Predictors of Response to Neoadjuvant Docetaxel-Carboplatin Chemotherapy for Patients With Stage II and III Triple Negative Breast Cancer
Neoadjuvant (preoperative) chemotherapy is an interesting research tool which allows
investigators to test new drugs and/or new schedules with a validated surrogate endpoint,
pCR. It also represents an ideal model to evaluate the relationships between treatments and
tumor biomarkers. Recent publications have shown that new molecular classifications of
breast cancer (intrinsic subtypes) have an important prognostic and predictive value. Using
microarrays for gene expression profiling seems to be the best way to perform this
classification; nevertheless such assays are not optimally available for common clinical
practice. The IHC-based classification systems are still useful, as fresh tissue is not
normally available in clinical practice, and has been shown to correlate well with intrinsic
classification using gene expression microarrays. Recently the PAM50 gene set provided a
risk of relapse score not only in ER-positive, node negative patients (similarly to the
Oncotype Dx Recurrence Score) but also in the ER negative disease. Additionally, the PAM 50
assay was highly predictive of neoadjuvant response when considering all patients. This
assay added significant prognostic and predictive value to pathologic staging, histologic
grade, and standard clinical molecular markers while using an easy technique that can be
performed in clinical practice because the qRT-PCR assay can be performed using FFEP tissue.
Triple Negative Breast Cancer (TNBC) is defined by a lack of expression of ER, PgR and
HER-2. DNA microarray profiling studies have led to the classification of invasive breast
carcinoma into five subtypes: luminal A and B, normal breast-like, HER2/neu overexpressing
and basal-like subtypes, with clinical implications. Later on, a new subtype, the
claudin-low, has been described. Although not synonymous, the majority of TNBCs carry the
basal-like breast cancer (BLBC) molecular profile. The triple negative subtype accounts for
11-20% of breast cancer in different studies, whereas in selected cohorts of patients with
advanced breast cancer or African-American ethnicity, TNBC may be diagnosed among as many as
23-28%. Patients with TN breast tumors treated with standard chemotherapy have a shorter DFS
and OS than non-TNBC, this difference have been shown to be independent from tumor grade,
nodal status and treatment in some studies. The peak risk of recurrence occurs within the
first 3 years after initial treatment, with the majority of deaths occurring in the first
Chemotherapy remains the only systemic treatment option available for TNBC patients. Several
studies have shown that TNBC/BLBC is associated with an increased response rate to
neoadjuvant chemotherapy when compared with luminal tumors. However, TNBC patients have a
significantly decreased DFS and OS in comparison with luminal patients. The largest study
exploring response and survival in early stage breast cancer treated with neoadjuvant
chemotherapy was reported by Liedtke et al. Although an increase pCR rate was observed among
the TNBC patients, they had a shorter lifespan than the non-TN ones. Patients experiencing
pCR had an excellent OS regardless of hormone receptor expression, but patients with
residual disease had a significantly shorter survival associated with TNBC compared with
non-TN ones. This demonstrates that poor OS is derived from chemo-resistant patients (what
unfortunately represent > 50% of them).
A relevant problem is the differential response to drugs of TN tumors. These tumors are
usually treated with multidrug combinations including anthracyclines and taxanes, with pCR´s
of 28-32%. Only recently, the results of a few small trials combining platinum salts and
taxanes have been reported, with encouraging results (pCR of 44-77%). The taxane-platinum
salt combinations have a biological background, since TN not associated BRCA1 mutations are
sensitive to taxanes and resistant to anthracyclines and platinum salts are effective in TN
tumors probably because a significant proportion of them have functional DNA repair
Role of anthracyclines and taxanes in TN breast cancer Efficacy results of
anthracycline-based regimens in patients with TNBC remain controversial. The analysis from
the MA5 study (which randomized patients between CMF and FEC), showed an increased 5-year
DFS in favor of CMF (71% vs 51%) in the basal-like subtype group. The test for interaction
between biologic phenotype and treatment arm almost reached significance (p=0,06) indicating
that patients with TNBC may not derive a particular benefit from anthracyclines.
Several phase III studies comparing classical anthracycline schedules with anthracycline
plus taxane treatment have performed retrospective analysis classifying patients between the
different breast cancer subtypes. Results from those analysis showed that TNBC/BLBC patients
treated with classic anthracycline regimens were having a very poor outcome (similar or in
some of these studies even worse than the HER2 overexpressing patients before the
trastuzumab era). In those studies the TNBC/BLBC populations were the ones benefiting the
most from the taxane addition.
In addition to that, a single study by our group has compared single agent doxorubicin
versus single agent docetaxel as neoadjuvant chemotherapy for locally advanced breast
cancer. In this study, both drugs were similar in luminal and her2 subtypes, but docetaxel
was significantly superior to doxorubicin in patients with basal-like tumors (good
pathological response rate of 56% vs 0%, p=0.034). Besides, triple negative status was the
only significant predictor of resistance to doxorubicin in multivariate analysis. Residual
cancer burden after neoadjuvant chemotherapy in triple negative tumors was also
significantly higher with doxorubicin than with docetaxel, thus indicating that this subtype
is more resistant to doxorubicin than to docetaxel. This study firmly suggest that docetaxel
should be the backbone of combination regimens for basal-like tumors and questions the role
of doxorubicin in these tumors.
Role of platinum salts in TN breast cancer The role of platinum salts in TNBC is currently a
matter of investigation. Basal-like breast cancers (BLBC) are highly aneuploid, associated
with BRCA1 germline mutations, and have loss of TP53, RB1 and Chromosome 5q. None of these
characteristics are observed in Claudin-low tumors suggesting a different etiology, and
possibly, a different response to DNA damaging agents. Phase II studies have suggested that
platinum salts have a significant activity en TNBC, particularly in BRCA-1 mutation
carriers. Unfortunately, we cannot distinguish TNBC from Claudin-low with conventional IHC
Activity and side effects of the combination docetaxel-carboplatin in breast cancer The
combination of carboplatin and docetaxel has been extensively studied mainly in ovarian and
lung cancer. Doses of AUC 5-6 of carboplatin in combination with 75 mg/m2 of docetaxel are
easily combined, being myelosuppression the most important toxicity. This combination has
been studied in metastatic breast cancer as well as in the neoadjuvant setting.
Perez et al studied docetaxel (75 mg/m2 IV over 1 hour) followed by carboplatin (AUC 6 IV
over 30 minutes) as first-line chemotherapy in 53 women with MBC. Patients received a median
of 6 cycles. An overall response rate (ORR) of 60% (complete response [CR] 6%, partial
response [PR] 54%) was noted. Grade 3/4 toxicities included anemia (11%), neutropenia (94%),
thrombocytopenia (17%), febrile neutropenia (15%), leukopenia (15%), fatigue (21%),
infection (11%), diarrhea (11%), hypersensitivity (8%), neurosensory (4%), and neuromotor
(4%). A total of 26 patients received granulocyte colony-stimulating factor (G-CSF) and/or
erythropoietin support. The authors concluded that although myelosuppression was noted,
docetaxel and carboplatin were an active treatment regimen for first-line therapy in MBC and
prophylactic hematopoietic growth factor support is recommended.
Docetaxel and carboplatin was evaluated in another phase II study in 40 patients with
previously untreated MBC. Patients received docetaxel (75 mg/m2) and carboplatin (AUC 5) on
day 1 every 3 weeks for up to 6 cycles. An ORR of 59% (CR 15.4%, PR 43.6%) was observed
among the 39 patients evaluable for response. Grade 3/4 toxicities included neutropenia
(n=28), febrile neutropenia (n=4), and thrombocytopenia (n=4). The authors concluded
docetaxel and carboplatin were efficacious as first-line treatment for metastatic breast
cancer, with an acceptable toxicity profile.
An additional phase II study with the same schedule was performed, as first-line
chemotherapy in 32 patients (30 female, 2 male) with metastatic breast cancer. An ORR of
62.07% (8 CRs, 10 PRs) was reported; five patients (17.24%) had progressive disease. Grade 3
toxicities included neutropenia (24%), anemia (15.6%); nausea, vomiting, fluid retention,
and peripheral neuropathy occurred in 15 patients. There were no reports of febrile
neutropenia, nor were there any deaths. The authors concluded that the combination of
docetaxel and carboplatin as first-line therapy in metastatic breast cancer patients was
promising with well-tolerated toxicities. A fourth trial also with the same schedule
determined the safety and efficacy of the combination in 25 women with MBC. An ORR of 56%
(CR 24%, PR 32%) was reported. Grade 3/4 toxicities included neutropenia (24%), one case of
febrile neutropenia that required hospitalization and two patients with diarrhea. Anemia
noted in seven patients was deemed "mild" and there were no reported toxic deaths. The
authors concluded combination docetaxel and carboplatin was safe and active as first-line
therapy in patients with MBC.
With regards to its use in the neoadjuvant treatment, this combination was studied in 57
patients with stage II/III breast cancer (10). Docetaxel (75 mg/m2) and carboplatin (AUC 6)
were given on day 1 with pegfilgrastim (6 mg subcutaneously) on day 2. This regimen was
repeated in a dose-dense manner every 2 weeks for 4 cycles. Fifty-one patients (89%) had
breast-conserving surgery within 6 weeks. Among all 57 patients, a pathological complete
response (pCR) of 16% was reported. Four out of 9 patients with triple negative tumors had
pCR (44%). Thrombocytopenia was the only grade 4 toxicity reported. Grade 3 toxicities in
addition to thrombocytopenia consisted of anemia, fatigue, diarrhea, nausea, and
hypokalemia. The authors concluded the combination of docetaxel, carboplatin, and
pegfilgrastim was feasible and tolerable in all patients.
In a phase II trial, Karmarkar et al investigated a neoadjuvant regimen of four cycles of
docetaxel (90 mg/m2) and carboplatin (AUC 6) on day 1 with filgrastim every 3 weeks in 22
patients with locally advanced breast cancer. After four cycles, patients underwent surgery.
A total of 16 patients were evaluable for efficacy and toxicity. There were five complete
responses and 11 partial responses reported. Grade 3/4 toxicities included myelosuppression
with infection (n=1), myalgia (n=2), diarrhea (n=1), fatigue/asthenia (n=5), and nausea
(n=4). The authors concluded that this neoadjuvant combination of docetaxel and carboplatin
was active and well tolerated; they also noted that the addition of filgrastim allowed a
dose intense regimen to be delivered.
A recently published phase II performed by Chang et al studied the same regimen but with a
lower docetaxel dose (75 mg/m2) and without G-CSF support. Seventy-three patients were
treated for 4 cycles (11 of them were TNBC). Patients HER2 positive were additionally
randomized to chemotherapy alone or in combination with trastuzumab weekly. Seventy-one
patients underwent surgery from which 19 (26.8%) had pCR (absence of invasive breast cancer
in the breast), 6 of them within the TNBC subgroup. Grade 3/4 toxicities other than
hematological, such as neutropenia (43%), and febrile neutropenia (4%) were rare. Grade 3
docetaxel hypersensitivity was noted in 4% of patients and all other grade 3/4 adverse
events occurred in less than 2% of them.
All shown data, together with the potential anthracycline cardiotoxicity and risk of
anthracycline-induced leukemias in patients with a high probability of being cured,
challenge the role of anthracyclines in the treatment of early stage TNBC patients. The
combination of taxanes and platinum salts is, therefore, increasingly used as neoadjuvant
chemotherapy for triple negative breast cancer. The docetaxel-carboplatin (TCb) regimen is
an active and tolerable regimen in metastatic and locally advanced breast cancer, and the
efficacy and toxicity characterization in the clinical setting are regaining interest in the
era where the role of anthracyclines is controversial in the adjuvant setting. The avoidance
of potentially serious long-term toxicities in specific breast cancer subtypes is a real
challenge in an attempt to individualize therapies.
In the daily practice, however, we have problems identifying basal-like tumors, since not
all triple negative tumors belongs to this subtype. We need, therefore, predictive markers
of response to neoadjuvant chemotherapy in general and the docetaxel-carboplatin regimen in
Primary Objective The primary objective of the study is to identify predictors of response
to docetaxel-carboplatin in patients with triple negative primary tumors. Response is
defined as lack of invasive tumor in breast plus axilla after neoadjuvant chemotherapy (PCR,
pathological complete response).
Secondary objectives are the following:
- To identify predictors of good pathological response according to Symmans criteria
(i.e. Symmans class 0+1).
- To identify predictors of chemoresistance (class III od Symmans)
- To assess the clinical response rate by standard methods (MRI, clinical examination,
mammogram) in patients treated with this regimen.
- To evaluate breast conserving surgery rate in patients treated with this regimen.
- To evaluate the pCR rate in patients with known BRCA mutations.
Patients with triple negative tumors according to a core biopsy scheduled to be treated with
docetaxel plus carboplatin (i.e., no contraindications for the regimen) will be candidate
for the study. After detailed information of study purposes, they will be asked to sign an
informed consent Triple negative status is defined as ER <1% stained cells, PR <1% stained
cells and HER2 negative (IHC of 0-1+ or or 2-3+ with FISH/CISH negative testing).
Patients will have 6 cycles of docetaxel (75 mg/m2 IV day 1) plus carboplatin (AUC 6, IV day
1) every 3 weeks (TCb regimen). Patients with objective response or stable disease will
undergo surgery after the sixth cycle.
While on treatment, patients will be assessed as clinically indicated to discard progression
with breast MRI. A biopsy will be performed to confirm progression and the patient will be
removed from the study and treated according to investigator's criteria, usually with
anthracycline-containing regimens (i.e. FE90C, 5FU 600 mg/m2 IV, epirubicin 90 mg/m2 IV,
cyclophosphamide 600 mg/m2 IV, day 1 every 3 weeks).
Patients who achieve a pathological complete response at surgery will not receive additional
chemotherapy (radiation therapy will be administered as indicated by local criteria, i.e.,
breast preserving surgery, large tumors >5 cm, axillary involvement). Those patients who do
not achieve a pathological complete response at surgery will receive 3 additional cycles of
FE90C chemotherapy after the surgical procedure.
Observational Model: Case Control, Time Perspective: Prospective
predictors of response to docetaxel-carboplatin in patients with triple negative primary tumors
The primary objective of the study is to identify predictors of response to docetaxel-carboplatin in patients with triple negative primary tumors. Response is defined as lack of invasive tumor in breast plus axilla after neoadjuvant chemotherapy (PCR, pathological complete response).
Spain: Comité Ético de Investigación Clínica