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.

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 non-inflammatory 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 non-inflammatory 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 inter-individual 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: 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 involvement, 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.

 

 

New and Emerging Directions in IBC Treatment

What's Newly Added:

v FTI Tipifarnib (Zarnestra) Trial Results
v The Melphalan / Etoposide +  ASCT Regimen
v Reishi Inhibition of IBC Progression 

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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 & Christofanilli (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-stitched 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 indeterminate 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 sufficiently 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, 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 (hematopoietic 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%).


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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), which 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 with LABC 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)
  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 21 previously untreated patients with inflammatory breast cancer (IBC) and locally advanced breast cancer (LABC), 20 of whom had IBC; 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: after just a single cycle of bevacizumab, overall response rate (ORR) was 67%.  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.
  
  And finally, there are the important results 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 particular 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.
  
  
  

• Farnesyltransferase Inhibitors (FTIs)
  Farnesyltransferase (FTase) inhibitors (FTIs) may hold promise in IBC treatment: see the study of Johnston et al. (J Clin Oncol (2003): Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer) which found that the farnesyl transferase inhibitor tipifarnib (R115777) demonstrated clinical activity in patients with metastatic breast cancer; also Lebowitz et al. (Clin Cancer Res (2005): A Phase I Trial and Pharmacokinetic Study of Tipifarnib, a Farnesyltransferase Inhibitor, and Tamoxifen in Metastatic Breast Cancer) found that tipifarnib and tamoxifen can be given safely with minimal toxicity in treating metastatic breast cancer.
  
  (new) The findings of Kenneth van Golen  at the  University of Michigan and colleagues (van Golen et al. (Mol Cancer Ther (2002): Reversion of RhoC GTPase-induced inflammatory breast cancer phenotype by treatment with a farnesyl transferase inhibitor)) found that an FIT can reverse the RhoC GTPase-induced IBC phenotype, suggesting that FTIs may be powerful new therapy against RhoC GTPase overexpressing tumors which include both IBC (and, for example, metastatic melanoma) tumors, and aggressive noninflammatory, metastatic breast cancers, and theirs is first report of FTI inhibition of the RhoC GTPase overexpression cancer phenotype, with a concomitant significant decrease in both tumor  cell motility and invasion (via the role of the MAPK pathway in RhoC-induced motility, invasion, and angiogenesis in inflammatory  breast cancer, later confirmed  by Francois Bertucci and colleagues (Cancer Res (2005): Gene Expression Profiling Identifies Molecular Subtypes of Inflammatory Breast Cancer). See also Clinical trials: Tipifarnib, Doxorubicin, and Cyclophosphamide in Treating Women With Locally Advanced Breast Cancer.  Note  that this trial has completed, with 17% (2 of  12) of patients achieving breast pathological complete response (breast pCR) from tipifarnib added to the AC regimen, as reported by  Joseph Sparano and colleagues (Sparano JA, Moulder S, Kazi A, et al.  Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer. Clin Cancer Res 2009 Apr 7). See also: Van Golen, KL.  Inhibition of the RhoC GTPase-Mediated Inflammatory Breast Cancer Phenotype by Farnesyl Transferase Inhibitors.  Department of Defense Breast Cancer Research Program. Abstract BC023187. 
  
  
  
• (new) The Melphalan / Etoposide +  ASCT Regimen 
  Claude Sportès and colleagues at NCI (Sportès C, Steinberg SM, Liewehr DJ, et al.  Strategies to improve long-term outcome in stage IIIB inflammatory breast cancer: multimodality treatment including dose-intensive induction and high-dose chemotherapy. Biol Blood Marrow Transplant 2009 Aug; 15(8):963-70) in a small Phase II trial used a multimodality intervention of a high-dose of the alkylating agent melphalan (Alkeran) plus the topoisomerase II inhibitor etoposide (VP-16, Toposar, VePesid, Etopophos) plus autologous stem cell transplantation (ASCT) to treat 21 non-metastatic IBC patients, tolerated with acceptable morbidity and no post-ASCT 100-day mortality. The estimated progression-free survival (PFS) was 67%, with an event-free survival (EFS) of 55%, and overall survival (OS) at 6 years from on-study date of 69% at a median follow-up of approximately 8 years, one  of the most promising mature outcome data for IBC, suggesting that ASCT may play a significant role in the first line IBC treatment.
  
  

• 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).
  
  
  
• 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).
  
  
• Targeted EC ---> TH
  The German research team of M Untch and coresearchers (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%.
  
  
• Dual TKI Inhibitor Lapatinib (Tykerb)
  From systematic review, it is known that preclinical and phase I studies suggest that the dual (ErbB1(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 (Herceptin) 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 exploring 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 conducted 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).

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  Angiogenesis and NF-kB Inhibition Therapy
  Recent research has clarified the molecular mechanisms underlying IBC, and from this we know that compared to non-inflammatory 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 mechanism can block apoptosis, promote proliferation and mediate tumorigenesis.
  
  Natural NF-kB Inhibitors: Curcumin
  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 anti-inflammatory 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 metastasis 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 established role of NF-kB in chemoresistance. Finally, it is noteworthy 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.
  
  
  
  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 established 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 furthermore VEGF 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 angiogenesis 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).

(new) Reishi (Ganoderma lucidum) Mushroom Extract
Michaela Hoffmeyer at the University of Texas and colleagues (Hoffmeyer M, Martinez-Montemayor M, Dharmawardhane SF.  Investigation Of Inflammatory Breast Cancer Biology And Potential Therapeutic Approaches. Department of Defense Breast Cancer Research Program. Abstract BC031906) recently tested the hypothesis that the immunomodulatory, anti-inflammatory, and anti-cancer effects of  the traditional Chinese medicinal (TCM) agent  Reishi (Ganoderma lucidum) mushroom extract, may be effective against IBC progression and invasion, given accumulating evidence of its ability to inhibit proliferation, adhesion, migration, and invasion of cancer cells via the  triterpenes component which exhibits cytotoxicity against cancer cells at high concentrations, and component polysaccharides that are  immunostimulatory.  Whole Reishi extract was tested on normal mammary epithelial (MCF-10A) and IBC (SUM-149) cell lines, finding that the Reishi extract effectively inhibited proliferation of the IBC cell line, reducing  cell-cell attachments and decreasing invasion of IBC cells, but not the normal mammary epithelial cell line.  Reishi also down-regulated 52% of tumorigenesis genes in the IBC cells treated, and furthermore inhibited the matrix-metalloproteinases MMP-2  and MMP-9 levels.  From these results, the authors concluded that Reishi inhibits IBC progression via cell proliferation reduction, prevention of tumor emboli formation, and inhibition of invasion by reduced matrix MMP levels, suggesting that Reishi extract is natural potential therapeutic effective in inhibiting IBC progression.

 

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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.

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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 nocturnal 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.