Transcript 17- neoadjuvant target therapy in her

Neoadjuvant Target Therapy in
Her-2 Positive Breast Cancer
Dr. Khaled Abulkhair, PhD
Medical Oncology SCE, Royal College, UK
Ass. Professor of Clinical Oncology
Mansoura University, Egypt
A long Road Searching for optimum NeoAdjuvant Therapy in Her -2 Positive
Breast Cancer
• What is the optimum Chemotherapy?
• What is the optimum Targeted Therapy?
• Did we reach the best available treatment?
Pertuzumab (Neo-Sphere), 2010.
29%
45.8
%
16.8
%.
24%
• Dual blockade is active in the neoadjuvant setting yet
Chemotherapy is still the corner stone.
Searching For The Best….is a
Continuous Efforts
Every time they give us a car we believe it
is the Safest, Fastest, and Strongest?
MTX…1951
Anthracycline…1990
CMF…..1973
Taxanes…Late Nineties
Neoadjuvant Chemotherapy
- Concept
developed
concurrently
with
adjuvant
chemotherapy in the 1970s.
- During the 1980s, several randomized and non-randomized
studies were conducted to evaluate the worth of
preoperative chemotherapy for operable breast cancer.
- All of these studies demonstrated that preoperative
chemotherapy results in a high rate of primary tumor
response
Adjuvant OR Neoadjuvant
• Does the patient desire breast preservation?
• Is there a benefit from knowledge of in-vivo
chemosensitivity?
To investigate this, the NSABP and EORTC
independently conducted clinical trials that compared
neoadjuvant
chemotherapy
with
adjuvant
chemotherapy for patients with stage II or III disease.
- Data published 2001, Both trials found that BCS rates
were higher (22% BCS rate vs 8%) in the neoadjuvant
arm due to down-staging of T3 disease.
Short Messages About Adjuvant
Chemotherapy For Breast Cancer
Review of the serial reports of the EBCTCG's metaanalyses.
1. Chemotherapy reduces the risk of recurrence and death.
2. Combination is more effective than single-agent .
3. Chemotherapy is more effective for women younger than
50 years of age than for older women.
4. Anthracyclines-containing regimens are more effective.
5. Six months of chemotherapy considered optimum.
6. Addition of Taxanes significantly improves RFS and OS.
Adding Docetaxel…Improved cCR…Improved
pCR…Improved RFS...Improved OS in pCR
Neoadjuvant Before The Era of
Targeted Therapy
• Neo-Adjuvant chemotherapy adds many
advantages to the management of breast
cancer.
• Anthracyclines are integral part in the
neoadjuvant setting.
• Adding Taxanes to Anthracyclines boosts both
DFS and OS.
• Weekly Paclitaxel is preferred over Q 3 weeks.
Effect of HER-2 amplification on breast
cancer cells (Sinn, 1990).
Human breast cancer cells
DNA synthesis 50–75%
Cell growth rate 30–50%
MCF-7
Transfect with
MCF-7
Growth in soft agar 225%
HER2 gene
expression of MMP-2.
HER2
–ve
HER2
+ve
Transformed
Aggressive
phenotype
Metastatic potential 220%
in nude mice
HER-2 Oncogene: overexpressed in 20-25% of breast cancers.. Tissuespecific expression of myc, ras, and HER-2 in mammary glands of transgenic mice has
been shown to result in an increased incidence of both benign and malignant breast
pathology (Sinn, 1990).
Biological Target…Her- Family
A New Story Began Searching for
optimum Neo-Adjuvant Therapy in Her -2
Positive Breast Cancer
• Integrating Biological Agents?
• Which One is The Best?
• Did we reach the best available treatment?
Trastuzumab ..…The Gold Standard
Fast Trip from metastatic to
neoadjuvant
Trastuzumab
• Trastuzumab is a humanized recombinant monoclonal
antibody directed against HER-2 receptors.
• According to the international panel on neoadjuvant
therapy, it should be part of the neoadjuvant treatment
regimen in patients with HER-2 positive breast cancer.
• Many studies have shown that blockade of these
receptors has therapeutic implications (Zhang et al.,
1999).
• Furthermore, these antibodies have synergistic
interactions with cytotoxic agents, such as the
anthracyclines, the platinum analogs, and the taxanes
(Baselga et al., 1994).
• Trastuzumab in the adjuvant setting produced
spectacular results with about 50% decrease in
recurrence as shown in 6 randomized trials.
• After follow-ups ranging from 1 to 2 1/2 years,
five trials (NSABP B- 31, N9831, BCIRG006,
FinHER and HERA) demonstrated such marked
benefit that the trials were stopped and the results
reported.
• Trastuzumab-treated patients had about a 46% to
58% reduction in risk of recurrence in these five
trials.
• Significant survival benefits have emerged in five
of the six trials, with a 33% to 59% reduction in
mortality.
Lapatinib
• Lapatinib is an orally active, small molecule which
reversibly inhibits HER1 and HER2 tyrosine kinase.
• This inhibition leads to blockade of different
signaling pathways, resulting in growth arrest and/or
apoptosis.
• Some data indicate that lapatinib can also block
HER2-HER3 mediated cell growth [22, 23].
• Lapatinib as a small molecule can penetrate the
blood-brain barrier and, therefore, was claimed for
therapy and prevention of brain metastases.
Pertuzumab
• Pertuzumab is the humanized monoclonal antibody
that binds to dimerization domain II of HER-2
receptor, which is necessary for HER-2 activation
and cell signaling.
• Clinically, the most important action of Pertuzumab
is inhibition of HER2-HER3 dimerization.
• Pertuzumab affects important signaling pathways
that mediate cell proliferation and synergistically
with Trastuzumab inhibits breast tumor cells
survival.
Which Regimen Is The Best?
• A number of chemotherapy + Trastuzumab combinations
have proven good response rates with good tolerability.
However, several aspects have yet to be clearly defined:
• Which regimen has superior efficacy?
• if Anthracyclines should be used or not; and if they should
only be used sequentially or also concurrently with
Trastuzumab?
• Sequential Anthracycline - Taxanes plus Trastuzumab gives
a pCR of 40% versus 17% with chemotherapy alone .
• New era began with the Dual HER-2 blockade?
Trastuzumab In The Neoadjuvant Setting
• In the first reported randomized trial, Buzdar et al 2005,
evaluated patients with HER2-positive, early-stage operable
breast cancer, who were assigned to receive FECx4 with or
without Trastuzumab weekly .
• Adding Trastuzumab to neoadjuvant therapy significantly
increased the pCR rate from 26.3% to 65.2%.
• These results led to a premature closure of the study .
Unfortunately, such high pCR rates have not been observed
in successive trials.
• The Neoadjuvant Herceptin (NOAH) trial, 2010, found that
adding Trastuzumab significantly improved overall response
rate (ORR) (87% versus 74%; 𝑃 = 0.009) and pCR rate (43%
versus 22%; 𝑃 = 0.0007).
• The famous German (GeparQuattro) trial, 2010 which
included 1509 patients with either locally advanced (T3 or
T4), any hormonal status but lymph-node-positive tumours.
A
31%.
Docetaxel (100mg/m2) x4
B
EC X 4
TRASTUZUMAB
For
HER+++
Docetaxel (75mg/m2) + Capecitabine
(1800mg/m2) x4
S
U
R
G
E
R
C
Docetaxel (75mg/m2) x4 followed by
capecitabine (1800mg/m2) x4
16%.
Y
Trastuzumab
for 1-Year in
Her-2 Positive
• (TECHNO), 2011 Taxol Epirubicin Cyclophosphamide
Herceptin NeOadjuvant study multicentre, prospective,
open-label, phase II clinical trial enrolled 217.
EC X 4
Paclitaxel 175 mg/m2 Q3W +
Trastuzumabx4
Surgery
Trastuzumab
to complete
1 year
• The primary endpoint was pCR.
• A 39 % had pCR. With significant better 3 year DFS and OS
in the group of pCR.
• A systematic review and meta-analysis, 2011 concluded
that the use of Trastuzumab combined with neoadjuvant
chemotherapy in patients with HER2-positive breast
cancer seems to offer substantial benefit in terms of
pCR.
Dual Blockade in Neoadjuvant Setting
(Neo-Sphere), 2010.
29%
45.8
%
27%.
16.8
%.
24%
• Adding Pertuzumab to Trastuzumab is active and
substantially increases the pCR
Dual Blockade in Neoadjuvant Setting
• (NeoALTTO) trial, 2012 included 455 HER2-positive patients
who had tumours at least 2 cm in diameter .
• Combination of lapatinib and Trastuzumab led to a significantly
higher pCR rate (51.3%) than that of the monotherapy arms. The
response to lapatinib was numerically lower than to Trastuzumab,
although the difference did not reach statistical significance.
• The dual combination was associated with higher toxicity,
especially diarrhoea and hepatotoxicity, and more patients
discontinued therapy because of adverse events.
The comparison of Lapatinib versus Trastuzumab
was the aim of the GeparQuinto trial, 2012
• This randomized phase III study included 620 patients with
operable or locally advanced HER2-positive breast cancer.
• The results have confirmed a higher pCR rate for the
Trastuzumab arm (30.3%) compared with that of
lapatinib (22.7%).
Trastuzumab plus Pertuzumab in Neoadjuvant HER2Positive Breast Cancer trial (TRYPHAENA), 2013.
• The primary endpoint of cardiac safety was met, with a low
incidence of left ventricular systolic dysfunction across all arms.
• pCR rates were similar across the three arms and regardless of
the chemotherapy chosen reached from 57% to 66% with
DCTP. Better results were seen in patients with hormonenegative disease.
• The efficacy of pCR as a measure of evaluating therapies
for breast cancer has been a closely watched issue in
oncology drug development.
• In September 2013, the FDA approved an expanded
indication for Pertuzumab in combination with
Trastuzumab (Herceptin) and Docetaxel preoperatively in
patients with high risk, HER2 positive early stage breast
cancer.
• The decision marked the first time that the FDA has
formally approved a neoadjuvant breast cancer treatment.
• A meta-analysis by Cortazar et al,2014 showed that
achieving pCR following preoperative chemotherapy was
an especially strong predictor of event free survival in
aggressive forms of breast cancer.
• Attaining pCR reduced the risk of death by 92% in cancers
that were HER2 positive and hormone receptor–negative
cancers and by 84% in (TNBCs).
Comparative Effectiveness of Neoadjuvant
Therapy for HER2–Positive Breast Cancer:
A Network Meta-Analysis
• In a recent meta-analysis published JNCI J Natl
Cancer Inst (2014).
• Evaluating a total of 10 eligible trials including
2247 patients in seven different treatment arms were
assessed. Chemotherapy +\- Anti-HER-2 agents that
included Trastuzumab, Lapatinib, and Pertuzumab.
• This study indicates that combining two anti-HER-2
agents with Chemotherapy is the most effective
treatment modality in the neoadjuvant setting for
HER-2 positive breast cancer.
Value of pCR in HER2-Positive Breast Cancer
• Studies showed that pCR means better DFS, OS and lower
relapse rate. pCR is considered a surrogate marker for outcome
in HER-2.
• However, value of pCR differs according to the hormonal
status.
• The MDACC group, 2006 detected ER-negative is associated
with higher pCR rates, regardless of type and duration of
chemotherapy. It is still true for target therapy too.
• A recent analysis, 2011 also showed that pCR was associated
with significantly higher DFS only in hormone negative but
not in hormone positive disease.
• Accordingly, we have to be careful in using pCR as a marker
in the case of hormone positive Her-2 positive disease..
Efforts to Omit Anthracyclines
• Feasible and can decrease the toxicity supported by
series of phase II neoadjuvant studies that reported
pCR rates ranging from 19% to 76% using
Trastuzumab, a Taxanes, and a platinum compound
and supported by results of TCH/DCTP.
• TRYPHAENA supported omitting Anthracyclines.
• However, the BCIRG 006 study demonstrated in the
adjuvant setting a slightly inferior disease-free
survival for the TCH against ACTH regimen.
Conclusions
• HER-2 disease presents a heterogeneous group of
diseases. Its management has significantly improved in
recent years, and neoadjuvant treatment has become
widely accepted.
• Neoadjuvant Trastuzumab had a substantial impact on the
outcome of this disease.
Western
• Dual blockadeMiddle
hasEastrevealed significant
efficacy and
presents a new therapeutic approach. Yet, cost is an
important issue beside confirming OS benefits.
• Guidelines for management of Her-2 positive MBC is
rapidly changing due to availability of many new
targeted agents e.g. TDM-1, Neratinib, Afatinib…..
• Concurrent Anthracyclines Trastuzumab looks feasible
with accepted toxicity. Would this apply to Our
patients?
Now, Do We Have The Fastest, Safest and
Strongest?
• I believe we did not reach the best yet.
• How to accurately define those who will be pCR?