Inflammatory Breast Cancer

Inflammatory breast cancer[1] is one of the most aggressive types of breast cancer that can occur in women of any age (and, extremely rarely, in men). It is called inflammatory because it frequently presents with symptoms resembling an inflammation. Despite the name, whether inflammation contributes to the development of “inflammatory breast cancer” remains an area of ongoing research.[2] However it can present with very variable signs and symptoms, frequently without detectable tumors and therefore is often not detected by mammography or ultrasound.[3]

Typical presentation is rapid swelling, sometimes associated by skin changes (peau d’orange), and nipple retraction. Other symptoms include rapid increase in breast size, redness, persistent itching, skin hot to touch. IBC often initially resembles mastitis.

Only about 50-75% cases have the typical presentation. Symptoms can be completely atypical such as acute central venous thrombosis as the sole presenting symptom.

IBC makes up only a small percentage of breast cancer cases (1-6% in the USA[4]). IBC is often diagnosed in younger women although average age of presentation does not differ much from other kinds of breast cancer (average age 57 years). African-Americans are usually diagnosed at younger ages than Caucasian women, and also have a higher risk of getting IBC.[5] Recent advances in therapy have improved the prognosis considerably and at least one third of women will survive the diagnosis by 10 years or longer.[6]

Symptoms are very variable and may not be present at all in occult inflammatory breast cancer. Quick onset of symptoms is typical, the breast often looks swollen and red, or “inflamed”, sometimes overnight, and are easy to misdiagnose as mastitis. Invasion of the local lymphatic ducts impairs drainage and causes edematous swelling of the breast. Because the skin of the breast is tethered by the suspensory ligament of Cooper, the accumulation of fluid may cause the skin of the breast to assume a dimpled appearance similar to an orange peel (peau d’orange). A palpable tumor is frequently not obvious as in other forms of breast cancer.

Symptoms may include:

  • Sudden swelling of the breast
  • Skin changes on breast
  • Reddened area with texture resembling the peel of an orange (peau d’orange)
  • Nipple retraction (flattened look) or discharge
  • Pain in the breast
  • Itching of breast
  • Swelling of lymph nodes under the arm or in the neck
  • Unusual warmth of the affected breast
  • Breast is harder or firmer

Other symptoms may rarely include:

  • Swelling of the arm
  • Breast size may decrease instead of increasing
  • Although a dominant mass is present in many cases, most inflammatory cancers present as diffuse infiltration of the breast without a well-defined tumor.
  • A lump may become present and grow rapidly

Most patients do not experience all the symptoms of IBC. Not all symptoms need to be present in order to be diagnosed.[7]

The only reliable method of diagnosis is full-thickness skin biopsy. Mammography, MRI or ultrasound often show suspicious signs; however in a significant proportion of cases they would miss a diagnosis.

Clinical presentation is typical only in 50-75% of cases; and many other conditions such as mastitis or even heart insufficiency can mimic the typical symptoms of Inflammatory Breast Cancer.

Temporary regression or fluctuation of symptoms, spontaneous or in response to conventional treatment or hormonal events should not be considered of any significance in diagnosis. Treatment with antibiotics or progesterone have been observed to cause a temporary regression of symptoms in some cases.[8][9][10][11][12]

Inflammatory breast cancer is a high grade aneuploid cancer, with mutations and overexpression of p53, high levels of E-cadherin and abnormal cadherin function. It is often regarded as a systemic cancer. A large number of IBC cases present as triple negative breast cancer (TNBC). Similar to TNBC as opposed to estrogen receptor-positive breast cancer, there is a high rate of relapses and metastases in the first 3 years after presentation but few late events (5 years or later).

It is characterised by the presence of cancer cells in the subdermal lymphatics on skin biopsy. Consequently, IBC is always staged at stage IIIB or above as locally advanced disease is a classic prognostic indicator.

Searches for biomolecular characteristics produced a broad number of possible markers, such as loss of LIBC and WISP3 expression. Inflammatory breast cancer is in many ways very similar to late stage or metastatic breast cancer; however, it can be distinguished from those cancer types both by molecular footprint and clinical presentation. On the molecular level some similarity exists with pancreatic cancer.

Estrogen and progesterone receptor status is frequently negative, corresponding with poor survival. The tumors are highly angiogenic and vascular, with high levels of VEGF and bFGF expression.

A number of proteins and signalling pathways show behaviour that can be considered paradoxical compared to their function in normal tissue and other breast cancer types.

  • caveolin-1 and -2 are overexpressed and may contribute to tumour cell motility[13]
  • E-cadherin is overexpressed and paradoxically associated with especially aggressive type.

RhoC GTPase is overexpressed, possibly related to overexpression (hypomethylation) of caveolin-1 and -2. Caveolin is paradoxically tumour promoting. NF-κB pathway activation overexpression may contribute to the inflammatory phenotype.

EGFR pathway is commonly active in inflammatory breast cancer and this has shown some clinical signal that EGFR targeting therapy may be effective inflammatory breast cancer.[14]

It occurs in all adult age groups. While the majority of patients are between 40 and 59 years old, age predilection is much less pronounced than in noninflammatory breast cancer. The overall rate is 1.3 cases per 100000, black women (1.6) have the highest rate, Asian and Pacific Islander women the lowest (0.7) rates.[4]

Most known breast cancer risk predictors do not apply for inflammatory breast cancer. It may be slightly associated with cumulative breast-feeding duration.[15]

Age distribution and relation to breastfeeding duration is suggestive of some sort of involvement of hormones in the aetiology, however significant differences exist compared to normal breast cancer.

Typically IBC shows low levels of estrogen and progesterone receptor sensitivity, corresponding with poor outcome. In cases with positive estrogen receptor status antihormonal treatment is believed to improve outcome.

Paradoxically some findings suggest that especially aggressive phenotypes of IBC are characterised by high level of NF kappaB target gene expression which can be – under laboratory conditions – successfully modulated by estrogen, but not by tamoxifen.

Staging is designed to help organize the different treatment plans and to understand the prognosis better. Staging for IBC has been adapted to meet the specific characteristics of the disease. IBC is typically diagnosed in one of these stages:

  • Stage IIIB – at least 1/3 of the skin of the breast is affected, and may have spread to tissues near the breast, such as the skin or chest wall, including the ribs and muscles in the chest. The cancer may have spread to lymph nodes within the breast or under the arm.
  • Stage IIIC – N3 nodal involvement with an inflamed breast will upgrade the disease from Stage IIIB to Stage IIIC.
  • Stage IV means that the cancer has spread to other organs. These can include the bones, lungs, liver, and/or brain.[16]

Surgery has traditionally played a limited role in the treatment of IBC because it is considered essentially a systemic cancer. However, the role of surgical intervention is being reevaluated and is now considered to be an important part of the overall treatment process. The standard treatment for newly diagnosed inflammatory breast cancer is to receive systemic therapy prior to surgery. Achieving no disease in the surgical samples gives the best prognosis. Surgery is modified radical mastectomy. Lumpectomy, segmentectomy, or skin sparing mastectomy is not recommended. Immediate reconstruction is not recommended. Upfront surgery is contraindicated. After surgery, all cases are recommended for radiation therapy unless it is contraindicated.[17]

Because the aggressive nature of the disease, it is highly recommended to be seen by IBC specialist by a multidisciplinary team.

Further, it is critical to seek novel targeted therapy in a clinical trial setting.[18] Three modalities, surgery, chemotherapy, and radiation are under-utilized in the USA.[19]Estrogen and Progesterone receptor positive cases have not shown to have a better prognosis.[20] Pathological complete response to preoperative chemotherapy imparts a more favorable prognosis than a pathologically incomplete response.[21] Loss of heterozygosity and extensive breast inflammation upon first clinical examination have a significantly worse prognosis.[22] Premenopausal cases have significantly worse prognosis. In postmenopausal cases lean women have significantly better prognosis than obese women. Among patients with distant metastasis at diagnosis (stage IV disease), The overall survival (OS) is worse in patients with IBC than in those with non-IBC.[16]

  1. ^ “Inflammatory Breast Cancer: Questions and Answers”. National Cancer Institute. 2016-01-15. Retrieved 2006-12-02.
  2. ^ Fouad, Tamer M; Kogawa, Takahiro; Reuben, James M; Ueno, Naoto T (2014). “The Role of Inflammation in Inflammatory Breast Cancer”. Inflammation and Cancer. Advances in Experimental Medicine and Biology. 816. pp. 53–73. doi:10.1007/978-3-0348-0837-8_3. ISBN 978-3-0348-0836-1. PMID 24818719.
  3. ^ “Facts for Life – Inflammatory Breast Cancer” (PDF). Susan G. Komen for the Cure. Retrieved 2006-12-02.
  4. ^ Jump up to: a b Wingo, Phyllis A; Jamison, Patricia M; Young, John L; Gargiullo, Paul (2004). “Population-Based Statistics for Women Diagnosed with Inflammatory Breast Cancer (United States)”. Cancer Causes & Control (Submitted manuscript). 15(3): 321–8. doi:10.1023/B:CACO.0000024222.61114.18. JSTOR 3554049. PMID 15090727.
  5. ^ Gordon, L (2001). “Inflammatory breast cancer”. Clinical Journal of Oncology Nursing. 5 (4): 175–6. PMID 12690620.
  6. ^ Giordano, Sharon H; Hortobagyi, Gabriel N (2003). “Inflammatory breast cancer: Clinical progress and the main problems that must be addressed”. Breast Cancer Research. 5 (6): 284–8. doi:10.1186/bcr608. PMC 314400. PMID 14580242.
  7. ^ “Inflammatory Breast Cancer Help—Signs and Symptoms.” Inflammatory Breast Cancer Association. 02 Apr. 2009 <http://www.ibchelp.org/symptoms/>
  8. ^ Kusama, M; Koyanagi, Y; Sekine, M; Serizawa, H; Ebihara, Y; Hirota, T; Nakamura, Y; Matsunaga, T (1994). “A case of inflammatory breast cancer successfully treated with 5′-DFUR and MPA”. Gan to Kagaku Ryoho. Cancer & Chemotherapy. 21 (12): 2049–52. PMID 8085857.
  9. ^ Yamada, T; Okazaki, M; Okazaki, A; Sato, H; Watanabe, Y; Toda, K; Okazaki, Y; Asaishi, K; Hirata, K; Narimatsu, E (1992). “A case of inflammatory breast cancer treated with medroxyprogesterone acetate (MPA) in combination with intra-arterial infusion chemotherapy”. Gan to Kagaku Ryoho. Cancer & Chemotherapy. 19 (11): 1923–5. PMID 1387777.
  10. ^ Van Laere, S. J (2006). “Nuclear Factor-κB Signature of Inflammatory Breast Cancer by cDNA Microarray Validated by Quantitative Real-time Reverse Transcription-PCR, Immunohistochemistry, and Nuclear Factor-κB DNA-Binding”. Clinical Cancer Research. 12 (11): 3249–56. doi:10.1158/1078-0432.CCR-05-2800. PMID 16740744.
  11. ^ Van Laere, S J; Van Der Auwera, I; Van Den Eynden, G G; Van Dam, P; Van Marck, E A; Vermeulen, P B; Dirix, L Y (2007). “NF-κB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation”. British Journal of Cancer. 97 (5): 659–69. doi:10.1038/sj.bjc.6603906. PMC 2360371. PMID 17700572.
  12. ^ Van Der Burg, Bart; Der Saag, Paul T.van (1996). “Endocrinology and paracrinology”. Molecular Human Reproduction. 2 (6): 433–8. doi:10.1093/molehr/2.6.433. PMID 9238713.
  13. ^ Van Den Eynden, Gert G; Van Laere, Steven J; Van Der Auwera, Ilse; Merajver, Sofia D; Van Marck, Eric A; Van Dam, Peter; Vermeulen, Peter B; Dirix, Luc Y; Van Golen, Kenneth L (2005). “Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer”. Breast Cancer Research and Treatment. 95 (3): 219–28. doi:10.1007/s10549-005-9002-1. PMID 16244790.
  14. ^ Zhang, D; Lafortune, T. A; Krishnamurthy, S; Esteva, F. J; Cristofanilli, M; Liu, P; Lucci, A; Singh, B; Hung, M.-C; Hortobagyi, G. N; Ueno, N. T (2009). “Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Reverses Mesenchymal to Epithelial Phenotype and Inhibits Metastasis in Inflammatory Breast Cancer”. Clinical Cancer Research. 15 (21): 6639–48. doi:10.1158/1078-0432.CCR-09-0951. PMC 2783487. PMID 19825949.
  15. ^ Lê, Monique G; Arriagada, Rodrigo; Bahi, Jacqueline; Pfeiffer, Frédérique; Cammoun, Mohamed; Tabbane, Françoise; Rubino, Carole (2006). “Are risk factors for breast cancer similar in women with inflammatory breast cancer and in those with non-inflammatory breast cancer?”. The Breast. 15 (3): 355–62. doi:10.1016/j.breast.2005.08.018. PMID 16198566.
  16. ^ Jump up to: a b Fouad, Tamer M; Kogawa, Takahiro; Liu, Diane D; Shen, Yu; Masuda, Hiroko; El-Zein, Randa; Woodward, Wendy A; Chavez-Macgregor, Mariana; Alvarez, Ricardo H; Arun, Banu; Lucci, Anthony; Krishnamurthy, Savitri; Babiera, Gildy; Buchholz, Thomas A; Valero, Vicente; Ueno, Naoto T (2015). “Overall survival differences between patients with inflammatory and noninflammatory breast cancer presenting with distant metastasis at diagnosis”. Breast Cancer Research and Treatment. 152 (2): 407–16. doi:10.1007/s10549-015-3436-x. PMC 4492876. PMID 26017070.
  17. ^ Yamauchi, H; Woodward, W. A; Valero, V; Alvarez, R. H; Lucci, A; Buchholz, T. A; Iwamoto, T; Krishnamurthy, S; Yang, W; Reuben, J. M; Hortobagyi, G. N; Ueno, N. T (2012). “Inflammatory Breast Cancer: What We Know and What We Need to Learn”. The Oncologist. 17 (7): 891–9. doi:10.1634/theoncologist.2012-0039. PMC 3399643. PMID 22584436.
  18. ^ Yamauchi, Hideko; Ueno, Naoto T (2010). “Targeted therapy in inflammatory breast cancer”. Cancer. 116 (11 Suppl): 2758–9. doi:10.1002/cncr.25171. PMID 20503407.
  19. ^ Rueth, Natasha M; Lin, Heather Y; Bedrosian, Isabelle; Shaitelman, Simona F; Ueno, Naoto T; Shen, Yu; Babiera, Gildy (2014). “Underuse of Trimodality Treatment Affects Survival for Patients with Inflammatory Breast Cancer: An Analysis of Treatment and Survival Trends from the National Cancer Database”. Journal of Clinical Oncology. 32 (19): 2018–24. doi:10.1200/JCO.2014.55.1978. PMC 4067942. PMID 24888808.
  20. ^ Masuda, H; Brewer, T. M; Liu, D. D; Iwamoto, T; Shen, Y; Hsu, L; Willey, J. S; Gonzalez-Angulo, A. M; Chavez-Macgregor, M; Fouad, T. M; Woodward, W. A; Reuben, J. M; Valero, V; Alvarez, R. H; Hortobagyi, G. N; Ueno, N. T (2014). “Long-term treatment efficacy in primary inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes”. Annals of Oncology. 25 (2): 384–91. doi:10.1093/annonc/mdt525. PMC 3905780. PMID 24351399.
  21. ^ Palangie, T; Mosseri, V; Mihura, J; Campana, F; Beuzeboc, P; Dorval, T; Garcia-Giralt, E; Jouve, M; Scholl, S; Asselain, B (1994). “Prognostic factors in inflammatory breast cancer and therapeutic implications”. European Journal of Cancer. 30A (7): 921–7. PMID 7946584.
  22. ^ Lerebours, F; Bertheau, P; Bieche, I; Plassa, L. F; Champeme, M. H; Hacene, K; Toulas, C; Espie, M; Marty, M; Lidereau, R (2003). “Two prognostic groups of inflammatory breast cancer have distinct genotypes”. Clinical Cancer Research. 9 (11): 4184–9. PMID 14519644.

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