Transcript 14- final neoadjuvant therapy in her

Neoadjuvant 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
Questions?
1. Is systemic therapy needed in breast cancer?
2. Adjuvant or Neoadjuvant?
3. What is the best Chemotherapy?
4. Why Her-2 disease is a unique subtype?.
5. How to target Her-2 positive breast Cancer?
6. New perspectives?
Why To Offer Chemotherapy?
• 35% to 85% of patients with lymph node-positive
breast cancer will develop metastatic disease.
• A review of the literature suggests that even small
(<1 cm), node-negative tumors have reported
recurrence rates ranging up to 20% by 10 years.
• The
1990
NIH
consensus
conference
recommended the routine administration of
adjuvant systemic therapy to women with high-risk
histologically negative axillary nodes based on
newer data.
• WHAT IS THE BEST CHEMOTHERAPY?
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
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.
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
Advantages of Neoadjuvant Chemotherapy
•
•
•
•
Facilitates mastectomy in operable disease.
Increases rates of BCS for larger primary tumors.
Allows in-Vivo Monitoring the response to chemotherapy.
The pathological response of disease to neoadjuvant
chemotherapy is prognostic. An invaluable research tool to:
- Directly compare the effectiveness of two systemic
regimens
- Directly study biological factors that influence
chemotherapy
sensitivity/resistance
• Identify patients for trials of new agents because of their
high risk for recurrence despite receiving the best treatment.
Potential Disadvantages
Information concerning the pathological
extent of disease prior to treatment is
unknown. Accordingly, the following are less
certain:
- Margin status of a BCS?
- Risk of additional lymph node disease
when
a sentinel lymph node is
negative or shows
fibrosis and/or
treatment-induced changes
- Indications for post-mastectomy radiation
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.
NSABP B-18 Trial: Schema
Operable Breast Cancer
•Stratification
• Age
• Clinical tumor size
• Clinical node status
Operation
AC x 4
+ TAM if >50 yrs.
AC x 4
+ TAM if >50 yrs.
Operation
Un-answered question ….the need for
further therapy following initial treatment?
Many trials have been launched:
• the Aberdeen trial
• M. D. Anderson Trial 85-01
• NSABP protocol B27 published 2005.
NSABP B-27: Determining the effect of
combining Docetaxel with preoperative AC
Does the addition of Docetaxel to preoperative AC
affect response rates, DFS and OS?
Patients with
primary operable
ANY T SIZE
breast cancer;
HER2 status not
defined (N=2404)
AC
q3w x 4 cycles
Surgery
AC
q3w x 4 cycles
Docetaxel
100 mg/m2
q3w x 4
cycles
Surgery
Surgery
Docetaxel
100 mg/m2
q3w x 4
cycles
AC
q3w x 4 cycles
Tamoxifen was initiated concurrently with chemotherapy
Bear H, et al. 2006
Rastogi P, et al. 2008
Adding Docetaxel…Improved cCR…Improved
pCR…Improved RFS...Improved OS in pCR
Emerging lessons from NSABP B-27 Trial
• In spite lack of OS benefits, yet presence of better
R.R, higher BCS, improved RFS and in vivo
assessment of chemotherapy
all favour
Neoadjuvant.
• pCR linked to better OS.
• Assessing the response permits the activity of
different Chemotherapy regimens to be more
easily compared.
• Response data can also provide insights into the
biological
determinants
of
Chemotherapy
response.
Weekly paclitaxel (P) followed by FAC as primary
systemic chemotherapy (PSC) of operable breast cancer
improves pathologic complete remission (pCR) rates when
compared to every 3-week (Q 3 wk) paclitaxel followed by
FAC- final results of a prospective phase III randomized
trial. By Hortobagi et al. Proc Am Soc Clin Oncol 21: 2002
(abstr 135)
• Pathologic Complete Remission Rates (Breast and
Lymph Nodes) : Weekly vs. Q 3 Week Paclitaxel
Node Positive
Weekly (n = 50) Q 3 Week (n= 51)
(n = 67)
pCR 14 (28%)
7 (13.7%)
Node Negative
Weekly (n = 68)
Q 3 Week
20 (29.4%)
9 (13.4%)
Weekly Paclitaxel is superior to q 3 weeks.
Neoadjuvant Before Targeted Therapy
• Neo-Adjuvant chemotherapy adds many
advantages to the management of breast
cancer.
• Anthracyclines are integral part in the
neoadjuvant setting.
• Adding Taxanes 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
• What is the optimum Chemotherapy?
• What is the optimum Targeted Therapy?
• 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-2positive 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 blockage 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?
• Currently, I do not know the exact answer to this question.
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; how long the
neoadjuvant therapy should last; if Anthracyclines should
be incorporated 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 blockage?
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, which included
1509 patients with either locally advanced (T3 or T4), any
hormonal status but lymph-node-positive tumours.
A
Docetaxel (100mg/m2) x4
S
U
B
EC X 4
R
Docetaxel (75mg/m2) + Capecitabine
(1800mg/m2) x4
G
E
R
C
Docetaxel (75mg/m2) x4 followed by
capecitabine (1800mg/m2) x4
Y
Trastuzumab
for 1-Year in
Her-2 Positive
- pCR was doubled in HER-2 positive patients
compared to the HER2- negative group
(31.7%
versus
15.7%).
- In the HER2-positive group, a pCR was
observed in 48 (32.9%) first arm, 45 (31.3%)
second arm, and 47 (34.6%) the third arm.
- Even in case of irresponsiveness to EC therapy,
the pCR rate was higher in the HER2-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 Blockage 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%).
Pertuzumab (Neo-Sphere), 2010.
29%
45.8
%
16.8
%.
24%
• Dual blockade is active yet Chemotherapy is still a
corner stone.
Trastuzumab plus Pertuzumab in Neoadjuvant HER2Positive Breast Cancer trial (TRYPHAENA), 2013. Note
first to omit Anthracyclines
• 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.
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.
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 disease is
associated with higher pCR rates, regardless of type and
duration of chemotherapy.
• 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 triple-positive tumors.
Efforts to Omit Anthracyclines
• Several phase II trials have been reported to date in
which Anthracycline was substituted with
carboplatin, based on preclinical data suggesting
synergy between Trastuzumab, a Taxanes, and a
platinum compound and supported by results of
TCH.
• A series of phase II neoadjuvant studies reported
pCR rates ranging from 19% to 76%.
• 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.
New Approaches
• HER2 can stimulate angiogenesis through
vascular endothelial growth factor up-regulation.
Therefore, HER2 blockage, together with
inhibition of angiogenesis, could be another
treatment option.
• In phase II study, 2011, neoadjuvant therapy with
nab-paclitaxel, carboplatin and Bevacizumab led
to a pCR rate comparable to that found in
chemotherapy/Trastuzumab combinations
Conclusions
• HER-2 positive breast cancer presents a
heterogeneous group of diseases with various
biological characteristics.
• Management of patients with this type of breast
cancer has significantly improved in recent years,
and neoadjuvant treatment has become widely
accepted.
• The introduction of Trastuzumab to Neoadjuvant
setting has brought important progress in the
treatment of HER-2 positive breast cancer.
• All breast cancers are not the same, so it makes
sense that treatment can no longer be one-size-fits
all.
• Nowadays, sequential Anthracycline-Taxanesbased chemotherapy in combination with
Trastuzumab is considered the best-studied
therapy for HER-2 positive breast cancer in the
neoadjuvant setting.
• The dual blockage of HER-2 receptor has revealed
significant efficacy and presents a new therapeutic
approach. Yet, cost is an important issue beside
confirming OS benefits on follow up.
Now, Do We Have The Fastest, Safest and
Strongest?
• I believe we did not reach the best yet.
• What are the reliable biomarkers for anti-HER2
therapy?….How to define those who will be pCR?