QuoteReplyTopic: Current Perspective on Treatment Options Posted: Oct 05 2019 at 12:32pm
Triple-negative breast cancer: current perspective on the evolving therapeutic landscape
Abstract
Triple-negative
breast cancer (TNBC) is known to have a poor prognosis and limited
treatment options, namely chemotherapy. Different molecular studies have
recently classified TNBC into different subtypes opening the door to
potential new-targeted treatment options. In this review, we discuss the
current standard of care in the treatment of TNBC in the neoadjuvant,
adjuvant and metastatic settings. In addition, we summarize the ongoing
phase III clinical trials evaluating different associations between the 3
pillars of anticancer treatment: chemotherapy, targeted therapy and
immunotherapy.
Introduction
Breast cancer continues to be the second cause of death in women worldwide.1
Triple-negative breast cancer (TNBC) is defined by the lack of
expression of estrogen (ER), progesterone (PR) and HER2 receptors. TNBC
represents approximately 10–15% of all diagnosed breast cancers.2
The pattern of metastatic spread in TNBC is different from the other
breast cancer subtypes with a higher likelihood of brain and lung
involvement and less frequent bone lesions; in addition, this is the
tumor subtype with the poorest prognosis between all breast cancer
subtypes.3
In
the current era, more in-depth studies have divided TNBC into different
subtypes, according to their molecular characteristics. By analyzing
gene-expression profile of TNBC, Lehman et al showed the existence of 6
different subtypes: basal-like 1 and 2, immunomodulatory, mesenchymal,
mesenchymal stem-like and luminal androgen receptors.4
In a more recent study, the same authors re-classified these tumors
into 4 groups: basal-like 1, basal-like 2, mesenchymal and luminal
androgen receptor.5
Another classification for TNBC was suggested by Burstein et al
describing four subtypes: luminal androgen receptor, mesenchymal,
basal-like immune-suppressed and basal-like immune-activated.6
In the same study, the basal-like immune-activated subtype showed to be
associated with good prognosis, which is compatible with the results of
other studies showing better outcomes for TNBC having lymphocytic
infiltration.7,8
TNBC
is more often associated with hereditary conditions as compared to
other breast cancer subtypes. For instance, among newly diagnosed breast
cancer patients, <10% have BRCA1 or BRCA2 mutated genes but this percentage is higher among patients with TNBC with around 35% of BRCA1 and 8% of BRCA2 mutations in this population. Among BRCA1 mutation carriers, more than one-third have TNBC.9 TNBC diagnosed in women at the age of 60 years or less is considered a criterion to test for BRCA mutations.9 Tumors missing the germline mutations in BRCA1/2 but keeping the same characteristics are classified as “BRCAness.”10
In
this review, we discuss the standard of care in the treatment of TNBC
in the neoadjuvant, adjuvant and metastatic settings. In addition, we
summarize the ongoing phase III clinical trials evaluating different
associations between the 3 pillars of anticancer treatments:
chemotherapy, targeted therapy and immunotherapy.
Please click on the link to read. Very detailed and thorough discussion.
Residual disease and immune infiltration as a new surrogate endpoint for TNBC post neoadjuvant chemotherapy
Triple
negative breast cancer (TNBC) is distinguished from other breast cancer
subtypes by its lack of therapeutic targets, aggressive biology, and
poorest survival rates. In the early breast cancer setting, cytotoxic
chemotherapy remains the mainstay of systemic treatment options.
Multiple clinical trials and meta-analyses have demonstrated that
patients who achieve a pathological complete response (pCR) to
neoadjuvant chemotherapy (NAC) have an excellent prognosis [1].
Therefore, NAC is now extensively used for early stage TNBC (and
HER2-positive breast cancer) to improve prognostic stratification, but
also in the setting of residual disease, to enrich for high risk,
treatment resistant patients that may benefit from treatment escalation
or change of systemic therapy [2].
Reported rates of pathologic complete response (pCR) to neoadjuvant
chemotherapy (NAC) regimens in TNBC are typically in the vicinity of
40–60% depending on patient selection and chosen treatment regimen.
Higher levels of pre-treatment tumor-infiltrating lymphocytes (TIL) are
associated with high rates of pCR suggesting that the presence of robust
host immunity contributes to chemotherapy response [3, 4]. This suggests that substantial biological heterogeneity exists within the TNBC subtype.
We
rationalised that the most clinically relevant heterogeneity exists in
patients with tumors that do not achieve a pCR, and that biomarkers that
refine prognostic estimates and improve biological understanding in
this population might help guide the development of hypothesis-driven
clinical trials in the future. We recently reported results from our
analysis that combined four data series of patients with TNBC who
received NAC and did not achieve pCR, with a key focus on two highly
prognostic biomarkers – residual disease TILs, and residual cancer
burden (RCB) [5].
This editorial highlights some of the findings from this report,
discusses potential clinical implications, and future areas of research (Figure 1).
Flow
diagram demonstrating the potential clinical utility of residual cancer
burden (RCB) and residual disease tumor-infiltrating lymphocytes in
patients with residual disease after neoadjuvant chemotherapy for triple
negative breast cancer.
Future research questions are also proposed.
Our
study demonstrated that both RCB and residual disease TILs are powerful
prognostic markers that can further refine prognostic estimates in this
population. The best survival outcomes were observed for patients with
minimal residual disease burden (RCB class I). Other studies have
demonstrated that patients achieving RCB class I after NAC have a
similar prognosis to those who achieve pCR [6, 7].
Concordant with this, the 5 year overall survival (OS) estimate for
patients achieving RCB I in our cohort was high at 91% (95% confidence
interval [CI] 81–100%), and hence no significant prognostic influence of
residual disease TILs was observed. Given the excellent long term
prognosis we hypothesize that these patients are unlikely to gain large
absolute benefit from the addition of further adjuvant systemic therapy [2].
On
the other hand, the worst disease outcomes were observed for patients
with extensive residual disease burden (RCB class III), with a 5 years
OS estimate of 31% (95% CI 24–40). The majority of these patients (82%)
experienced disease recurrence, of which 72% had a recurrence which
occurred early (within 12 months of definitive surgery). In our cohort,
the median OS (from the time of recurrence) for patients who developed
an early recurrence in our cohort (irrespective of RCB class) was a
dismal 6.1 months (95% CI 5.2–8.8). This highlights an urgent need for
further research into these poor prognosis patients who are essentially
chemo-refractory. Notably, the efficacy of PD(L)-1 blockade in this
population remains unclear as patients with an early recurrence were not
eligible for the recently published IMpassion130 study [8].
Interestingly, our study found no significant positive prognostic
influence of higher residual disease TILs for patients with RCB class
III, suggesting either the immune infiltrates are significantly
suppressed, ineffective, or exhausted, despite these being predominantly
CD8+ T cells [9, 10].
Further research will be required to understand the biological
mechanisms underlying chemo-refractory primary TNBC, as well the exact T
cell phenotype, however it is extremely likely that novel therapeutic
strategies, including immunotherapy combinations, will be needed to both
effectively reduce tumor burden, and stimulate active anti-tumor immune
responses. We hypothesize that single agent PD(L)-1 inhibition will be
ineffective in this group.
The positive prognostic
influence of residual disease TILs was greatest in patients with
moderate residual disease burden (RCB class II), whereby prognosis could
be stratified to outcomes similar to that of RCB class I and RCB class
III depending on the quantity of residual disease TILs. The significant
prognostic influence of residual disease TILs, and the heterogeneity in
disease outcomes in this setting suggests that adjuvant immunotherapies,
such as with PD(L)-1 blockade with chemotherapy could potentially
result in survival gains for these patients. Further research into the
tumor intrinsic mechanisms underpinning the presence or absence of
residual disease TILs in RCB class II, as well as the immune checkpoint
molecules that are frequently expressed on T cells, will further help
refine therapeutic strategies for these patients.
Beyond
improved prognostic stratification, we believe that there is a need to
find a more refined biomarker surrogate for patient survival than pCR
alone. Therapeutic strategies that have led to significantly increased
pCR rates to neoadjuvant treatments have not uniformly lead to
significant survival benefits for patients [1].
We rationalise that a composite clinical trial endpoint for neoadjuvant
trials that encompasses both residual disease (RCB), as well as immune
response to therapy may function as a better predictor of survival
benefit. To develop such a surrogate marker we would require large
randomized clinical trials collecting pCR status, RCB class, and TIL
evaluation, alongside event-free and OS data, to understand how changes
in these parameters correlate to survival. A more accurate short-term
surrogate endpoint would be the Holy Grail for rapid and efficient drug
development. The prognostic significance of residual disease TILs, as
well as the value of early biopsy evaluating on-treatment TILs are also
worthy of exploration in other cancer types, however the value of these
biomarkers in predicting outcome may differ by cancer type and utilized
therapy.
In summary, we believe our
data can be used to improve prognostic stratification, help refine
target populations for research, and contribute to the design of future
neoadjuvant clinical trials.
Thank you for the article ... which highlighted 4 subtype of TNbc ... wondering how do we self identify our type for the non- mutations... the article highlighted the benefit of doing full dose vs low dose concurrent so long cycle seems no good any more?
Also, it doesn’t say anything for the Keytruda 522 trial III review, which shows great benefit for TNBC earlier stage...
It’s sad to hear that for TNBC, mutations have better outcomes v non...
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