NcXHF

DISIS AND STANTON
cells to become type II rather than type I cells. 4 Most antigens
present in breast cancer are self proteins, and the portions of
the proteins that are most likely to stimulate T cells induce a
regulatory immune response. 5 Furthermore, 30% to 50% of
all breast cancers have upregulated programmed death ligand
1 receptor (PD-L1) on the cell surface. 6 When PD-L1
binds with programmed cell death protein 1 (PD-1) on the
surface of T cells, the lymphocytes become inactivated. These
are just a few of the mechanisms by which robust type I immunity
is prevented from developing in breast cancer.
Breast cancer subtypes differ in the level of immune infıltration
observed in the tumor. More patients with TNBC fall
into the category of having a robust tumor T-cell infıltrate
than any other subtype. Hormone receptor–positive disease
is the subtype associated with the least robust number of TIL.
HER2-positive disease has also been shown to have a number
of patients with signifıcant TIL in their tumor. In HER2-
positive breast cancer, the numbers of TIL can be further increased
by treatment with trastuzumab. 7 However, the
prognostic signifıcance of a robust TIL response is most pronounced
for the TNBC subtype.
TUMOR LYMPHOCYTIC INFILTRATES IN TRIPLE-
NEGATIVE BREAST CANCER
The clinical importance of tumor immune infıltrates has
been an emerging area of research in breast cancer, particularly
in TNBC where increased immune infıltrate predicts
both response to chemotherapy and improved survival. 8,9
Tumors that have greater than 50% lymphocytic infıltrate are
called lymphocyte-predominant breast cancer (LPBC) and
KEY POINTS
In triple-negative breast cancer (TNBC), robust levels of
tumor infiltrating lymphocytes (TIL) are associated with
improved disease-free and overall survival as well as
pathologic complete response in the neoadjuvant setting.
Only a minority of TNBC express robust TIL; most tumors
show low to no levels of infiltrating lymphocytes.
Increased incidence of robust TIL in TNBC, as compared
with other breast cancer subtypes, could be caused by
increased mutations creating a neoepitope signature, as
well as increased B cells augmenting adaptive immunity via
antibody-dependent cell-mediated cytotoxicity.
The immune checkpoint inhibitor protein programmed cell
death protein 1 (PD-1) is commonly expressed in TNBC, with
70% of patients demonstrating PD-1 upregulation on T cells
and approximately 50% of triple-negative tumors expressing
coreceptor programmed death ligand 1 receptor (PD-L1).
In metastatic TNBC, clinical trials of monoclonal antibodies
blocking immune checkpoint proteins PD-1 and PD-L1 show
similar overall response rates (approximately 20%), as has
been observed for metastatic melanoma where immune
checkpoint inhibitors are now a U.S. Food and Drug
Administration–approved therapy.
have the best prognosis. Interestingly, TNBC is most likely to
have LPBC. 2,10 The presence of LPBC has been shown to predict
improved pathologic complete response (pCR) to neoadjuvant
chemotherapy. LPBC is associated with a pCR of
approximately 40%, whereas tumors with no lymphocytic infıltrate
have a 4% pCR rate (OR 1.39; 95% CI, 1.08 to 1.78; p
0.012). 1 Specifıcally, in TNBC, LPBC was an independent
predictor for improved pCR in multivariate analysis (OR
2.17; 95% CI, 1.27 to 3.72; p 0.005). 1 A meta-analysis of
studies examining TIL and pCR in all breast cancers with TIL
present in the pretreatment biopsy predicted a 2.5-times increased
pCR rate in TNBC (OR 3.30; 95% CI, 2.31 to 4.73; p
0.0001). 11 The presence of TIL has also been shown to predict
an improved clinical outcome in TNBC. In a study of 256
triple-negative tumors, LPBC was associated with both an
improved DFS (p 0.018; hazard ratio [HR] 0.30; 95% CI,
0.11 to 0.81) and OS (p 0.036; HR 0.29; 95% CI, 0.091 to
0.92), and when TIL were evaluated as a continuous variable,
every 10% increase in TIL correlated with a 17% decrease in
the risk of recurrence (p 0.023; HR 0.83; 95% CI, 0.71 to
0.98) and a 27% decreased risk of death (p 0.035; HR 0.73;
95% CI, 0.54 to 0.98). 2 Similar results from a study of 278
patients showed that 5-year OS of patients with TNBC with
LBPC compared to those without TIL was 91% and 55%, respectively,
(HR 0.19; 95% CI, 0.06 to 0.61; p 0.0017) further
emphasizing that high TIL predict a portion of patients with
TNBC who do well in this otherwise poor outcome subtype. 8
When a meta-analysis of TIL was performed in almost 3,000
patients with TNBC with a median 113-month follow-up, increased
TILs were associated with 30% reduction in risk of
recurrence (HR 0.70; 95% CI, 0.56 to 0.87; p 0.001), 22%
decreased risk of distant recurrence (HR 0.78; 95% CI, 0.68 to
0.90; p 0.0008), and a 35% decreased risk of death (HR
0.66; 95% CI, 0.53 to 0.83; p 0.0003). 10 Although LPBC has
been shown to predict benefıt in TNBC, it has not been
shown to predict improved OS or DFS in HR-positive or
HER2-positive breast cancer. 2
Although evaluation of TIL gives a global measure of lymphocytic
immune infıltrate, it does not defıne the specifıc
phenotype of populations of immune cells infıltrating the tumor,
and these immune subsets may further defıne clinical
outcome and guide further immune therapy. Triple-negative
tumors have been evaluated for cytotoxic CD8 T-cell infıltrate,
which has been shown to predict improved OS in breast
cancers in general. 12 Intratumoral CD8 T-cell infıltration
above the mean per high-powered fıeld predicted a pCR of
46% compared with a low CD8 T-cell infıltration (15%; p
0.002), with an increased intratumoral CD8/FOXP3 ratio independently
predicting improved pCR (OR 5.32; 95% CI,
1.62 to 19.98; p 0.005) in a study of 110 patients with TNBC
after receiving neoadjuvant chemotherapy. 13 Furthermore,
in multiple studies, the presence of CD8 T-cell infıltrate has
been associated with improved survival in TNBC, although response
with increasing levels of CD8 T-cell infıltrate has not
been quantifıed as it has with LPBC. Improved relapse-free survival
was found in a study of 448 triple-negative tumors either
with intratumoral (p 0.016) or stromal (p 0.001) CD8 T
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