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Inflammatory
Breast Cancer: Background
What
is IBC?
Inflammatory breast cancer (IBC) is considered
the most aggressive manifestation of primary breast
carcinoma, with the clinical and biological characteristics
of a rapidly proliferating disease. Part of its aggressive
status is due to the fact that it is not detectable
by mammography or ultrasound, so that it is typically
already in an advanced stage at time of initial diagnosis.
Another confounding factor is that some of IBC's symptomology
can resemble mastitis (breast infection) symptoms, so
that it has not been infrequent that a patient with
IBC be misdiagnosed and placed on an antibiotics regimen
before the diagnosis is corrected, usually by breast
biopsy. Clinicians need to therefore explore the full
spectrum of careful differential diagnosis to avoid
common IBC misdiagnosis.
IBC
Patient Resources
As this site is oriented primarily to health professionals,
this author, as medical editor for the human-edited
directory service Best of
the Web (BOTW), has
compiled a collection of regularly-updated patient-oriented
resources on inflammatory breast cancer (IBC): see IBC
Resources.
(new) In
addition, there is a fine patient's perspective offered
by G. Owen Johnson and colleagues (Marilyn Kirschenbaum,
Ginny Mason, Linda Riley Rush) of the IBC Research Foundation:
Breast Dis (2005-2006): Inflammatory
Breast Cancer - The Patient Advocate View.
Signs and Symptoms
In terms of symptomology, IBC typically presents clinically
with rapid onset of breast erythema, warmth, and edema,
with possible presentation of ridges or raised or pitted
marks on breast skin (termed peau d’orange,
as it resembles the surface of orange peel), with or
without nipple retraction, inversion or discharge, with
or without swollen lymph nodes, and with or without
change in breast size and/or shape. A discrete underlying
palpable mass is often not present, but breast swelling
is typically quite pronounced, with significant consequent
tenderness. The pathology of IBC is characteristically
one of tumor emboli invasion of the dermal lymphatic,
causing blockage of the breast lymphatics and consequent
breast edema.
IBC As a Distinct Clinicopathologic
Entity
Furthermore IBC appears to be a clinicopathologic entity
distinct from noninflammatory locally advanced breast
cancer (LABC); that is, although IBC is technically
considered a subtype of LABC, it has distinct biologic
features and clinical behavior. In fact, however, IBC
is typically treated and managed like other inoperable
locally advanced breast cancer (stage IIIB and C).
Statistics and Trends
A recent historical appreciation undertaken by NCI in
2005 (Hance et al., J Natl Cancer Inst (2005): Trends
in Inflammatory Breast Carcinoma Incidence and Survival:
The
Surveillance, Epidemiology, and End Results Program
at the National Cancer Institute) noted that
although IBC incidence rose throughout the 1990s, survival
improved modestly, in accordance also with the experience
of BC (British Columbia) Cancer Agency reported in their
recent retrospective analysis showing that chemotherapy
regimens improve breast cancer–specific survival
(Panades et al, J Clin Oncol (2005): Evolving
treatment strategies for inflammatory breast cancer:
a population-based survival analysis). The NCI
study further found substantial racial differences noted:
black women with IBC had poorer survival than white
women with IBC, however IBC Watch notes that
this is true for all noninflammatory locally advanced
breast cancer (LABC) as well, and may import little
other than to reflect well-known differentially negative
determining socioeconomic factors affecting diagnosis/screening,
treatment and quality of care for black women in general.
New statistics are currently being accumulated for post-1990's
trends, although it is anticipated based on preliminary
results that survival improvement will continue to grow,
primarily due, we note, to the advent of more decisive
multimodality therapies as well as biologically targeted
therapy, and a modest but significant resurgence of
clinical and research interest in this rare disorder,
probably favored also by earlier detection. Thus although
formerly often classified as the "enigma"
of breast cancer types (see Cristofanilli et al., J
Clin Oncol (2004): Inflammatory
Breast Carcinoma: The Sphinx of Breast Cancer Research),
our systematic review found that IBC is recently becoming
both less enigmatic and more effectively treatable with
improved survivability.
Risk and Prognostic Factors
Obesity and menopausal status have been postulated as
potential risk factors on survival in IBC patients,
but research suggests that although factors associated
with larger body size at diagnosis appear to contribute
to shorter survival among postmenopausal IBC women,
this was not evidenced among pre-menopausal IBC women,
who typically have poor survival independent of body
size (Chang et al., Breast Cancer Res Treat (2000):
Inflammatory Breast Cancer Survival: The
Role of Obesity and Menopausal Status at Diagnosis).
The strongest prognostic factors however for locally
advanced breast cancer, including IBC are pCR (pathologic
complete response) in breast and axilla to induction
(neoadjuvant) chemotherapy (Kuerer et al., J Clin Oncol
(1999): Clinical
Course of Breast Cancer Patients With Complete Pathologic
Primary Tumor and Axillary Lymph Node Response to Doxorubicin-Based
Neoadjuvant Chemotherapy, and Buchholz et al.,
J Clin Oncol (2002): Pathologic
tumor size and lymph node status predict for different
rates of locoregional recurrence after mastectomy for
breast cancer patients treated with neoadjuvant versus
adjuvant chemotherapy); indeed, recently researchers
at the M.D. Anderson Cancer Center (Hennessey et al.,
J Clin Oncol (2005): Outcome
After Pathologic Complete Eradication of Cytologically
Proven Breast Cancer Axillary Node Metastases Following
Primary Chemotherapy) found that (1) residual
primary tumor did not affect outcome of those with ALN
(axilliary lymph node) pCR, and that (2) combination
anthracycline/taxane-based primary chemotherapy resulted
in significantly more ALN pCRs, (3) outcome after ALN
pCR was not improved by taxanes. These findings demonstrate
that ALN pCR is associated with an excellent prognosis,
even in cases of residual primary tumor, allowing ALN
pCR to be an early surrogate marker of long-term outcome,
and suggesting significant biologic differences between
primary cells and metastatic cells.
And delivery of HDC (high-dose chemotherapy) rather
than standard CT (chemotherapy) HDC is more specifically
one of the strongest independent prognostic factors
identified to date ((Bertucci et al., Bone Marrow Transplant
(2004): Multivariate
analysis of survival in inflammatory breast cancer:
impact of intensity of chemotherapy in multimodality
treatment)).
New Understanding of IBC Pathogenesis:
Biologic, Molecular and Clinicopathologic Determinants
Considerable research is currently focusing on on discovering
the differential "molecular fingerprint" -
patterns of gene expression - as it were that biologically
distinguish IBC cancer cells from other cancer cell
types and from normal cells, to ultimately arrive at
a set of specific genetic markers in the tumors of IBC
newly diagnosed patients, to enable designing much more
targeted treatment regimens. On the value of gene expression
profiling for targeted IBC treatment, see Bertucci et
al. (Cancer Res (2004): Gene
expression profiling for molecular characterization
of inflammatory breast cancer and prediction of response
to chemotherapy) and Bertucci et al. (Cancer
Res (2005): Gene
Expression Profiling Identifies Molecular Subtypes of
Inflammatory Breast Cancer), following up the
original study of van Golen et al. (Mol Cancer Ther
(2002): Reversion
of RhoC GTPase-induced inflammatory breast cancer phenotype
by treatment with a farnesyl transferase inhibitor)
establishing the overexpression of RhoC GTPase
in >90% of IBC cases.
Investigations continue into the unique molecular determinants
of IBC development (see the important work of Kleer
et al. at the University of Michigan (Breast Cancer
Res (2004): WISP3
and RhoC guanosine triphosphatase cooperate in the development
of inflammatory breast cancer) who have found
that consistent alterations of two genes in 90% of IBC
tumors when compared with stage-matched non-IBC tumors:
overexpression of RhoC guanosine triphosphatase
and loss of WNT-1 induced secreted protein 3 (WISP3),
proposing that RhoC (an oncogene) and WISP3 (a
tumor suppressor gene) cooperate in the development
of IBC.
The Role of Angiogenesis
Van der Auwera et al. (Clin Cancer Res (2004): Increased
angiogenesis and lymphangiogenesis in inflammatory versus
noninflammatory breast cancer by real-time reverse transcriptase-PCR
gene expression quantification) have further
clarified IBC development, finding both intense angiogenic
activity and the presence of active lymphangiogenesis,
helping to explain the IBC's well-known high metastatic
potential by lymphatic and hematogenous route, and suggesting
both pathways as potential targets for targeted IBC
treatment.
Gene Expression Profiles
See also the research of Bièche et al. (Clin
Cancer Res (2004): Molecular
profiling of inflammatory breast cancer: identification
of a poor-prognosis gene expression signature)
on the molecular pathogenesis of IBC: their findings
identified a gene expression profile, based on the MYCN,
EREG, and SHH genes, which discriminated subgroups of
IBC patients with good, intermediate, and poor outcome,
and Gonzales-Angula (Clin Cancer Res (2004): p53
expression as a prognostic marker in inflammatory breast
cancer) have found nuclear p53 protein
expression to represent an adverse prognostic marker
in IBC.
And more recently, the associations between patient
survival, pharmacokinetics, and drug metabolism-related
genetic polymorphisms has been further clarified. Chemotherapy-naïve
patients with either metastatic or inflammatory breast
cancer receiving standard-dose chemotherapy followed
by high-dose cyclophosphamide, cisplatin, and carmustine
were studied by Petros et al. (J Clin Oncol (2005):
Associations
Between Drug Metabolism Genotype, Chemotherapy Pharmacokinetics,
and Overall Survival in Patients With Breast Cancer),
who found that patients having a variant genotype of
cytochrome P450 3A4 displayed or carrying a genetic
variant of P450 3A5 had higher blood concentrations
of parent (inactive) cyclophosphamide and consequently
a shorter survival; and similarly, patients with a polymorphism
in a gene regulating metallo
nein had
lower platinum concentrations and again shorter survival.
These finding may be clinically valuable in charting
optimal therapeutic regimens for metastatic or inflammatory
breast cancer patients, as the pretreatment evaluation
of drug metabolism genes may suggest and account for
interindividual differences in both anticancer drug
pharmacokinetics and associated response.
Based on this and other emerging discoveries, various
new combination regimens are being explored, including
angiogenic modulators, farnesyl transferase
inhibitors, and p53 modulators.
Understanding Curative vs Palliative
Intent:
(new) The
Role of Distant Metastases
Miguel Panades
and his Canadian research team offered this definition
of curative intent in IBC therapy: "Curative
intent was defined as delivery of more than four cycles
of anthracycline-based CT plus locoregional RT in
patients without distant metastases" (J
Clin Oncol (2005): Evolving
treatment strategies for inflammatory breast cancer:
a population-based survival analysis)
thus highlighting the key role of absence of distant
metastases, in keeping with the usage of MD Anderson
teams under Zhongxing Liao and colleagues (Int J Radiat
Oncol Biol Phys (2000): Locoregional
irradiation for inflammatory breast cancer: effectiveness
of dose escalation in decreasing recurrence),
and those under leading researcher Vicente Valero refine
this understanding, noting that "patients with
ipsilateral supraclavicular metastases but no other
evidence of distant metastases warrant therapy administered
with curative intent" (Rogelio Brito et al,
J Clin Oncol (2001):
Long-Term Results of Combined-Modality Therapy for
Locally Advanced Breast Cancer With Ipsilateral Supraclavicular
Metastases: The University of Texas M.D. Anderson Cancer
Center Experience). Thus, current clinical practice
in IBC therapy is for IBC patients with either
(1) no metastatic involvment, or
(2) metastases confined locoregionally with no evidence
of distant metastases
to be treated with curative intent.
And although therefore the generally accepted usage
is that only IBC with manifest distant metastasis is
considered to be more appropriately approached from
a palliative therapy perspective, even this does not
rule out protracted survival of 15 years and better:
as oncologist Charles Vogel with US Oncology observed
in a recent interview:
"But for the average patient with metastatic
breast cancer, we can get them into remission very easily
with either hormonal therapy or chemotherapy, and patients
often live many, many years. We all have women in our
practices who are now out 10, 12, 14 years or more with
metastatic disease that is controlled and living reasonably
normal lives most of the time". [BreastCancerUpdate,
Vol. 5, Issue 4: The Bond that Heals).
and this author is acquainted with IBC patients surviving
and already at the decade and a half point. Thus even
IBC with frank distant metastases no longer fully precludes
protracted survival, even with satisfactory quality-of-life
in many instances, and further new and emerging oncotherapy
options founded on a more intimate understanding of
the molecular pathways underlying IBC disease, and the
associated identified therapeutic targets, should continue
to improve these circumstances.
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New
and Emerging Directions in IBC Treatment
Treatment
Strategies and Advances
The optimal standard
treatment of IBC entails coordination of a multimodal
therapy strategy among medical, radiation, and surgical
oncologists.
In a recent overview, The MD Anderson Cancer Center
IBC experts Yang & Christofannilli (Breast Dis (2005-2006):
Systemic
Treatments for Inflammatory Breast Cancer) noted
that "novel targeted therapies that have recently
become available promise improved responses and survival.",
and Bristol & Buchholz (Breast Dis (2005-2006):
Inflammatory
Breast Cancer: Current Concepts in Local Management)
where it is observed that "over the last two
decades, local control rates for patients with IBC have
dramatically improved. Utilization of a combined-modality
approach employing neoadjuvant chemotherapy followed
by mastectomy and adjuvant chemotherapy with accelerated
hyperfractionated radiation to 66 Gy has transformed
what was once a disease with local control rates less
than 50% to one with local control rates on the order
of 70%-80%. In patients whose disease responds to chemotherapy,
the 5-year local control rates are even higher. These
improvements in local control have translated into improvements
in survival."
The IBC Treatment Standard
Treatment initiation consists of induction chemotherapy
with an anthracycline-based regimen (like doxorubicin
(Adriamycin), epirubicin (Ellence), among others)
or an anthracycline and taxane (paclitaxel
(Taxol), docetaxel (Taxotere)) combination; CAF
(cyclophosphamide, doxorubicin, and fluorouracil)
is one common regimen, among several others.
Combined Modality Therapy
Cristofanilli et al. (Oncologist (2003): Update
on the Management of Inflammatory Breast Cancer)
have outlined both their clinical experience and the
state-of-the-art as of 2003: that the multidisciplinary
management of IBC places preoperative or neoadjuvant
chemotherapy as the mainstay of treatment, with anthracyclines
and taxanes being the most effective cytotoxic agents
for IBC treatment, and locoregional treatment including
radiotherapy with or without surgery following initial
treatment. After local therapy, IBC patients typically
receive further adjuvant chemotherapy, given that the
risk of relapse remains high, finally followed by adjuvant
radiotherapy, if not previously given, and patients
with hormone-receptor-positive tumors should be treated
with 5 years of adjuvant hormonal therapy to minimize
the risk of recurrence, or the modern variant of combination
of shorter-term tamoxifen and aromatase inhibitors.
On this see, among others cited below, S. Giardano,
Oncologist (2003): Update
on Locally Advanced Breast Cancer).
The standard of IBC care was defined at M.D. Anderson
Cancer Center (first by Ueno et al., Cancer Chemother
Pharmacol (1997): Combined-modality
treatment of inflammatory breast carcinoma: twenty years
of experience at M. D. Anderson Cancer Center,
and more recently by Cristofanilli et al. (Oncologist
(2003): Update
on the Management of Inflammatory Breast Cancer)
as combined modality therapy (that is, chemotherapy,
then mastectomy, then chemotherapy and radiotherapy),
which yielded a significant fraction of patients (28%)
remaining free of disease beyond 15 years (in contrast,
single-modality treatments yielded a DFS of less than
5%), and these researchers also found - in essential
agreement with the findings of Fleming, Panades, and
Low (cited below in our discussion of The Mastectomy
Controversy) - that patients who had a complete
response to chemotherapy had a 44% disease-free survival
rate at 15 years compared with only a 7% rate in those
patients who were nonresponders.
Much of the outlined treatment guidelines are in essential
agreement with treatment guidelines for LABC in general
(see Shenkier et al, CMAJ (2004): Clinical
practice guidelines for the care and treatment of breast
cancer: 15. Treatment for women with stage III or locally
advanced breast cancer).
The Mastectomy Controversy
After this, definitive local therapy is usually achieved
with radiation therapy, mastectomy, or both. IBC
Watch notes however that there is some question
as to the real defensive value of mastectomy: since
IBC generally involves lymphatic vessels of the skin,
and since the skin is re-skitched after mastectomy,
this may potentially increase the risk of recurrence;
more research is required the settle the issue. In addition,
some research has failed to find a clinical advantage
for surgery in patients with IBC when added to chemotherapy
and radiotherapy (Boer et al., Ann Oncol (2000): Multimodality
therapy in inflammatory breast cancer: is there a place
for surgery?).
However, IBC Watch notes that the matter is somewhat
more complicated than this: as Arthur et al. (Int J
Radiat Oncol Biol Phys (1999): Accelerated
superfractionated radiotherapy for inflammatory breast
carcinoma: complete response predicts outcome and allows
for breast conservation) concluded, mastectomy
should be reserved for incomplete responders and avoided
in those achieving a complete response. And Cucio et
al. (Ann Surg Oncol (1999): Beyond
palliative mastectomy in inflammatory breast cancer--a
reassessment of margin status [pdf]) concluded
that in patients with IBC and nonmetastatic disease,
an aggressive surgical approach with the goal of a negative
surgical margin may be beneficial, as achieving such
local control was associated with better overall outcome.
It may indeed be more narrowly that patients who had
no significant response to induction (neoadjuvant) chemotherapy
who received no survival or local disease-control benefit
from the addition of mastectomy to the treatment regimen,
but in patients with a clinical complete or partial
response to induction chemotherapy, on the other hand,
the addition of mastectomy to chemotherapy plus radiotherapy
improved both distant disease-free and overall survival
(Fleming et al., Ann Surg Oncol (1997): Effectiveness
of mastectomy by response to induction chemotherapy
for control in inflammatory breast carcinoma),
a critical finding recently confirmed by Panades et
al (J Clin Oncol (2005): Evolving
treatment strategies for inflammatory breast cancer:
a population-based survival analysis) who concluded
that mastectomy, in conjunction with CT (chemotherapy)
and RT (radiotherapy enhanced locoregional control,
whereas modern CT in the form of more intensive regimens
seemed to improve BCSS (breast cancer–specific
survival); see also Low et al. (J Clin Oncol (2004):
Long-Term
Follow-Up for Locally Advanced and Inflammatory Breast
Cancer Patients Treated With Multimodality Therapy).
After local therapy, patients would receive further
adjuvant chemotherapy since the risk of relapse remains
high, followed by adjuvant radiotherapy, if not previously
given. And patients with hormone-receptor-positive tumors
should be treated with 5 years of adjuvant hormonal
therapy to minimize the risk of recurrence.
The Role of SNB (Sentinel Node
Biopsy)
Although a major innovation in other forms of breast
carcinoma, it does not appear that sentinel lymph node
biopsy (SNB) is reliable for patients with inflammatory
carcinoma: see Stearns et al. (Ann Surg Oncol (2002):
Sentinel
Lymphadenectomy After Neoadjuvant Chemotherapy for Breast
Cancer May Reliably Represent the Axilla Except for
Inflammatory Breast Cancer) who conclude that
SLNB after neoadjuvant chemotherapy does indeed reliably
predict axillary staging but not in IBC.
IBC Watch Commentary on SNB
in IBC
However, IBC Watch does not find this result
wholly convincing, as the sample size of IBC patients
was quite small: of the eight patients with inflammatory
breast cancer, the study found that sentinel lymphadenectomy
was unsuccessful in two, and in an additional two patients
the sentinel node was negative and the other axillary
nodes were positive. Furthermore, IBC Watch notes that
the study used only the blue dye technique, but we know
now that blue dye alone is inferior to blue dye in combination
with radio-labelled colloid (Syme et al., ANZ J Surg
(2005): Comparison
of blue dye and isotope with blue dye alone in breast
sentinel node biopsy) so that it is indeterminant
whether the more sophistication combination if used
would not perhaps have led to significantly different
findings.
Seemingly more decisive on this issue is the latest
review of the evidence for SNB by ASCO (Lyman et al.,
J Clin Oncol (2005): American
Society of Clinical Oncology Guideline Recommendations
for Sentinel Lymph Node Biopsy in Early-Stage Breast
Cancer) which argues against SNB in the IBC
population largely because of the unacceptably high
false-negative rate for SNB for this population, probably
due to the fact that in IBC subdermal lymphatics are
partially obstructed, contain tumor emboli, and are
functionally abnormal; their guideline in this circumstance
is therefore that there are insufficient data on women
with inflammatory breast cancer to recommend the use
of SNB. However, this in fact despite appearances, does
not add significantly to the conversation, as IBC
Watch notes that the sole foundation cited by the
ASCO SNB Guideline is the afore cited Stearns study.
We conclude therefore that the Stearns study and the
ASCO guidance founded on it are not dispositive of the
issue, and that therefore further sufficxiently powered
clinical research is required to determine the true
potential role of SNB in the treatment of inflammatory
breast cancer.
The Issue of High/Intense-Dose
Chemotherapy
The question of the role of high-dose or intense chemotherapy
in the treatment of IBC has been raised in several studies,
and there appears to be little support for its benefit
in terms of DFS (disease-free survival) or OS (overall
survival): see Attia-Sobel et al. Eur J Cancer (1993):
Treatment
results, survival and prognostic factors in 109 inflammatory
breast cancers: Univariate and multivariate analysis;
and Chevallier et al., Br J Cancer (1993): The
Centre H. Becquerel studies in inflammatory non metastatic
breast cancer. Combined modality approach in 178 patients).
However, newer approaches begin to diverge and reflect
accumulating knowledge of the biological basis and the
distinct clinicopathologic status of IBC, and IBC
Watch summarizes these below.
The New Role of Taxanes
Note also that is now well-established that the addition
of a taxane to an anthracycline-based regimen improves
overall survival for patients with node-positive breast
cancer (see Henderson et al., J Clin Oncol (2003): Improved
outcomes from adding sequential Paclitaxel but not from
escalating Doxorubicin dose in an adjuvant chemotherapy
regimen for patients with node-positive primary breast
cancer, who demonstrated that the addition of
four cycles of paclitaxel (Taxol) after the completion
of a standard course of CA improves the disease-free
and overall survival of patients with early breast cancer).
Evans et al. (J Clin Oncol (2005): Phase
III Randomized Trial of Doxorubicin and Docetaxel Versus
Doxorubicin and Cyclophosphamide As Primary Medical
Therapy in Women With Breast Cancer: An Anglo-Celtic
Cooperative Oncology Group Study) have presented
an important clarification: in contrast to the positive
results reported for sequential docetaxel
after doxorubicin and cyclophosphamide (Cytoxan /Neosar
/ Endoxanal), there was no benefit for simultaneous
doxorubicin and docetaxel as primary chemotherapy in
women with primary or locally advanced breast cancer
(including IBC).
Indeed, other studies confirm that the sequential administration
of taxane- and anthracycline-based therapy may be superior
to concomitant administration (see Estevez & Gradishar,
Clin Cancer Res (2004): Evidence-based
use of neoadjuvant taxane in operable and inoperable
breast cancer) who noted that sequential docetaxel
after anthracycline-based neoadjuvant chemotherapy significantly
enhanced the clinical response rate and pathological
complete response, and yielded a significant 3-year
survival advantage, versus anthracycline-based neoadjuvant
chemotherapy alone,
Furthermore, the Phase III National Surgical Adjuvant
Breast and Bowel Project (NSABP) trial B27 (Bear et
al., J Clin Oncol (2003): The
Effect on Tumor Response of Adding Sequential Preoperative
Docetaxel to Preoperative Doxorubicin and Cyclophosphamide:
Preliminary Results From National Surgical Adjuvant
Breast and Bowel Project Protocol B-27) showed
that sequential docetaxel after doxorubicin-cyclophosphamide
significantly increased both clinical and pathological
response rates for operable breast cancer, with the
benefit evident impressively in both estrogen receptor-positive
and estrogen receptor-negative patients. And Espinoza
et al. (Cancer Chemother Pharmacol (2004): Docetaxel
and high-dose epirubicin as neoadjuvant chemotherapy
in locally advanced breast cancer) have found
that docetaxel plus high-dose epirubicin (Pharmorubicin)
showed promising activity in patients with LABC and
IBC, at the cost of moderate toxicity; see also Kummel
et al. (Acta Oncol (2005): Primary
systemic chemotherapy with sequential, dose-dense epirubicin
and docetaxel for inoperable, locally advanced inflammatory
breast cancer: a phase II study) which evaluated
sequential, dose-dense epirubicin plus docetaxel (3
cycles of epirubicin 120 mg/m2 every 2 weeks followed
by 3 cycles of docetaxel 100 mg/m2 every 2 weeks, with
granulocyte colony-stimulating factor) as primary systemic
therapy for women with inoperable, locally advanced
breast cancer (LABC) or inflammatory breast cancer (IBC),
finding high response rate with moderate toxicity.
IBC Watch notes that it would have been interesting
to have comparative findings for docetaxel and low-dose
epirubicin, given the known high degree of cardiotoxicity
of the epirubicin component (in this context note that
the small trial of Ozmen et al. (Breast J (2003: Inflammatory
breast cancer: results of anthracycline-based neoadjuvant
chemotherapy) may suggest the superiority of
doxorubicin-containing chemotherapy over epirubicin-containing
chemotherapy).
Important IBC Watch Note:
Despite the fact that these results are often stated
as establishing the superiority of a sequential anthracycline-taxane
regimen, in fact the positive results are limited only
to docetaxel (Taxotere), with no comparable Phase III
trials of paclitaxel (Taxol) versus a non-taxane-based
comparator having been conducted to date. Therefore
we can concluded more narrowly that current best
evidence supports the inclusion of the taxane docetaxel
(Taxotere) (over paclitaxel (Taxol)) in neoadjuvant
chemotherapy schedules for patients with large and locally
advanced breast cancer, including IBC.
Differential Role of Taxanes:
Docetaxel (Taxotere) v Paclitaxel Taxol)
However, researchers at the M. D. Anderson Cancer Center
(Cristofanilli et al, Clin Breast Cancer (2004): Paclitaxel
Improves the Prognosis in Estrogen Receptor–Negative
Inflammatory Breast Cancer: The M. D. Anderson Cancer
Center Experience), the leading IBC treatment
and research center, have found the addition of paclitaxel
to anthracycline-based therapy resulted in a statistically
significant improvement in outcome in patients with
ER-negative inflammatory breast cancer, and this coupled
with the results above suggests a potential discrimination
in favor of of docetaxel (Taxotere) in ER-positive IBC
and in favor of paclitaxel (Taxol) in ER-negative IBC.
And the case report of Okawa et al. (Breast Cancer (2004):
Successful
combination therapy with trastuzumab and Paclitaxel
for adriamycin- and docetaxel-resistant inflammatory
breast cancer) found a role for weekly combination
therapy of trastuzumab and paclitaxel in the treatment
of adriamycin-and docetaxel-resistant metastatic IBC,
so providing a valuable second therapeutic option if
resistance presents. This is additional reinforced by
the finding that paclitaxel when added to anthracycline-based
chemotherapy results in a statistically significant
improvement in outcome in patients with ER-negative
IBC (Cristofanilli et al., Clin Breast cancer (2004):
Paclitaxel improves the prognosis in estrogen receptor
negative inflammatory breast cancer: the M. D. Anderson
Cancer Center experience), and it also appears
that there is a significant role for high-dose chemotherapy
(HDC) with HSCS (haematopoietic stem cell support) as
part of the therapeutic approach in IBC (Bertucci et
al., Bone Marrow Transplant (2004): Multivariate
analysis of survival in inflammatory breast cancer:
impact of intensity of chemotherapy in multimodality
treatment), indeed with delivery of HDC being
found the strongest independent prognostic factor.
Furthermore, as Estevez and Gradishar (above) have found,
the best evidence suggests that taxane-based neoadjuvant
chemotherapy is an effective alternative
to surgery followed by adjuvant chemotherapy in both
early and locally advanced breast cancer, with acceptable
tolerability. In addition, such neoadjuvant chemotherapy
improves the rate of breast-conserving therapy, so
all patients with breast cancer, regardless of initial
tumor size should be offered potential breast conservation
through taxane-based neoadjuvant chemotherapy as an
option.
Note that the exact role of intensified ("high-dose")
chemotherapy regimens in the improvement of outcome
for certain IBC patients is a matter of some debate:
see the study of Somlo et al. (J Clin Oncol (2004):
Prognostic
Indicators and Survival in Patients With Stage IIIB
Inflammatory Breast Carcinoma After Dose-Intense Chemotherapy),
and the commentary on that study by Gonsalez-Angulo,
Morandi, & Cristofanilli of the MD Anderson Cancer
Center (J Clin Oncol (2005:
Inflammatory Breast Cancer and High-Dose Chemotherapy:
Back to the Past), and Somlo's response in turn
(J Clin Oncol (2005): In
Reply).
A New Option:
Intermittent-Week Radiotherapy
An intermittent schedule of radiotherapy when
added to chemotherapy consisting of either continuous
infusion or bolus paclitaxel (Taxol) ± vinorelbine
(Navelbine) is effective locoregional therapy for ULABC
(unresectable locally advanced breast cancer) or IBC,
with an acceptable toxicity profile, as established
by researchers at the University of Chicago and Pritzker
School of Medicine (Kao et al., Int J Radiat Oncol Biol
Phys (2005): Concomitant
radiation therapy and paclitaxel for unresectable locally
advanced breast cancer: Results from two consecutive
Phase I/II trials); the intermittent radiotherapy
consisted of 60–70 Gy to the breast or chest wall
with 60 Gy to draining lymphatics in a week-on/week-off
(WO/WO) schedule. IBC Watch notes that the same
intermittent (WO/WO) schedule was previously found effective
in the treatment of FABC (far advanced unresectable
and metastatic breast cancer) and IBC: the same research
team (Kao et al., RSNA (Radiological Society of North
America) Annual Meeting (2003): Concurrent
Radiation Therapy (RT) and Paclitaxel for Far Advanced
Unresectable and Metastatic Breast Cancer (FABC): Results
From Two Consecutive Phase I-II Trials) found
that concurrent paclitaxel based chemotherapy with radiation
therapy on a WOWO schedule was feasible in locally advanced
breast cancer and IBC, allowing high rates of pCR (pathological
complete response) to be achieved with this approach,
with encouraging long-term tumor control and survival
(an approach we note that has had considerable success
in the treatment of other cancers, especially glioblastoma).
HER2
and the Role of Monoclonal Antibodies
Recently, Parton et al. (Breast 2004): High
incidence of HER-2 positivity in inflammatory breast
cancer) examined the incidence of HER-2
status in IBC, finding that HER-2 protein over-expression
in IBC is higher than previously reported in non-IBC
(at least 50% of IBC patients are HER2-positive); this
suggests that early HER-2 directed therapy (such as
the monoclonal antibody trastuzumab (Herceptin))
may improve outcome when part of multimodal treatment.
See also the clinician comments on trastuzumab deployment
in IBC treatment at the 2004 Miami Breast Cancer Conference
(21st Annual Miami Breast Cancer Conference Special
Report (2004): Clinical
Trials of Adjuvant Trastuzumab).
Nomura et al. (Nomura et al., Breast Cancer (2005):
Pathological Complete Response to Trastuzumab and
Paclitaxel in a Patient with Inflammatory Local Recurrence
following Breast Conserving Surgery) present
a highly promising case report of biological therapy
(BT) + taxane to treat a local recurrence that developed
as inflammatory breast cancer after BCS (breast conserving
surgery) consisting of irradiation followed by tamoxifen.
Using trastuzumab + paclitaxel they were able to attain
pathological CR (pCR),with the patient receiving trastuzumab
alone every other week and retaining pCR status 10 months
postoperatively when last observed, suggesting that
trastuzumab and paclitaxel combination therapy for inflammatory
local recurrence after breast conserving surgery is
a highly effective treatment strategy.
Trastuzumab is currently being further tested in an
actively recruiting Phase II clinical trial (Clinical
Trials: Trastuzumab,
Docetaxel, and Carboplatin in Treating Women With Stage
II, Stage III, or Inflammatory Breast Cancer)
at UMDNJ - Robert Wood Johnson Medical School (New Brunswick,
NJ) as part of a combination regiment with docetaxel
(Taxotere) and carboplatin (paraplatin) in the treatment
of women with stage II, stage III, or inflammatory breast
cancer.
Emerging Treatment Directions
with Monoclonal Antibodies
The clinical concern with trastuzumab is cardiotoxicity,
and for this reason new generation antibody agents with
potential less cardiotoxic activity like the recombinant
humanized monoclonal antibody pertuzumab (pertuzumab
is also known as an HER-dimerization inhibitors (HDI))
and the tyrosine kinase agent lapatinib (a reversible
inhibitor of ErbB1 and ErbB2 receptors) are currently
being studied under clinical trial: for pertuzumab,
see the promising results of Agus et al. (J Clin Oncol
(2005): Phase
I clinical study of pertuzumab, a novel HER dimerization
inhibitor, in patients with advanced cancer)
As to lapatinib, see Clinical Trials: Phase
III Randomized Study of Capecitabine With Versus Without
Lapatinib in Women With Refractory Locally Advanced
or Metastatic Breast Cancer, where preliminary
results from this ongoing multi-center, open label study
for the first 41 subjects, as reported at the 40th 0th
Annual Meeting of the American Society of Clinical Oncology
(ASCO) in New Orleans (2004) indicated that a once daily
oral dose of lapatinib might effect an improved or stable
disease state in women with breast cancer refractory
to standard treatment regimens including trastuzumab).
Burris et al. (J Clin Oncol (2005): Phase
I Safety, Pharmacokinetics, and Clinical Activity Study
of Lapatinib (GW572016), a Reversible, Dual Inhibitor
of Epidermal Growth Factor Receptor Tyrosine Kinases
in Heavily Pretreated Patients With Metastatic Carcinomas)
confirmed the clinical activity of lapatinib in heavily
pretreated patients. Lapatinib is also under another
clinical trial (Clinical Trials: Study
Of Lapatinib In Patients With Relapsed Or Refractory
Inflammatory Breast Cancer)
The Role of Taxane/Platins Therapy
But this raises the question of optimizing the treatment
of HER2-non-overexpressing tumors where
trastuzumab monoclonal antibody therapy would obviously
not be motivated. In this connection, Lee et al. (Clin
Breast Cancer (2004): Docetaxel
and Cisplatin as Primary Chemotherapy for Treatment
of Locally Advanced Breast Cancers) have examined
the effectiveness of docetaxel and cisplatin
(Platinol) as primary or neoadjuvant chemotherapy of
locally advanced breast carcinoma (LABC), including
IBC, finding that the docetaxel/cisplatin combination
was an effective and well-tolerated induction treatment
of LABC/IBC, even in very large and primarily mostly
HER2-nonoverexpressing tumors.
Furthermore, Judith Hurley and fellow researchers at
the University of Miami have reported (Clin Breast Cancer
(2005): Weekly
Docetaxel/Carboplatin as Primary Systemic Therapy for
HER2-Negative Locally Advanced Breast Cancer)
results for the docetaxel/carboplatin regimen
in HER2-negative locally advanced or inflammatory breast
cancer (IBC), finding that weekly docetaxel/carboplatin
appears to be active and feasible as primary systemic
therapy (PST) in such patients with large breast tumors
(significant adverse hematologic events were was grade
3 neutropenia in 9% of patients, while adverse nonhematologic
events were fatigue and alopecia (each at 84%).
Other
Emerging Therapies
-
Anthracycline-based
CT (Chemotherapy)
Out of 30+ high methodological quality studies on
IBC oncotherapy evaluated by Kim and colleagues at
Tufts-New England Medical Cente (Kim et al, San Antonio
Breast Cancer Symposium - SABCS (2005): A
systematic review and descriptive analysis of inflammatory
breast cancer clinical trials), 24 were anthracycline-based,
most using the traditional (in the US) doxorubicin
(Adriamycin), but with some recent studies using the
alternate anthracycline, epirubicin (Ellence), including
the French FASG (French Adjuvant Study Group) GETIS
02 trial of Corinne Veyret at the Henri Becquerel
Center and her coresearchers (Veyret et al., Cancer
(2005): Inflammatory
breast cancer outcome with epirubicin-based induction
and maintenance chemotherapy), who used a
FEC-HD chemotherapy regimen consisting of fluorouracil
(5-FU) + epirubicin (Ellence) + cyclophosphamide (Cytoxan),
with or without G-CSF support, obtaining a pCR (pathologic
complete response) in 23.5% of patients with breast
tumors, and 31.4% of patients with involved axillary
lymph nodes, and with 35.7% DFS (disease-free survival)
on 10-year follow-up.
-
TAX:
Docetaxel (T) + Doxorubicin (A) + Capecitabine (Xeloda)
The substitution of capecitabine (Xeloda) for cyclophosphamide
(Cytoxan) in the TAC regimen results in the TAX regimen,
(with T, A and X every 28 days administered during
4 cycles), whch appears to be a highly active regimen
in locally advanced (LABC) or inflammatory breast
cancer (IBC): in the neoadjuvant study conducted by
Perez-Manga and colleagues (ASCO Annual Meeting (2005):
Preliminary results of a phase II study of neoadjuvant
treatment with docetaxel (T), doxorubicin (A) and
capecitabine (X) in locally advanced or inflammatory
breast cancer), of 21 evaluable patients with
LABC or IBC, 6 achieved CR and 15 PR, resulting in
an ORR of 100%, using a TAX regimen of T (30 mg/m2)
iv day 1, 8 and 15, A (50 mg/m2) iv day 1 and X (1500
mg/m2 o. d.) days 1-14, in a 4 weeks course, with
the scheme repeated up to 4 cycles followed by surgery.
The same investigators (perez-Manga et al., San Antonio
Breast Cancer Symposium - SABCS (2005): Preliminary
results of a phase II study of neoadjuvant treatment
with docetaxel (T), doxorubicin (A) and capecitabine
(X) in locally advanced or inflammatory breast cancer)
again evaluated the TAX regimen as neoadjuvant chemotherapy
in patients withLABC and IBC using the same treatment
plan (see above), finding that of 29 evaluable patients
for efficacy, 9 achieved CR, 19 PR and 1 PD resulting
in an ORR of 96.6%; TAX was well-tolerated, with grade
III/IV toxicity per patient being neutropenia (70.6%),
leucopenia (50.0%), febrile neutropenia (8.8%); diarrhea
(11.8%), mucositis (11.8%), nausea/vomiting (5.9%),
dysgeusia (2.9%) and asthenia (2.9%).
-
Bevacizumab
Avastin (Bevacizumab) is an angiogenesis inhibitor
which binds to vascular endothelial growth factor
(VEGF,) a protein well known to stimulate tumor angiogenesis
and progression, with its antiangiogenic activity
thought to be in part related to its downregulation
of NF-kB (see below).
Various bevacizumab combination regimens - with taxanes,
anthracyclines, and other chemotherapies - are now
being further explored: in a small recent study presented
at the 41st Annual Meeting of the American Society
of Clinical Oncology (ASCO), Wedham et al. (J Clin
Oncol (2006): Antiangiogenic
and Antitumor Effects of Bevacizumab in Patients With
Inflammatory and Locally Advanced Breast Cancer)
sought to evaluate parameters of angiogenesis by administering
bevacizumab to previously untreated patients with
inflammatory breast cancer (IBC) and locally advanced
breast cancer (LABC); the regimen consisted of bevacizumab
for cycle 1 (15 mg/kg on day 1) followed by six cycles
of bevacizumab with doxorubicin (50 mg/m2) and docetaxel
(75 mg/m2) every 3 weeks, with patients receiving
post-locoregional therapy of eight cycles of bevacizumab
alone, and hormonal therapy as indicated, the results
confirming bevacizumab's inhibitory effects on VEGF
receptor activation and vascular permeability, with
induction of apoptosis in tumor cells. And Lyons et
al. (ASCO Annual Meeting (2006): Toxicity
results and early outcome data on a randomized phase
II study of docetaxel ± bevacizumab for locally
advanced, unresectable breast cancer) conducted
a randomized phase II trial evaluating the vascular
effects on tumor regression of a combination BV +
T (bevacizumab + docetaxel (Taxotere)) regimen vs.
docetaxel monotherapy in the treatment of IBC and
LABC (locally advanced breast cancer), finding that
among the 49 patients (16 with IBC), there were 39
with clinical benefit (clinical complete or partial
response: 7 with clinical complete response, 32 partial
response), 5 with no response, and 5 with disease
progression, with the BV + T regimen well tolerated.
These studies confirm earlier results on the benefit
of bevacizumab in the IBC context (Wedham et al.,
ASCO Annual Meeting (2004): A
pilot study to evaluate response and angiogenesis
after treatment with bevacizumab in patients with
inflammatory breast cancer) who foudn a decrease
in VEGF after bevacizumab therapy, and a decrease
in tumor cell proliferation after bevacizumab and
AT chemotherapy (doxorubicin (50mg/m2) and docetaxel
(75mg/m2) q3wk and G-CSF in cycle 2–7), and Wedham
et al. (J Clin Oncol (2005): Antiangiogenic
and Antitumor Effects of Bevacizumab in Inflammatory
and Locally Advanced Breast Cancer Patients)
where it was found that bevacizumab has inhibitory
effects on VEGF receptor activation and vascular permeability,
and induces apoptosis in tumor cells, again using
a BV + AT regimen of bevacizumab for cycle 1 (15 mg/kg
on day 1) followed by six cycles of bevacizumab with
doxorubicin (50 mg/m2) and docetaxel (75 mg/m2) every
3 weeks, and with patients receiving eight cycles
of bevacizumab alone, and hormonal therapy when indicated,
after locoregional therapy.
(new) And
finally, there are the important reults on metronomic
AC ---> P, as reported by Georgiana Ellis of
the Seattle Cancer Care Alliance and coresearchers
in the dramatic results of the SWOG-0012 trial at
ASCO 2006 (SWOG
0012, a randomized phase III comparison of standard
doxorubicin (A) and cyclophosphamide (C) followed
by weekly paclitaxel (T) versus weekly doxorubicin
and daily oral cyclophosphamide plus G-CSF (G) followed
by weekly paclitaxel as neoadjuvant therapy for inflammatory
and locally advanced breast cancer). As I
have clarify elsewhere, metronomic therapy involves
using low-dose chemotherapy on regular continuous
schedules, weekly and often daily. This is of aprticular
relevance to IBC because it's been demonstrated that
IBC tumors are highly angiogenic and lymphangiogenic
(new vasculature (blood vessel supply networks) promoting
and feeding tumor growth) in nature, far more so than
(non-IBC) disease, and metronomic therapy exerts profound
anti-angiogenic activity (effectively starving the
tumor cells of their vital supporting vasculature).
The SWOG-0012 trial used metronomically-dosed AC (doxorubicin
weekly at 24 mg/m2, and cyclophosphamide daily at
60 mg/m2) with G-CSF support, achieving striking response
rates: for IBC patients, compared to standard (conventionally
dosed) AC, metronomic-AC achieved a pCR (pathological
complete response) of 32% (compared to 12% for standard
AC), the highest pCR - complete response! - rates
ever reported in the treatment of IBC to date.
- Granulocyte-colony-stimulating
Factors (G-CSF)
G-CSF agents stimulate the bone marrow production
of red blood cells and platelets, and white blood cell
neutrophils to assist in fighting infection, potentially
allowing higher doses of chemotherapy to deployed, and
two such G-CSF drugs are being studied in combination
regimens in clinical trials: filgrastim (Clinical
Trials: Doxorubicin,
Cyclophosphamide, and Paclitaxel With or Without Filgrastim
in Treating Women With Inflammatory or Locally Advanced
Breast Cancer) and pegfilgrastim (Clinical
trials: Epirubicin,
Docetaxel, and Pegfilgrastim in Treating Women With
Locally Advanced or Inflammatory Breast Cancer).
- (new)
Multidisciplinary Therapy (MDT):
The Greek research team of Alexandros Ardavanis and
colleagues (Oncologist (2006): Multidisciplinary
Therapy of Locally Far-Advanced or Inflammatory Breast
Cancer with Fixed Perioperative Sequence of Epirubicin,
Vinorelbine, and Fluorouracil Chemotherapy, Surgery,
and Radiotherapy: Long-Term Results) assessed
in patients with newly diagnosed inoperable stage IIIB
or inflammatory breast Cancer (IBC) a multidisciplinary
regimen of perioperative chemotherapy integrated with
surgery and radiotherapy, using fluorouracil (5-FU,
Adrucil) 600 mg/m2 day 1, epirubicin (Ellence, Pharmorubicin)
75 mg/m2 day 1, and vinorelbine (Navelbine) 25 mg/m2
day1 and day8), all i.v. every 21 days, followed by
radical or conservative surgery according to clinical
response, and four postoperative identical chemotherapy
courses aimed to eradicate micrometastatic disease;
locoregional radiotherapy was offered to all patients
upon chemotherapy completion followed by endocrine therapy
according to hormone receptor status. They found that
all tumors were converted to operable, 31.3% with breast
conservation and the clinical response rate (RR) was
77.7% (with 22.2% complete) and pathological RR was
73.3% (complete, 20% in both primary and axilla). Furthermore,
after a median follow-up of 72 months, 62.5% of patients
remain relapse free at 3 years with 83% alive, and 16.7%
were relapse-free at 5 years with 58.3% were alive.
Another novel multidisciplinary therapy (MDT) was recently
explored by S Farjami and coresearchers (ASCO Annual
Metting (2006): High
dose chemotherapy with autologous stem cell rescue as
a part of combined modality therapy in stage IIIB inflammatory
breast cancer) deploying HD-CT (high-dose chemotherapy)
consisting of the alkylating agent triethylenethiophosphoramide
(ThioTEPA) (250mg/m2 days 1, 2 & 3 with a total
dose of 750mg/m2), mitoxantrone (Novantrone) (40mg/m2
on day 1) and carboplatin (Paraplatin) (333mg/m2 on
days 1, 2 & 3 with a total dose of 1gm/m2), and
autologous stem cell rescue, in 28 patients with confirmed
stage IIIB IBC, finding the regimen to be safe and efficacious
(and significantly better EFS and OS in patients with
estrogen receptor (ER) positive tumors).
- (new)
Targeted EC ---> TH
The German research team of M Untch and coresarchers
(Untch et al., SABCS - San Antonio Breast Cancer Symposium
(2005): A
multicenter phase II study of preoperative epirubicin,
cyclophosphamide (EC) followed by paclitaxel (P) plus
trastuzumab (T) in Her2 positive primary breast cancer)
conducted a multicenter phase II study of preoperative
EC (epirubicin + cyclophosphamide) followed by paclitaxel
(T) plus trastuzumab (H) in 238 (119 analyzed for primary
endpoints) patients (age 18 – 65) with breast cancer
> 2 cm or IBC, HER-2+ patients, with primary clinical
endpoints of histopathological response (breast and
axilla) and overall cardiac toxicity, finding a histopathological
complete response of 37%.
- (new)
Dual TKI Inhibitor Lapatinib (Tykerb)
From systematic review, it is known that preclinical
and phase I studies suggest that the dual (EGFR/ErbB2
(Her2/neu) TKI (tyrosine kinase inhibitor ) lapatinib
(Tykerb) is particularly effective against inflammatory
breast cancer: see Spector et al. (J Clin Oncol (2005):
Study
of the Biologic Effects of Lapatinib, a Reversible Inhibitor
of ErbB1 and ErbB2 Tyrosine Kinases, on Tumor Growth
and Survival Pathways in Patients With Advanced Malignancies)
who first reported preliminary evidence of biologic
and clinical activity of lapatinib in ErbB1 and/or ErbB2-overexpressing
tumors, and Burris et al. (J Clin Oncol (2005): Phase
I Safety, Pharmacokinetics, and Clinical Activity Study
of Lapatinib (GW572016), a Reversible Dual Inhibitor
of Epidermal Growth Factor Receptor Tyrosine Kinases,
in Heavily Pretreated Patients With Metastatic Carcinomas)
who found that lapatinib was well tolerated (dose range
from 500 to 1,600 mg daily), with clinical activity
observed in heavily pretreated patients with ErbB1-expressing
and/or ErbB2-overexpressing (HER2) metastatic cancers,
including four partial responses in patients with trastuzumab-resistant
breast cancers and prolonged stable disease in 10 patients.
These studies also establish the high incidence of HER2-overexpression
in IBC patients: whereas in the general population,
HER-2 is over-expressed in around 25% of human breast
cancers, more than double (52%) of that number of IBC
patients are HER2-positive (see the findings on this
of the Royal Marsden team of Parton et al., Breast (2004):
High incidence of HER-2 positivity in inflammatory
breast cancer, as well as the earlier similar
findings of Turpin et al., Oncogene (2002): Increased
incidence of ERBB2 overexpression and TP53 mutation
in inflammatory breast cancer) suggesting that
early HER-2 directed therapy as a part of multimodal
treatment may improve outcome.
These findings have been more recently confirmed by
Spector et al. (J Clin Oncol (2006 ASCO Annual Meeting
Proceedings (Post-Meeting Edition): EGF103009,
a phase II trial of lapatinib monotherapy in patients
with relapsed/refractory inflammatory breast cancer
(IBC): Clinical activity and biologic predictors of
response) who assessed, in a phase II clinical
trial reported at the 2006 ASCO annual meeting, response
rates to lapatinib (Tykerb) monotherapy (1500
mg/day) in patients with relapsed or refractory IBC;
among the 24 women with ErbB2 (HER2) overexpression,
62% experienced a partial response from lapatinib treatment,
with a much lower response rate among women without
ErbB2 overexpression; adverse events were mild, with
GI and skin toxicity being the most commonly observed.
This confirms the earlier findings of Storniolo et al.
(ASCO Ann Proc (2005): A
phase I, open-label study of lapatinib (GW572016) plus
trastuzumab; a clinically active regimen) where
the combination of lapatinib (Tykerb) and trastuzumab
(Hercepin) in 46 Her2 overexpressing MBC patients resulted
in an impressive 33% (16 patients) experiencing either
objective response (8 patients, with one complete response),
or disease stabilization (8 patients) lasting at least
6 months.
And Denise Yardley at the Sarah Cannon Research Institute
in Nashville is conducting a phase II trial of the GEA
(Gemcitabine (Gemzar), Epirubicin (Ellence), and
Abraxane (nab-paclitaxel) regimen for IBC (ClinicalTrials:
Neo-Adjuvant
Gemcitabine, Epirubicin, ABI-007 (GEA) in Locally Advanced
or Inflammatory Breast Cancer). Also Joseph
Sparano of the Albert Einstein College of Medicine is
conducting a clinical trial evaluating the novel FTI
(farnesyltransferase inhibitor) tipifarnib (Zarnestra)
combined with doxorubicin (Adriamycin), and cyclophosphamide
(Cytoxan) in IBC patients (Clinical Trials: Tipifarnib,
Doxorubicin, and Cyclophosphamide in Treating Women
With Locally Advanced Breast Cancer). IBC Watch
notes that related to this trial is that of Linda Vahdat
at New York Weill Cornell Cancer Center evaluating the
same FTI agent tipifarnib (Zarnestra) with the pure
anti-estrogen fulvestrant (Faslodex) in hormone
responsive inoperable locally advanced or MBC (Clinical
Trials:
Tipifarnib and Fulvestrant as Second-Line Therapy
in Treating Postmenopausal Women With Hormone Receptor-Positive
Inoperable Locally Advanced or Metastatic Breast Cancer
With Progressive Disease After Previous First-Line Endocrine
Therapy).
In addition two trials are explorating the VEGF TKI
and signalling inhibitor AZD2171 for benefit
to IBC and other refractory stage IV patients (Clinical
Trials: AZD2171 in Treating Patients With Refractory
Stage IV Breast Cancer conducted by Harold Burstein
at the Dana-Farber Cancer Institute; and Clinical Trials:
AZD2171 and Combination Chemotherapy in Treating
Women With Locally Advanced Breast Cancer conduceted
by Neelima Denduluri of NCI), already been studied in
advanced non-small cell lung cancer (NSCLC) or Colorectal
Cancer (CRC); AZD2171 also exhibits angiogenic activity.
A novel investigation by Kimberly Blackwell at Duke
Comprehensive Cancer Center is exploring hyperthermia
therapy which kills tumor cells by heating them
to above normal body temperature, with ThermoDox, a
heat activated liposomal encapsulation of doxorubicin
in locally recurrent breast cancer including IBC (Clinical
Trials: Temperature-Sensitive
Liposomal Doxorubicin and Hyperthermia in Treating Women
With Locally Recurrent Breast Cancer).
(new)
Angiogenesis and NF-kB
Inhibition Therapy
Recent research has clarified the molecular mechanisms
underlying IBC, and from this we know that compared
to noninflammatory breast cancer (NIBC), angiogenic
factors are overexpressed in human IBC, as determined
by Kazuo Shirakawa with the National Cancer Center
Research Institute of Japan and coresearcher: Shirakawa
et al., Int J Cancer, (2002): Tumor-infiltrating endothelial
cells and endothelial precursor cells in inflammatory
breast cancer using semiquantitative reverse
transcriptase polymerase chain reaction RT-PCR) examination
of resected specimens). IBC is distinguished by marked
angiogenic activity, as found by Colpaert et al, (Br
J Cancer (2003): Inflammatory
breast cancer shows angiogenesis with high endothelial
proliferation rate and strong E-cadherin expression)
who concluded that such intense angiogenesis along
with strong E-cadherin expression appear to be contributants
to the highly metastatic phenotype of IBC. Collectively,
these findings suggest that the IBC tumor is a highly
angiogenic tumor, further confirmed by Ilse Van der
Auwera with the Translational Cancer Research Group
in Antwerp and coresearchers (Van der Auwera, Clin
Cancer Res (2004): Increased
Angiogenesis and Lymphangiogenesis in Inflammatory
versus Noninflammatory Breast Cancer by Real-Time
Reverse Transcriptase-PCR Gene Expression Quantification)
who found in addition that IBC demonstrated significantly
higher expression of lymphangiogenic genes (as measured
by cellular mRNA using real-time quantitative reverse
transcriptase-PCR and corroborated by the significantly
higher fraction of proliferating lymphatic endothelial
cells, as a measure of lymphangiogenesis), which correlates
well with the fact of extensive lymphatic spread in
the breast and particularly in cutaneous and subcutaneous
lymphatics in IBC disease, with virtually all IBC
patients presenting with lymph node involvement at
time of diagnosis. (IBC Watch notes that the
Auwera study did find evidence for the occurrence
of lymphangiogenesis in IBC, which the earlier Shirakawa
study failed to find).
The clinical significance of this body of recent data
is that given that occurrence of breast cancer metastasis
is known to be correlated with the extent of new blood
vessel growth (Weidner et al., N Eng J Med (1999):
Tumor
angiogenesis and metastasis--correlation in invasive
breast carcinoma), then level of angiogenic
activity can serve both as a prognostic indicator
and a target for therapy.
Critical to the highly angiogenic and lymphangiogenic
nature of the IBC tumor, is the high number of nuclear
factor-kappaB (NF-kB) target genes with
elevated expression in IBC versus non-IBC, as shown
by the research of Van Laere et al. (SABCS - San Antonio
Breast Cancer Symposium (2005): Involvement
of NF-kappaB in inflammatory breast cancer through
the induction of epithelial to mesenchymal transition)
who found that there was a high number of NF-kB
target genes and upstream activators of NF-kB
among IBC patients, suggesting that the nuclear transcription
protein NF-kB contributes to the aggressive
and invasive phenotype of IBC. NF-kB represents
a family of related protein dimers binding to a common
DNA sequence motif called the kB (kappaB) site,
and is an important activator protein in cancer development
and progression, controlling the transcription of
many angiogenic factors and other cytokines, being
involved in regulation of COX-2 and iNOS expression.
NF-kB is increased in tissue inflammation,
cell proliferation, and cancers, induces the overactivation
of COX enzymes, and is associated with increased angiogenesis
(Shibata et al., Breast Cancer Res Treat (2002): Inhibition
of NF-kB Activity Decreases the VEGF mRNA Expression
in MDA-MB-231 Breast Cancer Cells); and it
has been established agents that activate NF-B are
either tumor initiators or tumor promoters, and the
NF-B activation mechansism can block apoptosis, promote
proliferation and mediate tumorigenesis.
Several phytochemical derivatives are potent inhibitors
of NF-kB, including curcumin, EGCG (green tea),
6-gingerol (ginger), ginseng, and resveratrol, among
others (Yance & Sagar, Integr Cancer Therap (2006):
Targeting Angiogenesis With Integrative Cancer
Therapies [pdf]).
Curcumin in particular is inhibits COX-2 and has powerful
antiangiogenic activity derived through the inactivation
of NF-kB; indeed, it is thought that both the
antiinflammatory and anticarcinogenic activity of
curcumin may be derived from its ability to inhibit
cellular gene expression regulated by transcription
factors NF-kB; see Jobin et al., J Immunol
(1999):
Curcumin Blocks Cytokine-Mediated NF-B Activation
and Proinflammatory Gene Expression by Inhibiting
Inhibitory Factor I-B Kinase Activity; Kohli
et al., Indian J Pharmacol (2005):
Curcumin: A natural antiinflammatory agent;
and especially the research of Bharat Aggarwal and
colleagues of the Cytokine Research Laboratory at
MD Anderson Cancer Center in Ann N Y Acad Sci (2004):
Suppression
of the Nuclear Factor-B Activation Pathway by Spice-Derived
Phytochemicals: Reasoning for Seasoning, and
in Clin Cancer Res (2005): Curcumin
Suppresses the Paclitaxel-Induced Nuclear Factor-B
Pathway in Breast Cancer Cells and Inhibits Lung Metastasis
of Human Breast Cancer in Nude Mice) in which
the researchers hypothesized that curcumin would potentiate
the effect of chemotherapy in ABC (advanced breast
cancer) and in addition inhibit lung metastasis given
its suppression of NF-kB) activation which
mediates cell survival, proliferation, invasion, and
metastasis, testing the hypothesis by using paclitaxel
(Taxol)-resistant breast cancer cells and a human
breast cancer xenograft model (IBC Watch notes
in connection with the protective effect of curcumin
against lung metastatis that (1) NF-kB) activation
has been implicated in chemical carcinogenesis and
tumorigenesis, and that (2) cigarette smoke-induced
NF-kB activation and NF-kB-regulated
gene expression in human NSCLC (non-small cell lung
carcinoma) cells is suppressed by curcumin; see Shishodia
et al., Carcinogenesis (2003): Curcumin
(diferuloylmethane) down-regulates cigarette smoke-induced
NF-kB activation through inhibition of IkBa kinase
in human lung epithelial cells: correlation with suppression
of COX-2, MMP-9 and cyclin D1).
They found that curcumin blocked NF-kB activation
in breast cancer cells, and also also enhanced apoptosis
and that iIn a human breast cancer xenograft model,
dietary administration of curcumin significantly decreased
the incidence of breast cancer metastasis to the lung
and suppressed the expression of not only of NF-kB,
but also of cyclooxygenase 2 (COX-2), and MMP-9 (matrix
metalloproteinase-9), concluding that curcumin was
a pharmacologically safe compound with a therapeutic
potential in preventing breast cancer metastasis,
possibly through suppression of NF-kB and NF-kB–regulated
gene products, and may assist in reversing chemoresistance,
given the establiseh role of NF-kB in chemoresistance.
Finally, it is notworthy that this study used a 10
mg/kg dose of paclitaxel which is a dose lower than
previously shown to be effective yet using this relatively
less effective dose, they determined that the addition
of curcumin resulted in antimetastatic therapy that
was as effective as higher, potentially toxic doses
of the paclitaxel chemotherapeutic drug.
(new)
The Unique Molecular Pathways Underlying IBC: What
We Know Today
Compared to non-IBC, IBC has statistically higher
Ki-67 and also significantly higher expression
of both BAX (itself activated by p53)
and e-cadherin (Dang Nyugen and colleagues
at Balylor Breast Center, Clin Cancer Res (2006):
Molecular
Heterogeneity of Inflammatory Breast Cancer: A Hyperproliferative
Phenotype), and as shown by Van der Auwera
et al. (Clin
Cancer Res (2004): Increased
angiogenesis and lymphangiogenesis in inflammatory
versus noninflammatory breast cancer by real-time
reverse transcriptase-PCR gene expression quantification),
both angiogenesis and lymphangiogenesis
activity is highly elevated.
In addition, IBC has been establsihed as displaying
epidemiologic, histoclinical, and prognostic differences
with non-IBC: high histologic grade, negativity of
hormone receptors, neoangiogenenesis and tissue invasiveness,
and an aggressive clinical behavior with high frequency
of axillary lymph node involvement at diagnosis (Francois
Bertucci and colleagues, Cancer Res (2005): Gene
Expression Profiling Identifies Molecular Subtypes
of Inflammatory Breast Cancer).
It is also the case that IBC exhibits up-regulation
of a number of growth factors, including vascular
endothelial growth factor, aka VEGF (Kazuo
Shirakawa and colleagues, Clin Cancer Res (2002):
Hemodynamics
in Vasculogenic Mimicry and Angiogenesis of Inflammatory
Breast Cancer Xenograft), which is not surprising
given the fact that VEGF in crtitcally involved in
angiogenesis, ands also given that besides being lymphotactic,
IBC tumors tend to be highly vascular because of their
angiogenic and angioinvasive potential (as noted by
Celina Kleer and colleagues at the University of Michigan:
Breast Cancer Res (2000): Molecular
biology of breast metastasis: Inflammatory breast
cancer - clinical syndrome and molecular determinants),
and analysis of IBC tumor cell lines and archival
tumor specimens demonstrated that high levels of vascular
endothelial growth factor (VEGF). These considerations
concerning VEGF in IBC form the motivation for deploying
the anti-VEGF, anti-angiogenic biologic bevacizumab
(Avastin), and Massimo Cristofanilli and colleagues
at MD Anderson Cancer Center noted that "the
therapeutic use of agents that target VEGF receptors
proved, as predicted, to be more effective in the
human IBC xenograft model", and that furthermoreVEGF
coupled with the e-cadherin overexpression characteristic
of IBC "together, these unique molecular features
suggest that angiogenesis has an important role in
IBC and indicate that angiogenesis modulation may
be an important therapy" (Cristofanilli et
al., Oncologist (2003): Update
on the Management of Inflammatory Breast Cancer).
And of course we now have direct clinical evidence
of the benefit of anti-VEGF therapy in IBC, as concluded
by Suparna Wedam and colleagues: "bevacizumab
has inhibitory effects on VEGF receptor activation
and vascular permeability, and induces apoptosis in
tumor cells" in their study of the addition of
bevacizumab to a standard AC regimen on IBC and LABC
(Wedam et al., J Clin Oncol (2006): Antiangiogenic
and Antitumor Effects of Bevacizumab in Patients With
Inflammatory and Locally Advanced Breast Cancer).
And as noted above, elevated expression of nuclear
factor-kappaB (NF-kB) is
critical to the highly angiogenic and lymphangiogenic
nature of the IBC tumor compared to non-IBC, as shown
by the research of Van Laere et al. (SABCS - San Antonio
Breast Cancer Symposium (2005): Involvement
of NF-kappaB in inflammatory breast cancer through
the induction of epithelial to mesenchymal transition)
suggesting that the nuclear transcription protein
NF-kB contributes to the aggressive and invasive
phenotype of IBC. Since NF-kB is an important
activator protein in cancer development and progression,
controlling the transcription of many angiogenic factors
and other cytokines, and being involved in regulation
of COX-2 and iNOS expression, inducing the overactivation
of COX enzymes, and being associated with increased
angiogenesis (Shibata et al., Breast Cancer Res Treat
(2002): Inhibition
of NF-kB Activity Decreases the VEGF mRNA Expression
in MDA-MB-231 Breast Cancer Cells; see also
Paolo Madeddu on the central role of VEGF in agiogenesis
and vasculogenesis (de novo vessel formation): Exp
Physiol (2005): Therapeutic
angiogenesis and vasculogenesis for tissue regeneration
and also the McMaster University researchers Joanne
Yu and Janusz Yak, Breast cancer Res (2003): Host
microenvironment in breast cancer development: Inflammatory
and immune cells in tumour angiogenesis and arteriogenesis)
as well as blocking apoptosis, promoting proliferation
and mediating tumorigenesis, it becomes a singularly
important target of IBC oncotherapies (see Steven
J. Van Laere and colleagues, Clin Cancer Res (2006):
Nuclear
Factor-B Signature of Inflammatory Breast Cancer by
cDNA Microarray Validated by Quantitative Real-time
Reverse Transcription-PCR, Immunohistochemistry, and
Nuclear Factor-B DNA-Binding). Both CAM (complementary
and alternative medicine) agents curcumin and
the green tea extract/polyphenol EGCG are well-evidenced
down-regulators of NF-kB activation (see our discussion
on Breast
Cancer Prevention Watch), as well as
resveratrol (Young-Joon Surh and colleagues at the
Seoul National University, Mutat Res (2001): Molecular
mechanisms underlying chemopreventive activities of
anti-inflammatory phytochemicals: down-regulation
of COX-2 and iNOS through suppression of NF-kB activation,
who found that curcumin, EGCG and resveratrol suppress
activation of NF-kB).
Melatonin
Radio/Chemo-Protection
Melatonin (at levels of
20mg/daily) may be a radioprotector agent, protecting
against the harm of radiation and radiotherpy (see
Weiss and Landauer, Toxicology (2003): Protection
against ionizing radiation by antioxidant nutrients
and phytochemicals; also Blask et al., Curr
Top Med Chem (2002): Melatonin
as a chronobiotic/anticancer agent: cellular, biochemical,
and molecular mechanisms of action and their implications
for circadian-based cancer therapy); see also
Karslioglu et al. (J Radiat Res (Tokyo) (2005): Radioprotective
effects of melatonin on radiation-induced cataract)
who conclude that "supplementing cancer patients
with adjuvant therapy of melatonin may reduce patients
suffering from toxic therapeutic regimens such as
chemotherapy and/or radiotherapy and may provide an
alleviation of the symptoms due to radiation-induced
organ injuries").
Note that other natural agents appear to have a similar
chemo-protective activity: a recent study by Branda
et al. (Cancer (2005): Effect
of vitamin B12, folate, and dietary supplements on
breast carcinoma chemotherapy-induced mucositis and
neutropenia) determined that the neutrophil
count decrease consequent to chemotherapy was ameliorated
by dietary supplementation with a multivitamin
or vitamin E (but this neutrophil decrease was
actually exacerbated by high serum folate levels).
These findings are cross-validated in the review of
Vijayalaxmi et al. (Int J Radiat Oncol Biol Phys (2004):
Melatonin as a radioprotective agent: a review)
where it was found that melatonin administration,
either alone or in combination with traditional radiotherapy,
results in a favorable efficacy:toxicity ratio during
the treatment of human cancers.
Melatonin: Aromatase Inhibition
Furthermore, the research findings of Cos et al. J
Pineal Res (2005): Melatonin
modulates aromatase activity in MCF-7 human breast
cancer cells) have demonstrated that melatonin,
at physiological concentrations, decreases aromatase
activity and expression in MCF-7 cells, and that
this aromatase inhibitory effect of melatonin, together
with its already known antiestrogenic properties interacting
with the estrogen-receptor,strongly suggests a role
in the prevention and treatment of hormone-dependent
mammary neoplasia; see also the study of COs et al.
(Int J Cancer (2005): Melatonin
inhibits the growth of DMBA-induced mammary tumors
by decreasing the local biosynthesis of estrogens
through the modulation of aromatase activity),
which investigated the in vivo aromatase-inhibitory
properties of melatonin, noting that melatonin inhibits
the growth of breast cancer cells by interacting with
estrogen-responsive pathways, thus behaving as an
antiestrogenic hormone, and concluding from their
in vivo study that melatonin could exert its antitumoral
effects on hormone-dependent mammary tumors by inhibiting
the aromatase activity of the tumoral tissue.
Melatonin: Chemotherapy Enhancement
Taking the protective role for melatonin further,
Kim et al. (J Cardiovasc Pharmacol (2005): Modulation
by Melatonin of the Cardiotoxic and Antitumor Activities
of Adriamycin) have shown that given melatonin's
oncolytic activity, the combination of adriamycin
and melatonin improved the antitumor activity of adriamycin,
as indicated by an increase in the number of long-term
survivors as well as decreases in body-weight losses
resulting from adriamycin treatment, suggesting that
melatonin not only protects against adriamycin-induced
cardiotoxicity but also enhances its antitumor activity
and further suggesting that a melatonin and adriamycin
combination represents a potentially useful regimen
for the treatment of human neoplasms, by virtue of
the fact that it allows the use of lower doses of
adriamycin, thereby avoiding the toxic side effects
associated with this drug.
Night-shift Breast Cancer
Update
These findings are in keeping with what is known about
so-called night-shift breast cancer phenomenon: an
increased risk of breast cancer is seen among subjects
not sleeping during the period of the night when nocturnal
melatonin levels are typically at their highest, and
hence with graveyard shiftwork, with even some indication
of an increased risk among subjects with the brightest
bedrooms (Davis et al, J Natl Cancer Inst: Night
Shift Work, Light at Night, and Risk of Breast Cancer,
where it was concluded that "to the extent that
graveyard shiftwork and nonpeak sleep reflect exposure
to light at night, the results of this study add to
a growing body of evidence that such exposure, for
whatever reason, may be linked to breast cancer risk",
speculated to be due to the fact that light at night
exposure reduces nocturnal melatonin levels, which
can result in increased circulating estradiol concentrations
in the blood). (See also Schernhammer et al, J Natl
Cancer Inst: Rotating
Night Shifts and Risk of Breast Cancer in Women Participating
in the Nurses' Health Study and Schernhammer
et al, Cancer Epidemiol Biomarkers Prev: Epidemiology
of urinary melatonin in women and its relation to
other hormones and night work).
IBC Watch Commentary
Although a recent study (Travis et al, J Natl Cancer
Inst: Melatonin
and Breast Cancer: A Prospective Study) found
no evidence that the level of melatonin is strongly
associated with the risk for breast cancer, this study
measured the level of 24-hour melatonin excretion
despite the fact, as pointed out by Hrushesky &
Black (J Natl Cancer Inst (2004): Re:
Melatonin and Breast Cancer: A Prospective Study)
in their commentary that differences in the nocturnal
duration of melatonin secretion and thus its distribution
across the night cannot be accounted for by measuring
24-hour excretion levels, and it may be necessary
to examine whether instead cancer risk is conferred
not by average 24-hour melatonin exposure, but by
the circadian temporal organization of melatonin availability.
Hrushesky & Black also correctly point out that
in those studies which have evidenced a relationship
between cancer risk and melatonin excretion, have
discovered the relationship based on circadian amplitude
or phase (time of melatonin upswing), not on the 24-hour
average amount of melatonin metabolite excreted.
Nor did the Travis study (above) control for the potentially
confounding factor of the relative nighttime light
exposure of case patients and control subjects, given
the well-established fact light exposure and especially
nocturnal light exposure may confer cancer risk through
modulation of the melatonin circadian pattern: see
Schernhammer & Hankinson (J Natl Cancer Inst (2005):
Urinary
Melatonin Levels and Breast Cancer Risk) who
used a prospective case–control study nested
within the Nurses' Health Study II cohort, finding
the prospective data supporting the hypothesis that
higher melatonin levels are associated with a lower
risk of breast cancer; also Schernhammer et al. (Cancer
Epidemiol Biomarkers Prev (2004): Epidemiology
of Urinary Melatonin in Women and Its Relation to
Other Hormones and Night Work) who also concluded
that women working on rotating night shifts appear
to experience changes in hormone levels, as measured
by urinary melatonin, that may be associated with
the increased cancer risk observed among night-shift
workers; and similar findings have emerged with respect
to colorectal cancer (see Schernhammer et al., J Natl
Cancer Inst (2003): Night-Shift
Work and Risk of Colorectal Cancer in the Nurses’
Health Study who found that working a rotating
night shift at least three nights per month for 15
or more years may increase the risk of colorectal
cancer in women.
Although the exact mechanisms involved in noctural
light, decreased melatonin levels, and increased cancer
risk are still being study, the molecular mechanisms
are beginning to be defined: the recent animal research
of Flipski et al. (J Natl Cancer Inst (2005): Effects
of Light and Food Schedules on Liver and Tumor Molecular
Clocks in Mice) has found that altered light-dark
modifies the expression of molecular clock genes and
genes involved in carcinogenesis and tumor progression.
In addition,
Megdal et al. (Eur J Cancer (205): Night
work and breast cancer risk: A systematic review and
meta-analysis) conducted a systematic review
and meta-analysis of 13 qualifying observational studies
between January 1960 to January 2005 in order to assess
the effects of night work on breast cancer risk, concluding
that the studies to date collectively show an increased
breast cancer risk among women, with publication bias
unlikely to have influenced the results.
In conclusion, therefore, IBC Watch finds that
numerous systematic reviews and meta-analyses, and
their underlying research, provide in the balance
compelling evidence of an increased risk of
breast cancer consequent to night shift work and its
known adverse impact on melatonin production.
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