Subtipo triple negativo:
¿debe de ser Nab-Paclitaxel un estándar?
Miquel Àngel Seguí Palmer
• Despite a better response to neoadjuvant treatments over non-TNBC tumours, the long-term prognosis of TNBC patients overall is poorer than that of other breast cancer subtypes, particularly in the first 3 years after treatment.
• Patients achieving pCR have an at least similar survival compared with non-TNBC patients, but survival for TNBC patients with residual disease remains poor in comparison.
• This paradox may be explained by the presence of
residual, resistant disease remaining in the majority of
patients (>60%)
Cortazar P, et al. Lancet. 2014
Long-term outcomes in TNBC. pCR vs. no pCR
This suggests that additions or alterations to standard NACT that
significantly increase the pCR rate could improve long-term outcomes.
Overlap of Triple-Negative, Basal-like,
and BRCA1-Mutant Breast Cancers
Distribution of clinical groups in the Claudin-low, Basal-like, HER2-enriched, Luminal B, and Luminal A within each subtype
Prat A, Perou CM. Mol Oncol. 201
Given the association between achievement of a pCR and superior long-term outcomes in TNBC,
should the standard neoadjuvant regimen
for TNBC be updated to reflect results from
trials that report higher pCR rates, or
should any revision await demonstration of
improvements in recurrence-free or overall
survival?
Answering this question is
especially challenging in TNBC,
given its aggressive biology
and limited treatment options.
While patients with HER2 + disease can benefit from anti-HER2 therapy and patients with ER + disease can benefit from endocrine therapy, the only recommended treatment for TNBC is standard chemotherapy; there is no targeted therapy specifically recommended for patients with TNBC.
Efforts so far to identify targeted therapy for
TNBC have not been successful.
Liedtke C, et al. J Clin Oncol 2008
Efficacy of neoadjuvant regimens in TNBC
Anthracycline/taxane based regimen are standard of care for neoadjuvant therapy in TNBC
Nab-paclitaxel is a solvent-free formulation of
paclitaxel encapsulated in albumin which might
further improve the pCR rate in breast cancer
patients receiving neoadjuvant treatment and
cause lower toxicity.
Untch M, el al. Lancet Oncol. 2016
Untch M, el al. Lancet Oncol. 2016
276
Untch M, el al. Lancet Oncol. 2016
GeparSepto: Primary Endpoint (pCR: ypT0 ypN0)
Untch M, el al. Lancet Oncol. 2016
GeparSepto: pCR in Stratified Subgroups
Untch M, el al. Lancet Oncol. 2016
29
38
25.7
48.2
0 10 20 30 40 50 60
PACLITAXEL NAB-PACLITAXEL
Overall
pCR % TNBC
GeparSepto: pCR in TNBC
pCR rates acccording to nP dose in TNBC
Von Minckwitz G, et al. SABCS 2015
GeparSepto: Selected Toxicities
Untch M, el al. Lancet Oncol. 2016
Time to resolve peripheral sensory neuropathy
Von Minckwitz G, et al. SABCS 2015
• The study met its primary endpoint overall, with an increase in pCR from nab-paclitaxel (OR 1.53; p<0.001); TN subset greatest benefit (OR 2.69).
• Dose reduction amendment was required.
Greater hematologic toxicity and sensory neuropathy.
• Not clear that the pCR will be enough to
translate into DFS and OS benefit, especially
taking into account the toxicity differential.
Gianni L, el al. ASCO 2016
Both Followed y Anthra y line in HER2− High-Risk Breast Cancer
Gianni L, el al. ASCO 2016
Both Followed y Anthra y line in HER2− High-Risk Breast Cancer
Parameter, n (%) P
n = 349
nab-P n = 346
Total N = 695 Disease stage
Non–locally advanced Locally advanced
261 (75) 88 (25)
264 (76) 82 (24)
525 (75.5) 170 (24.5) Tumor subtype
Luminal B intermediate Luminal B high
Triple-negative
50 (14) 189 (54)
110 (31.5)
49 (14) 188 (54)
109 (31.5)
99 (14) 377 (54)
219 (31.5)
Median age (range), years 50 (25 - 79) 50 (26 - 77) 50 (25 - 79) Tumor stage
cT2 cT3 cT4a - c cT4d
245 (70) 76 (22)
18 (5) 8 (2)
258 (75) 56 (16)
24 (7) 7 (2)
503 (72) 132 (19) 42 (6) 15 (2) Nodal status
cN0 cN1 cN2 cN3
167 (48) 153 (44) 29 (8)
6 (2)
181 (52) 138 (40) 27 (8)
8 (2)
348 (50) 291 (42) 56 (8) 14 (2)
Baseline Characteristics
Gianni L, el al. ASCO 2016
Both Followed y Anthra y line in HER2− High-Risk Breast Cancer
Primary End-Point: pCR rate
Gianni L, el al. ASCO 2016
Both Followed y Anthra y line in HER2− High-Risk Breast Cancer
Subgroup Analysis: pCR rate
Gianni L, el al. ASCO 2016
18.6
22.5
37.3
41.3
0 5 10 15 20 25 30 35 40 45
PACLITAXEL NAB-PACLITAXEL
Overall
pCR % TNBC
ETNA: pCR in TNBC
Both Followed y Anthra y line in HER2− High-Risk Breast Cancer
Safety: Select TEAEs and RD
TEAE
Any TEAE, % Grade ≥ 3 TEAE, %
P n = 335
nab-P n = 337
RD (P - nab-P)
P n = 335
nab-P n = 337
RD (P - nab-P) Peripheral neuropathy 53.7 62.6 −8.9 1.8 4.5 −2.7
Nausea 55.8 56.1 −0.3 3.9 3.6 0.3
Neutrophil count decreased 36.4 41.8 −5.4 19.7 30.6 −10.9
Asthenia 39.4 39.8 −0.4 1.8 2.7 −0.9
Fatigue 31.3 36.8 −5.5 1.2 2.4 −1.2
Vomiting 19.7 24.6 −4.9 2.4 4.2 −1.8
Diarrhea 23.9 23.4 0.5 0.9 2.1 −1.2
WBC count decreased 20.6 22.3 −1.7 7.2 8.3 −1.1
Rash 13.4 13.9 −0.5 0.9 — 0.9
ALT increased 11.6 8.0 3.6 1.5 0.3 1.2
Lacrimation increased 3.3 8.6 −5.3 — — —
AST increased 6.0 4.7 1.3 0.6 — 0.6
Hypersensitivity 6.0 1.8 4.2 0.6 0.3 0.3
Gianni L, el al. ASCO 2016
Both Followed y Anthra y line in HER2− High-Risk Breast Cancer
• Improved pCR rate after nab-P did not reach statistical significance.
• At these schedules and doses, nab-P caused an overall rate of grade ≥ 3 neuropathy of 4.5% (2.7% more than the P regimen).
• In this study, the taxane schedule (qw 3/4 vs
continuous) and the dose of P (90 vs 80
mg/m 2 ) were different from those in
GeparSepto.
25.7
48.2 37.3
41.3
0 10 20 30 40 50 60
PACLITAXEL NAB-PACLITAXEL
GEPARSEPTO
pCR % ETNA
GEPARSEPTO & ETNA: pCR in TNBC
Reconciling results of GeparSepto with ETNA
One possible explanation is the lower dose intensity of nab- paclitaxel used (125 mg/m
2QW 3/4 – equivalent to 93.75 mg/m
2/week, compared with 125 mg/m
2/week in GeparSepto).
Although the dose intensity of paclitaxel was also lower in
ETNA (90 mg/m
2QW 3/4 – equivalent to 67.5 mg/m
2/ week,
compared with 80 mg/m
2/week in GeparSepto), the relative
reduction in dose intensity between the two trials was
greater for nab-paclitaxel (25% reduction in dose intensity
with nab-paclitaxel compared with a 16% reduction in dose
intensity with paclitaxel).
Gluz O, el al. SABCS 2015
WSG-ADAPT TN
Gluz O, el al. SABCS 2015
How high a bar to change neoadjuvant therapy for triple-negative breast cancer?
The answer relies on the quantity and quality of
available data and the risks and costs associated with
the proposed treatment
Both Carboplatin and Bevacizumab Improve pCR in Neoadjuvant Treatment of TNBC
pCR: carboplatin versus no-carboplatin
Chen XS, et al. PLoS One. 2014
Both Carboplatin and Bevacizumab Improve pCR in Neoadjuvant Treatment of TNBC
pCR: bevacizumab versus no-bevacizumab
Chen XS, et al. PLoS One. 2014
Nab-Paclitaxel, Bevacizumab & Carboplatin: pCR in TNBC
How high a bar to change neoadjuvant
therapy for triple-negative breast cancer?
Nab-Paclitaxel, Bevacizumab & Carboplatin: pCR in TNBC
How high a bar to change neoadjuvant
therapy for triple-negative breast cancer?
Nab-Paclitaxel, Bevacizumab & Carboplatin: pCR in TNBC
How high a bar to change neoadjuvant
therapy for triple-negative breast cancer?
Nab-Paclitaxel, Bevacizumab & Carboplatin: pCR in TNBC
How high a bar to change neoadjuvant
therapy for triple-negative breast cancer?
Nab-Paclitaxel, Bevacizumab & Carboplatin: pCR in TNBC
How high a bar to change neoadjuvant
therapy for triple-negative breast cancer?
nabTUNE Trial
So, are we ready to add nab- Paclitaxel to the standard neoadjuvant regimen for TNBC?
Without RFS or OS data, the
answer may have to be not yet.
So, are we ready to add nab-Paclitaxel to the standard neoadjuvant regimen for TNBC?
Questions before nab-paclitaxel is incorporated into standard clinical practice:
1) the relative dose intensity needed of nab-paclitaxel to achieve an improved pCR.
2) translation of the improved pCR leading to an improved efficacy outcomes (e.g. disease free survival) in GeparSepto.
3) demonstration of resolution of the grade 3-4
peripheral sensory neuropathy to grade 0-1, is
needed.
On the other hand, in patients with larger tumors, and those with axillary nodal involvement, we must seriously consider the use of nab-paclitaxel in the hope of improving locoregional response, and discuss the pros and cons of this approach with the patient, while awaiting further data on its impact on distant recurrence and death.
So …………..
Thank you !!
0 10 20 30 40 50 60
% pCR
Nab-Paclitaxel, Bevacizumab & Carboplatin:
pCR in TNBC
Phase II trial CALGB 40603
Sikov WM, et al. J Clin Oncol 2015
