18, NUMBER 6
Herceptin in early breast cancer:
A call for judicious use
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch
A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch
C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang C-S, Andersson
M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H,
Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Süt
T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber
RD, for the Herceptin Adjuvant (HERA) Trial Study Team. (Department
of Medicine, Breast International Group Secretariat and Breast
European Adjuvant Study Team Data Centre; Jules Bordet Institute,
Université Libre de Bruxelles, Brussels; Frontier Science
[Scotland], Kingussie, Scotland; Department of Oncology, Gerald
Bronfman Centre for Clinical Research in Oncology, McGill University,
Montreal; Department of Medicine, European Institute of Oncology,
Milan, and the Oncology Institute of Southern Switzerland,
Bellinzona, Switzerland; Klinik für Frauenheilkunde und
Geburtshilfe, Ludwig-Maximilians-Universität München,
Grosshadern, Munich, Germany; Breast Unit, Royal Marsden Hospital
and Institute of Cancer Research, London; Struttura Complessa
Oncologia Medica 1, Istituto Nazionale per lo Studie e la Cura
dei Tumori, Milan; Medical Oncology Service, Vall d’Hebron
University Hospital, Barcelona; Andrew Love Cancer Centre,
Geelong Hospital, Geelong, Australia; Department of Gynecology,
Philipps University of Marburg, Marburg, Germany; Department
of Oncology, Western General Hospital, Edinburgh; Department
of Academic Biochemistry, Royal Marsden National Health Service
Trust, London; Hospital São Lucas, Pontifìcia
Universidad Catòlica do Rio Grande do Sul School of
Medicine, Porto Alegre, Brazil; Department of Internal Medicine,
Medical University of Vienna, Vienna; Department of Surgery,
National Taiwan University Hospital and National Taiwan University
College of Medicine, Taipei; Department of Oncology, Finsen
Center, Rigshospitalet University Hospital, Copenhagen; Tel
Aviv Sourasky Medical Center, Tel Aviv, Israel; N.N. Blokhin
Cancer Research Center, Moscow; Department of Oncology, National
Institute of Oncology, Budapest, Hungary; Frauenklinik der
Heinrich Heine Universität Düsseldorf, Düsseldorf,
Germany; Department of Breast Oncology, Aichi Cancer Center,
Aichi, Japan; Klinik und Poliklinik für Gynäkologie,
Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany;
Department of Medical Oncology, British Columbia Cancer Agency,
Vancouver Centre, Vancouver, B.C., Canada; Swiss Cardiovascular
Center, Bern, Switzerland; Institut für Pathologie, Klinikum
Kassel, Kassel, Germany; F. Hoffmann-La Roche, Basel, Switzerland;
and Department of Biostatistics and Computational Biology,
Dana–Farber Cancer Institute, Boston.) Trastuzumab after
adjuvant chemotherapy in HER2-positive breast cancer. N Engl
J Med 2005;353: 1659–72.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson
NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky
TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers
G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL,
Klein PM, Ingle JN, Wolmark N. (National Surgical Adjuvant
Breast and Bowel Project, Pittsburgh; University of Kentucky,
Lexington; North Central Cancer Treatment Group, Rochester,
Minnesotta; Mayo Clinic Jacksonville, Jacksonville, Florida;
University of Pittsburgh, Pittsburgh; Mayo Clinic, Rochester,
Minnesotta; Allegheny General Hospital, Pittsburgh; Sidney
Kimmel Comprehensive Cancer Center at Johns Hopkins University,
Baltimore, Cancer Research Network, Plantation, Florida; Angeles
Clinic and Research Institute, Santa Monica, California; Norris
Cotton Cancer Center, Dartmouth–Hitchcock Medical Center,
Lebanon, New Hampshire; Cancer Therapeutics Branch, National
Cancer Institute, Bethesda, Maryland; Kaiser Permanente Medical
Center Northern California, Vallejo; Oncology Associates of
Cedar Rapids, Cedar Rapids, Iowa; University of Pittsburgh
Cancer Institute, Pittsburgh; Wichita Community Clinical Oncology
Program, Wichita, Kansas; Aultman Health Foundation, Canton,
Ohio; Genentech, South San Francisco, California.) Trastuzumab
plus adjuvant chemotherapy for operable HER2-positive breast
cancer. N Engl J Med 2005;353:1673–84.
In this trial, women were randomly assigned to one of three
arms—2 years of treatment with trastuzumab (1694 women),
1 year of treatment with trastuzumab (1694 women) and observation
(1693 women). The investigators reported the results only of
treatment with trastuzumab for 1 year and observation.
Patients treated for 1 year with trastuzumab received the first
dose of 8 mg/kg followed by 6 mg/kg every 3 weeks for 1 year.
Eight per cent of patients discontinued the treatment either
due to worsening of cardiac function (5.5%) or by their choice,
and 26% received taxanes in addition to anthracycline-based
At the first planned interim analysis (median follow up of
1 year), the unadjusted hazard ratio (HR) for an event in the
trastuzumab group as compared with the observation group was
0.54 (95% CI: 0.43–0.67; p<0.0001), representing an
absolute benefit of 8.4% in terms of disease-free survival
(DFS) at 2 years. Distant recurrence-free survival was also
better in the trastuzumab arm (HR: 0.49; 95% CI: 0.38–0.63;
p<0.0001). Overall survival in the two groups was not significantly
different (HR: 0.76). Severe cardiotoxicity developed in 0.5%
of women treated with trastuzumab.
This means that the use of trastuzumab in the adjuvant setting
for 1 year reduces recurrence by 46% and distant recurrence
by 51%. A 24% reduction in the risk of death reached statistical
significance within this short duration of follow up.
NSABP B31 and N9831 trials
NSABP B31.The National Surgical Adjuvant Breast and Bowel Project
trial B31 compared doxorubicin and cyclophosphamide followed
by paclitaxel every 3 weeks (group 1) with the same regimen
along with 52 weeks of trastuzumab beginning with the first
dose of paclitaxel (group 2). Groups 1 and 2 had 872 and 864
patients with follow up, respectively.
N9831.The North Central Cancer Treatment Group trial N9831
compared three regimens: doxorubicin and cyclophosphamide followed
by weekly paclitaxel (group A), the same regimen followed by
52 weeks of trastuzumab after paclitaxel (group B), and the
same regimen along with 52 weeks of trastuzumab initiated concomitantly
with paclitaxel (group C). Groups A and C had 807 and 808 patients
with follow up, respectively.
The studies were amended to include a joint analysis comparing
groups 1 and A (the control group) with groups 2 and C (the
trastuzumab group). Group B was excluded because trastuzumab
was not given concurrently with paclitaxel. Patients in the
trastuzumab arms received the first dose of 4 mg/kg followed
by 2 mg/kg every week for 1 year. About one-quarter of patients
(24.9%) discontinued the treatment either due to worsening
of cardiac function (18.9%) or by their choice.
The HR for an event in the trastuzumab group was 0.48 (p<0.0001).
The absolute difference in DFS between the trastuzumab group
and the control group was 12% at 3 years. Distant recurrence-free
survival was also better in the trastuzumab arm (HR: 0.47;
p<0.0001). Trastuzumab therapy was associated with a 33%
reduction in the risk of death (HR: 0.67; p=0.015). The three-year
cumulative incidence of class III or IV congestive heart failure
or death from cardiac causes in the trastuzumab group was 4.1%
in trial B31 and 2.9% in trial N9831.
This means that concurrent trastuzumab with paclitaxel in the
adjuvant setting for 1 year reduces recurrence by 52% and distant
recurrence by 53%. There is also a 33% reduction in the risk
The third week of October 2005 saw a remarkable triumph of
translational research. Simultaneous publication of these trials
of adjuvant trastuzumab (herceptin) declared it a new ‘standard-of-care’ in
the management of breast cancer. These results increase our
faith in basic and translational research. However, while we
celebrate this achievement of ‘bench-to-bedside medicine’,
we need to be careful of the possibility of a wave of aggressive
marketing, leading to indiscriminate use of the drug. This
may do more harm than good. The current evidence calls for
careful case selection and judicious use.
What is herceptin?
Trastuzumab is a monoclonal antibody against the HER-2 receptor
(human epidermal growth factor receptor) produced in only 15%–20%
of breast cancers.1 HER-2 positive
breast cancers have a worse prognosis than HER-2 negative ones.
This drug is effective
only in HER-2 positive breast cancers.
The HER-2/neu gene is a member of a family of genes encoding
transmembrane receptors for growth factors. The intracellular
domain of HER-2 has tyrosine kinase activity that regulates
important aspects of the physiology, growth and differentiation
Testing for HER2
Fluorescence in situ hybridization (FISH) detection of provides
the most accurate information about expression of the HER-2
gene. Immunohistochemistry (IHC), though widely available,
has many drawbacks such as variations in fixation methods,
techniques and interobserver variability. Also, detection of
HER-2 positivity by FISH correlates better with response to
therapy and survival than detection by IHC. Since FISH is not
yet widely available, screening for the HER-2 protein by IHC,
backed by rigorous quality controls and FISH testing of equivocal
cases with intermediate staining intensity (score 2; score
1 indicates negative HER-2 status and score 3 indicates positive
HER-2 status) appears to be the most feasible practical option.
What is the importance of the results of these trials?
After a long time, a cancer drug has offered such a remarkable
improvement in survival. Herceptin reduces the risk of recurrence
of cancer by almost 50%. Though these early results show a
24%–33% relative improvement in overall survival, a 50%
reduction in distant recurrence (which usually kills the patient)
strongly supports the possibility of similar reductions in
the risk of death.
The importance of this survival benefit is better assessed
by a comparison with other therapeutic options (Table I). Anthracycline-based
polychemotherapy4 improves survival (relative improvement)
by 38% in premenopausal and by 20% in postmenopausal women.
Tamoxifen improves survival by 31% in breast cancers expressing
oestrogen receptor (ER).4 Docetaxel, doxorubicin, cyclophosphamide
(TAC)5 show 30% improvement in survival as compared to fluorouracil,
doxorubicin, cyclophosphamide (FAC). If the benefit of TAC
is extrapolated to calculate its efficacy over no chemotherapy,
the improvement in survival will reach 50%.
|Table I. Comparison of survival benefit with different
adjuvant chemotherapy regimens for breast cancer
||Follow up (years)
||Relative risk (survival)
||Cardiac morbidity (%)
|Herceptin sequential (HERA trial)*†
|Herceptin sequential (HERA trial)‡
|Herceptin concurrent with taxanes (NSABP31 and N9831
|TAC v. FAC3
|Anthracyclines v. none (<50 years)4
||0.08 per year
|Anthracyclines v. none (>50 years)4
|CMF v. none (<50 years)4
||0.06 per year
|CMF v. none (>50 years)4
|* anthracycline or anthracycline and taxanes-based
chemotherapy † 2-year survival rates ‡ anthracycline
and taxane-based chemotherapy § 3-year survival rates
|| current standards of care
TAC docetaxel, doxorubicin and cyclophosphamide FAC fluorouracil,
doxorubicin and cyclophosphamide
CMF fluorouracil, methotrexate and cyclophosphamide
Note: A relative risk of 0.70 in disease-free survival means
a 30% relative reduction in the chance of recurrence.
What are the concerns of such therapy?
The most worrying adverse effect of this drug is its cardiotoxicity.
Cardiotoxicity is greater when patients have received anthracyclines
and when trastuzumab is used concurrently with chemotherapy.
The NSABP B31 trial5 reported a 4.1% incidence of severe
cardio-toxicity, and almost 19% of patients discontinued
trastuzumab due to
In a hypothetical patient with a possible absolute improvement
in survival of 4%, the entire benefit can get nullified by
the 4% chance of cardiotoxicity. Since it is impossible to
predict with certainty whether a particular patient will
benefit from the drug or not, and whether that patient will
side-effects or not, one has to depend on statistical probabilities.
Where does herceptin fit in with the current adjuvant therapy
One important difference in these trials is that only 26%
of patients in the HERA trial received taxanes. This probably
reflects in the overall results, where the control group
the HERA trial fares much worse compared with the control
group in the other two trials (2-year DFS 77.4% v. 83%; based
calculations from the survival graph). The reduction in recurrence
is 23% in the taxane subgroup in the HERA trial.
Additionally, the cardiotoxicity was much lower (1.7%) in
the HERA trial (sequential trastuzumab). This may mean that
is lower when trastuzumab is not used concurrently with the
taxanes, but the benefits of therapy are also reduced.
Current evidence favours the use of taxanes in adjuvant settings,
especially TAC5 in patients with a good performance status.
However, since adjuvant TAC itself has higher cardiac and
other toxicities, concurrent use of trastuzumab may prove
Hence, in all probability, herceptin sequential to TAC would
seem to be the best treatment option; but only in patients
with good performance status.
It is difficult to specify the cost of different chemotherapy
regimens available in India due to a wide range of generic
drugs and original research products. An anthracycline-based
chemotherapy regimen costs about Rs 20 000–30 000, a
docetaxel-based chemo-therapy regimen (TAC) costs about Rs
200 000–300 000 and 5 years of tamoxifen therapy costs
Rs 4000–5000. However, 1 year of herceptin therapy will
cost about Rs 2 000 000. All patients who can afford herceptin
will be able to afford any other form of systemic therapy.
Should all HER-2 positive patients be given herceptin?
Certainly not. This is where careful selection based on value
judgement is of paramount importance. The anticipated benefits
of trastuzumab in a particular patient will have to outweigh
its possible hazards before it can be recommended to that
patient. I provide 2 examples of such possible scenarios:
Example 1: A premenopausal patient with a 4 cm ER-negative
tumour with 4 of 16 lymph nodes showing metastasis has a
chance of recurrence. She will still have a 17%–20% chance
of recurrence after administration of the best adjuvant chemotherapy.
Her survival can be improved by almost 10% by administering
trastuzumab and the net benefit after accounting for cardiotoxicity
will still be more than 5%. Such a patient will be a well-deserving
candidate for trastuzumab.
Example 2: A 60-year-old lady with a 3 cm ER-positive tumour
without nodal metastasis has a 10%–12% chance of recurrence.
Her chances of recurrence will be reduced to 4%–5% after
the use of anthracycline-based chemotherapy and hormone therapy.
In such a patient trastuzumab will have a very modest benefit
of 2%–3%, not enough to recommend it to her in view of
the adverse effects.
Oncologists will have to assess the possible benefits and
harms for each patient before recommending such therapy.
to remember that only patients with good performance status
and cardiac function should receive this drug.
Duration of therapy. One year or 2 years and concurrent use
or sequential use are the questions that will probably be
answered once results from the other arms of these trials
How much improvement occurs in overall survival and what
the long term consequences of the cardiotoxicity are will
be known when longer follow up results are published.
Weekly administration or a 3-weekly schedule for trastuzumab
is a question that remains unanswered and a decision on this
will be based on the logistics of administration till the
question is conclusively answered, maybe in a new randomized
Recently, adjuvant TAC has emerged as a new standard-of-care.
This regimen itself has a higher cardiotoxicity and other
adverse effects, but also shows significant improvement in
How should one administer trastuzumab in a patient on adjuvant
TAC? Will it result in very high cardiotoxicity? These are
the questions only new trials and time can answer.
To conclude, herceptin is a promising new drug on the horizon
of breast cancer adjuvant treatment. It can only be used
in patients with HER-2 positive breast cancers and only after
careful case selection in view of the side-effects.
Burstein HJ. The distinctive
nature of HER-2 positive breast cancers. N Engl J Med
J, Mallon E, Cooke T. The clinical evaluation of HER-2
status: Which test to use?
Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver
C, et al. Adjuvant docetaxel for node-positive
cancer. N Engl J Med
Cancer Trialists’ Collaborative Group
(EBCTCG). Effects of chemotherapy and hormonal therapy
for early breast cancer on recurrence and 15-year survival:
overview of the randomised trials. Lancet
Tan-Chiu E, Yothers G, Romond E, Geyer
CE Jr, Ewer M, Keefe D, et al. Assessment of cardiac dysfunction
trial comparing doxorubicin and cyclophosphamide followed
by paclitaxel, with or without trastuzumab as adjuvant
therapy in node-positive, human epidermal growth factor
breast cancer: NSABP B-31. J Clin Oncol
MANGESH A. THORAT
Department of Surgical Oncology
Tata Memorial Hospital
Dr E. Borges Marg