2. • Triple-negative breast cancer (TNBC) accounts for approximately 15–
20% of all breast carcinomas
• Associated with earlier age of onset, aggressive clinical course, and
dismal prognosis compared to hormone receptor and HER2-positive
breast carcinomas.
• May be associated with an inherited mutation in BRCA1
3. • Cytotoxic chemotherapy, which reduces the risk of recurrence and death,
remains the standard-of-care for patients with early-stage TNBC.
• Even so, approximately 20–40% of patients with early-stage TNBC
develop metastatic disease.
• Chemotherapy is the mainstay of treatment in both early and advanced
settings.
• Treatment options have mostly remained unchanged over years
• Need to develop predictive markers to identify TNBC patients who are
likely to have excellent outcomes with standard chemotherapy, so that
research efforts can be focused on patients who are most likely to recur
after standard neo/adjuvant therapy
4. • Gene expression array analysis has identified seven different groups of
TNBC including
Two basal-like subtypes (BL1, BL2)
An immune-modulatory variant (IM)
A mesenchymal subtype (M)
A mesenchymal stem-like variant (MSL)
A luminal androgen receptor subtype. (LAR)
Claudin low
• Up to 70% of patients with BRCA1 mutations develop tumors that are
morphologically identical to the basal cell like carcinomas and are often
triple negative. These probably form a further subset of the basal-type
carcinomas, but not all BRCA1-associated tumors are TNBC
5. • Lehman re-classification:
Refined the classification into four molecular subtypes:
• Basal-like 1 (BL1)
• Basal-like 2 (BL2)
• Mesenchymal (M)
• Luminal androgen receptor-like (LAR)
8. NACT: addition of platinum
• About 80% of BRCA1 mutation–associated breast cancers are TNBC.
• Particularly sensitive to interstrand cross-linking agents, such as platinum
analogs, due to the defect in homologous recombination (HR)-based
DNA repair characteristic of a BRCA1 mutation.
• Additionally, a subset of TNBC tumors exhibit similar defects in HR-
based DNA repair, even in the absence of a
germline BRCA mutation, and these tumors may be carboplatin-
sensitive.
9. CALGB 40603: Addition of Carboplatin to
Neoadjuvnat Chemotherapy in Triple
Negative Breast Cancer
Stage II-III
Triple
Negative
Breast Cancer
Weekly Taxol x 12
Weekly Taxol x 12
Bevacizumab
Weekly Taxol x 12
Carboplatin
Weekly Taxol x 12
Carboplatin
Bevacizumab
ddAC x 4
ddAC x 4
dd AC x 4
ddAC x 4
16. • Such benefit was not observed for subjects with BRCA1 methylation,
BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay.
• significantly increased response to docetaxel relative to poor platinum
response in non-basal forms of TNBC.
• This suggests absence of targetable BRCAness in non-basal TNBC and
no evidence to change the standard of care from taxane to a platinum.
• Platinum is a reasonable option in those with basal TNBC
17. NACT: Nabpacliatxel
• In the phase III GeparSepto study, pCR was reached in 48% of TNBC
patients treated with weekly nab-paclitaxel 150 mg/m2 versus 26% of
patients treated with weekly paclitaxel 80 mg/m2 (p = 0.00027).
• A phase III trial (ETNA study) first presented at the the American
Society of Clinical Oncology (ASCO) 2016 showed a higher rate of
response in the nab-paclitaxel arm compared to the paclitaxel one (41.3%
vs 35.5%; p value not statistically significant).
• Similar pCR rates have been reported by Kuwayama et al in a subgroup
of TNBC patients treated with four cycles of weekly nab-paclitaxel 100
mg/m2
23. OlympiAD Trial-
n engl j med 377;6 nejm.org August 10, 2017
• 121 patients, all of whom had received an anthracycline and a taxane in either the
adjuvant or metastatic setting.
• HER2-negative metastatic breast cancer who carried a germline BRCA mutation.
• randomized, open-label, phase III trial, compared olaparib monotherapy to
physician’s choice chemotherapy.
• Primary end point was PFS
24. • Median PFS was significantly longer in the olaparib group than in the
standard therapy group (7.0 months vs. 4.2 months; hazard ratio for
disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80;
P<0.001).
• The response rate was 59.9% in the olaparib group and 28.8% in the
standard-therapy group.
25. EMBRACA trial
• Patients with advanced breast cancer and a germline BRCA mutation,
talazoparib improved PFS relative to single-agent chemotherapy.
• Randomised in a 2:1 ratio, to receive talazoparib (1 mg once daily) or
standard single-agent therapy of the physician’s choice (capecitabine,
eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles).
• Primary end point was PFS
n engl j med 379;8 nejm.org August 23, 2018
26. • The objective response rate was higher in the talazoparib group than in
the standard-therapy group (62.6% vs. 27.2%).
• Median progression free survival was significantly longer in the
talazoparib group than in the standard therapy group (8.6 months vs. 5.6
months, p <0.001)
• Updated analysis, April 2020, talazoparib did not produce a statistically
significant overall survival benefit.
• Hematologic grade 3–4 adverse events (primarily anemia) occurred in
55% of the patients who received talazoparib and in 38% of the patients
who received standard therapy;
29. IMMUNOTHERAPY
• The presence of tumor-infiltrating lymphocytes (TILs), assessed by
means of immunohistochemistry staining, is widely recognized as a
predictor of good prognosis in both adjuvant and neoadjuvant settings of
TNBC.
• The expression of immune evasion molecules in the tumor
microenvironment, such as programmed death-ligand 1 (PD-L1), has
also been shown to influence TNBC prognosis.
• In addition, a deeper characterization of immune infiltrates, including the
presence of a high number of cytotoxic (CD8+) TILs or a high
CD8+/FOXP3+ ratio, is able to define TNBC patients with a better
prognosis following neoadjuvant chemotherapy.
30. I-SPY 2study
• Addition of pembrolizumab to paclitaxel plus AC chemotherapy
increased the estimated pCR rate in patients with TNBC from 20 to 60%
35. IMpassion130 trial
• 41% of patients in the intent-to-treat (ITT) population had PD-L1+
disease
• In the impassion130 study, a PD-L1 expression above 1% in immune
cells was used to define the PD-L1+ group
• At a median follow-up of 12.9months, the median progression-free
survival (PFS) in the ITT population was significantly improved
following the addition of atezolizumab as compared to chemotherapy
alone (7.2 vs. 5.5months).
• Among the PD-L1+ population, the respective PFS benefit was more
pronounced (7.5 vs. 5.0 months)
Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative
breast cancer. N Engl J Med. 2018;379:2108–21.
36. • OS difference was not statistically significant in the ITT population
(median OS, 21.3months (atezolizumab + chemotherapy) vs. 17.6months
(chemotherapy alone)
• However, a statistically significant median OS increase of 9.5months was
observed with the addition of atezolizumab in the PD-L1+ population
(25.0 vs. 15.5 months).
• the objective response rate (ORR) was numerically higher following the
addition of atezolizumab in both the ITT population (56% vs. 46%) and
the PD-L1+ population (59% vs. 43%),
• more complete responses were observed with atezolizumab than without
(ITT, 7% vs. 2%; PD-L1+ population, 10% vs. 1%).
37. Keynote 355
JCO, may2020
Pts with ≥6 mo DFI were randomized 2:1 to pembro + chemo (nab-
paclitaxel; paclitaxel; or gemcitabine/carboplatin) or pbo + chemo for up to
35 administrations of pembro/pbo or until progression/intolerable toxicity.
Dual primary endpoints are PFS (RECIST v1.1, blinded independent central
review) and OS by tumor PD-L1 expression (CPS ≥10 and ≥1) and in all pts.
38.
39. • In addition to combination immunotherapy and chemotherapy studies,
there are various small studies of the single-agent anti-programmed cell
death protein-1 (PD-1) antibody pembrolizumab as well as anti-PD-L1
antibodies avelumab and atezolizumab.
• Response rates in these studies were generally <20 percent even in PD-
L1-selected tumors.
• Additional strategies, including combination immunotherapy with other
systemic therapy or with radiation, as well as other approaches
41. TILs
• Since patients with PD-L1− tumors may still obtain a clinical response
with ICIs, PD-L1 expression should be used only to define a subgroup of
patients expected to achieve greater benefit from ICIs rather than to
exclude patients from treatment.
• Variety of potential biomarkers are now being assessed to predict
immunotherapeutic efficacy in breast cancer beyond PD-L1 expression,
including-
• Gene signatures,
• TILs
• Tumor mutational burden (TMB)
• Microsatellite instability (MSI)
• Mismatch repair (MMR) deficiency
42. Tumor-infiltrating lymphocytes (TILs)
• KEYNOTE-173 trial
• Combination of pembrolizumab and chemotherapy in the neoadjuvant
setting of TNBC.
• Showed that high levels of pretreatment stromal TILs and PD-L1
expression, reported as a combined positive score, were significantly
associated with higher pathologic complete response and overall
response rates in TNBC patients treated with an immunotherapy-based
combination.
Loi S, et al. Relationship between tumor infiltrating lymphocytes (TILs) and response to pembrolizumab (Pembro)+
chemotherapy (Chemo) as neoadjuvant treatment (NAT) for triple-negative breast cancer (TNBC): phase Ib KEYNOTE-
173 trial. Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia
(PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-09.
43. TILs and increased chemotherapy RR in breast
cancer – combined analysis of 6 NACT trials
44. PI3K/AKTi/mTOR
• Activation of the phosphoinositide 3 kinase (PI3K)/Akt/mammalian
target of rapamycin (mTOR) pathway is common in breast cancer.
• PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to
phosphatidylinositol 3,4,5-triphosphate (PIP3), which in turn leads to
phosphorylation of Akt.
• Phosphorylation of AKT stimulates protein synthesis and cell growth by
activating mTOR
• Everolimus, an mTOR inhibitor, is currently approved for the treatment
of hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative breast cancer.
45. • Oral pan-PI3K inhibitors, such as buparlisib still investigational in TNBC
• BELLE4 trial- locally advanced or metastatic HER2-negative breast
cancer (25% TNBC) were randomized to buparlisib or placebo in
combination with paclitaxel as first-line therapy, failed to demonstrate a
significant improvement in PFS in the overall population or in those with
PI3K-activated tumors (36%).
• Ipatasertib, a highly selective AKT inhibitor, was evaluated in the phase
II studies.
50. • 108 patients with previously treated metastatic TNBC
• phase 1/2 single-group
• Received sacituzumab govitecan-hziy intravenously on days 1 and 8
of each 21-day cycle until disease progression or unacceptable toxic
effects.
• 10 mg per kilogram of body weight after receiving at least two
previous anticancer therapies for metastatic triple-negative breast
cancer.
• End points- objective RR, duration of response, PFS, OS
51. • Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia
and neutropenia.
• Febrile neutropenia- 9.3%
• RR- 33%
• The median duration of response was 7.7 months
• The clinical benefit rate was 45.4%.
• Median progression-free survival was 5.5 months
• overall survival was 13.0 months
52. Androgen blockade
• The androgen receptor (AR) is expressed in both normal and malignant
breast tissue.
• TNBC expresses AR approximately 30 percent of the time.
• Prognosis for those with AR-positive TNBC has been shown to be more
favorable than those with non-AR-positive TNBC.
• Several studies sought to define antitumor activity of AR inhibition in
advanced TNBC.
