-mutated breast cancer, a group that signifıcantly
overlaps with sporadic triple-negative disease. Several small
neoadjuvant trials showed higher than expected pCR rates
( 70%) with the addition of carboplatin to anthracycline/
taxane-based regimens in BRCA-mutation carriers. Thus, a
phase II randomized trial, Cancer and Leukemia Group B
40603, was undertaken to evaluate this strategy in unselected
patients with locally advanced, triple-negative disease. 14 This
trial randomly selected 443 patients to receive weekly paclitaxel
with or without concurrent carboplatin (every 3 weeks
at area under the curve 6), followed by four cycles of doxorubicin
and cyclophosphamide. A 2 2 factorial design was
employed to simultaneously evaluate the effect of adding bevacizumab
to this treatment strategy. The addition of carboplatin
to the standard chemotherapy regimen signifıcantly
increased the pCR rate (breast and axilla) from 41% to 54%
(p 0.0029). Several additional proximate outcomes showed
improvement as well, with carboplatin increasing the proportion
of patients who converted from clinical nodepositive
to pathologically node-negative status and the
proportion who became eligible for breast-conserving
therapy.
But these benefıts did come with a price. The overall number
of serious adverse events, defıned as any unexpected
grade 3 or higher toxicity or toxicity that required hospitalization
or surgical intervention, was higher in the carboplatin
arm, including higher rates of febrile neutropenia and severe
nausea, vomiting, and dehydration. Patients assigned to carboplatin
were more likely to miss two or more doses of paclitaxel
and required more dose reductions of paclitaxel, and
20% were unable to complete all planned doses of doxorubicin/cyclophosphamide.
Thus, the risk/benefıt equation of
adding carboplatin to standard neoadjuvant chemotherapy
for triple-negative breast cancer is complicated. In the absence
of EFS/OS data, the most appropriate candidates are
those who would benefıt most from surgical downstaging;
those with conditions that increase intolerance to standard
therapy could have that therapy compromised with the addition
of carboplatin. The treatment decision requires individualization
of therapy and extensive discussion with the
patient about possible implications before embarking on this
new treatment approach.
IMPLICATIONS OF NEOADJUVANT THERAPY ON
LOCOREGIONAL TREATMENT WITH RADIOTHERAPY
The increasing use of neoadjuvant systemic therapy for
breast cancer has had the dual effect of providing important
benefıts and causing signifıcant controversy regarding the locoregional
treatment of breast cancer with radiotherapy. One
of the clearly established benefıts of neoadjuvant therapy is
that it enables more women to undergo breast conservation
with lumpectomy and breast radiotherapy who otherwise
would have been treated with mastectomy. 1,2 Despite results
demonstrating in-breast recurrence after breast conservation
was similar for those who received neoadjuvant compared
with adjuvant chemotherapy, 1 there was some reluctance expressed
for breast-conservation approaches after neoadjuvant
therapy for those women whose extent of disease before
neoadjuvant therapy made them initial mastectomy candidates.
15 This was based on fındings from the NSABP B-18
clinical trial that reported the in-breast recurrence rate was
higher in patients who were initially mastectomy candidates
and were converted to breast conservation by neoadjuvant
therapy, compared with those who were initially candidates
for breast- conserving surgery (15.7% vs. 9.9%, respectively;
p 0.04). 16 More recent studies have found that this local
recurrence pattern is related to more aggressive biologic behavior
of larger, higher stage and grade breast cancers in the
group of women who are initially mastectomy candidates
and not because they underwent breast conservation as a result
of downstaging following neoadjuvant therapy. 17 A
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