2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

MANAGEMENT OF T1 BREAST CANCERS
93.5%, respectively. Adverse prognostic factors included TN
disease. Hazard function did not reach statistical significance
for HER2-positive disease.
Local-Regional Management
A major trend in BC therapy is the lessening extent of
axillary surgery. ALN dissection is completed for patients
with clinically node-positive disease but not for patients
with sentinel node (SN)-negative disease and is controversial
even for the patients with clinically negative, SNpositive
disease. SN sampling is occasionally omitted for the
elderly. Since ALN involvement is less common for small
primary tumors, there is a great temptation to avoid this
surgery. In various series of small primary tumors, the
likelihood of ALN involvement is between 3% and 37%. 33 In
this series of 888 T1ab tumors with a 12% ALN involvement
rate, factors associated with ALN involvement in these
small tumors included LVI (HR � 12.63), perineural invasion
(HR � 5.47), grade 3 tumor (HR � 3.07), and ERnegative
disease (HR � 1.84). 33
Rivadeneira et al found that 18% of 919 patients (199 T1a)
had ALN metastases following a standard ALND. 34 Although
tumor size was predictive, even the T1a group had a
16% rate of ALN involvement. Other factors included grade
3, LVI, and age younger than 50. These risk factors are
consistently observed in other series. 35 HER2 status was not
tested. In the very best group of older patients with welldifferentiated
T1a tumors without LVI, 13% still had metastases.
34 The authors recommend routine use of SLN biopsy.
Literature Conclusions
T1abN0 BC generally has an excellent prognosis. Consistent
adverse prognostic factors include HER2-positive disease,
ER-negative disease, high grade, T1b, and age younger
than 50 years. Because most of the articles treated these
patients variably, these prognostic factors actually are
mixed prognostic/predictive factors demonstrating benefit of
specific therapies. Grade is problematic because of poor
concordance between expert pathologists in its determination.
Ki67—prognostic in many articles—lacks standardization
between pathology laboratories. Age is a complex
variable: low comorbidity rates and high life expectancy
allow extended time for BC events; premenopausal status
with different hormonal milieu; different genetic drivers to
develop BC in the young; a different mix of molecular
subtypes; and independent of subtypes, a more aggressive
metastasis pattern in the young, perhaps related to the
immunologic and inflammatory signals generated by pregnancy
and weaning. 36
In addition to these factors, which ultimately reflect
molecular subtype, size, and premenopausal status, the fact
remains that most events in these patients with good prognosis
are unrelated to BC. Comorbidities—particularly cardiovascular
health—as competing risks may represent up to
80% of all events, particularly in the elderly. 22 Thus, the
best endpoints to help us make decisions may not be OS,
DFS, or RFS but the balancing of DDFS (or BCSS) and the
risks of treatment.
Most adjuvant trials find a strong correlation between an
intervention and the relative risk reduction independent of
stage. Thus, we expect approximately 25% risk reduction
with older polychemotherapy, approximately 40% risk re-
duction with docetaxel plus cyclophosphamide (TC), a reduction
of approximately 41% with tamoxifen, approximately
50% with aromatase inhibitors, and approximately 50%
reduction with the addition of trastuzumab to chemotherapy.
Thus, one can estimate the magnitude of absolute risk
reduction with these interventions by estimating the absolute
risk if untreated.
Guidelines
Both major guidelines (National Comprehensive Cancer
Network [NCCN] and St. Gallen’s Expert Panel) require the
oncologist to consider much, but detailed instructions are
nebulous, as paraphrased below.
NCCN 2009. If T1a/T1mic N0, or if T1b and G1, no
adjuvant therapy is recommended, although endocrine therapy
can be considered. If T1b N0 and grade 2 to 3, then
adjuvant endocrine therapy is recommended if ER positive.
If younger than age 60, adjuvant chemotherapy could be
considered. If T1b HER2 positive, endocrine therapy with or
without chemotherapy with or without trastuzumab could
be considered, but no further guidance is provided.
St. Gallen 2011. For luminal T1N0 ER-positive BC, antiestrogen
therapies are recommended but not chemotherapy.
For the HER2-positive subtype, the panel of experts was
willing to extrapolate the chemotherapy/trastuzumab studies
to T1bN0 BCs but would not recommend any adjuvant
therapy for T1a tumors. For the TN subtype, chemotherapy
is considered; no specific recommendation was made based
on tumor size. Trastuzumab with or without endocrine
therapy alone without chemotherapy was not considered to
be an acceptable adjuvant treatment for small HER2positive
BC by 78% of the experts unless a contraindication
to chemotherapy existed. 37 Chemotherapy would be more
strongly considered for large tumor size, involved nodes, or
bad biology (HER2� or TN, grade 3).
In My Opinion
ER-positive/HER2-negative BC. Adjuvant endocrine therapy
should be considered for all, particularly for the T1b
group, subject to the patient tolerance of the endocrine
therapy. DFS/RFS is uniformly greater than 90% and typically
approaches 97%. OncotypeRx is considered valid for
the T1bN0 ER-positive subset but has not been tested in the
T1mic or T1a groups. This test would be potentially useful in
T1b tumors that have adverse features such as higher grade,
low ER positivity, PR negativity, and possibly high Ki67
scores. Size and grade remain weak prognostic factors despite
RS, and a new integrated RS is anticipated to account
for size. 11 Chemotherapy could be considered for T1b disease
with high RS.
HER-positive/ER-positive BC. Treatment for this group is
highly controversial. 38 HER2 amplification increases recurrence
risk. Observation with or without endocrine therapy
alone has resulted in series with 5-year DFS of 85% to 92%,
particularly for the T1b group. Combination chemotherapy
plus trastuzumab with or without endocrine therapy has
resulted in extremely few recurrences; however, most patients
are therefore over-treated. This treatment commits
the patient to myelosuppression, acute chemotherapy toxicities,
increased cardiac morbidity, peripheral neuropathy
that can affect balance (particularly in the elderly), and
possible leukemia. Moreover, intravenous therapy is for a
year. Alternative approaches are beginning to be studied. A
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