1995: Glass, JL., & Frazee, RC. (1995). Inflammatory breast cancer. The American Surgeon, 61(2), 121-4.

Inflammatory breast cancer has historically carried a poor prognosis. This has led to the development of multimodal protocols in an attempt to improve survival. Twenty-three women were treated for inflammatory breast cancer at our institution between 1979 and 1992. The mean age at diagnosis was 55.8 years (40 to 77 years). Eighteen women (78%) presented clinically with an erythematous or swollen and tender breast, and 19 (80%) had pathologically demonstrated dermal lymphatic invasion. Five (21.7%) had evidence of distant metastasis at the time of presentation. Treatment consisted of modified radical mastectomy in 65% of patients in combination with preoperative or postoperative chemotherapy. The most common chemotherapeutic regimen was 5-Fluorouracil, Adriamycin, and Cyclophosphamide. Eleven women (48%) also received chest wall irradiation (4,200 to 6,000 cGy). Eleven women had classic multimodality therapy (surgery, chemotherapy, and radiation therapy). Median survival is 23.4 months (6 to 77 months). We concluded that with combination therapy, selected patients can experience long-term survival; however, overall prognosis remains poor, with eventual disease recurrence and death resulting from the disease.

1995: Bonnier, P., et al. (1995). Inflammatory carcinomas of the breast: a clinical, pathological, or a clinical and pathological definition?. International Journal of Cancer, 62(4), 382-5..

Some controversy remains about the clinical or pathological definition of the different types of inflammatory breast cancer (IBC) and especially the diagnostic and prognostic value of dermal lymphatic involvement. Our purpose was to classify the different types of IBC for which diagnosis was confirmed intraoperatively and ascertain features allowing reliable diagnosis. We studied clinical findings, biological data, and treatment outcome in a series of 144 successive patients. Our results suggest that there are 2 biologically different entities i.e., true IBC and pseudo-IBC. True IBC, whose course is currently fatal in all cases, can be divided into 2 sub-categories i.e., common true IBC (75.7% of cases), in which inflammatory signs occur primarily or secondarily, and occult true IBC (13.2% of cases). Dermal emboli have been observed in 61% of common true IBC, but their absence did not alter the rapidly unfavourable outcome. Extensive lymph-node involvement, other biological features and survival were the same in the 2 sub-categories. Pseudo-IBC (11.1% of cases) can easily be confused with common true IBC. The biological characteristics of pseudo-IBC differ from those of true IBC: no dermal lymphatic involvement and little or no lymph-node involvement. Despite large tumour size, outcome was particularly favourable. It is of great importance to differentiate true and pseudo-IBC, for which the treatments are different. Confirmation of true IBC requires pathological demonstration of dermal lymphatic emboli or extensive lymph-node involvement. Occult IBC must be identified for patients presenting rapidly growing tumours.

1995: Dahlbeck, SW., Donnelly, JF., & Theriault, RL. (1995). Differentiating inflammatory breast cancer from acute mastitis. American Family Physician, 52(3), 929-34.

Inflammatory breast cancer is a devastating disease with an extremely high rate of morbidity and mortality. Differentiating this disease from acute mastitis may be difficult on initial diagnosis. The expeditious diagnosis and treatment of inflammatory breast cancer has important ramifications for the patient’s prognosis. Unfortunately, no clear guidelines are available to help the primary care physician differentiate between acute mastitis and inflammatory breast cancer. We present our recommendations and guidelines for a diagnostic approach to this problem. Inflammatory breast cancer typically occurs in older women, while acute mastitis usually affects younger, lactating women. If a trial of antibiotics does not decrease the signs and symptoms in the inflamed breast, inflammatory breast cancer must be considered, especially in older, nonlactating women.

1996: Lopez, MJ., & Porter, KA. (1996). Inflammatory breast cancer. The Surgical Clinic of North America, 76(2), 411-29.

Multimodal therapy with induction chemotherapy has improved significantly local disease control and overall survival in patients with IBC. This is now considered standard therapy for patients with this disease. Although survival has been improved, well over 50% of these patients will succumb to this disease. Ongoing and future investigations may better define the optimal approach for local control, the optimal duration of maintenance chemotherapy, and the possible role of biologic response modifiers and growth factors in further improving the outcome for patients with this disease.

1997: Bonnier, P. (1997). Influence of pregnancy on the outcome of breast cancer: a case-control study. Societe Francaise de senologie et de pathologie mammaire study group. International Journal of Cancer, 72(5), 720-7.

The relationship between pregnancy and the outcome of breast cancer remains controversial. The purpose of this study was to determine the prognostic value of pregnancy at the time of diagnosis of primary infiltrating breast cancer. In a retrospective multi-center study we compared a group of 154 patients presenting pregnancy-associated (PA) breast cancer with a control group of 308 patients presenting non-pregnancy-associated (non-PA) breast cancer. Classic prognostic factors, treatment modalities, disease-free survival and overall survival were compared in the 2 groups. The relative importance of pregnancy was assessed by Cox multivariate analysis. There was a significantly higher proportion of inflammatory breast cancer, large tumors and negative receptor status in the PA group. Five-year recurrence-free survival, metastasis-free survival and overall survival were lower both in the whole PA group and in the PA sub-group excluding patients with inflammatory breast cancer than in the corresponding non-PA groups. According to clinical stage, histoprognostic grade and microscopic lymph-node involvement, probability of 5-year metastasis-free survival and overall survival was lower in the PA group. Outcome was significantly poorer after chemotherapy for patients in the PA sub-group than in the non-PA sub-group. Multivariate analysis demonstrated that pregnancy was an independent and significant prognostic factor. Pregnancy has an adverse effect on the outcome of breast cancer. Concurrent or recent pregnancy should be taken into account in the development of new systemic therapies. Our findings have important implications for further research into the basic mechanisms of cancer.

1997: Yamamoto, T., Iriyama, K., & Araki, T. (1997). Male inflammatory breast cancer. Surgery Today, 27(7), 669-71.

We report herein the case of a 68-year-old man diagnosed with inflammatory breast cancer. The patient presented following the rapid onset of redness and swelling over the left anterior chest wall. On examination, the left chest wall and left axilla were extensively hard, and the left upper limb was swollen. Ultrasonography and computed tomography (CT) scanning disclosed a mass in the left breast, about 2 cm in diameter with an unclear margin, and swelling of the major and minor pectoral muscles. Needle biopsy of the breast mass confirmed invasive lobular carcinoma. As a radical operation was considered contraindicated, systemic and intraarterial chemotherapy using 5-fluorouracil (5-FU) and Adriamycin (ADR) were performed. Nevertheless, the patient died of carcinomatous pleurisy 6 months after the initial onset of the disease.

1998: Brooks, HL., et al. (1998). Inflammatory breast carcinoma: a community hospital experience. Journal of the American College of Surgeons, 186(6), 622-9.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare form of rapidly progressive breast cancer. We reviewed the diagnosis, treatment, and outcome of IBC in our inner city community-based hospital and compared results with previous published reports. STUDY DESIGN: Twenty-five patients were diagnosed and treated for IBC at the Catholic Medical Center of Brooklyn and Queens during the 6-year period of January 1989 through December 1995. Criteria for inclusion in this study were clinical or histopathologic evidence, or both, of inflammatory carcinoma. RESULTS: IBC comprised 2.0% (25 of 1,257) of all breast cancer patients initially diagnosed during this study. All presented with clinical signs of IBC. Invasion of dermal lymphatics by neoplastic cells was demonstrated in 68% (17 of 25) of biopsy specimens. Sixty-eight percent (17 of 25) of patients presented with metastatic (ie, stage IV) disease and 28% (7 of 25) with stage IIIb; one patient (4%) died before staging. Estrogen and progesterone receptor studies were done on 72% (18 of 25) of all specimens. Of those patients who died, 85% were estrogen and progesterone receptor negative; of those surviving, 60% were estrogen receptor positive. Twenty (80%) of the 25 patients died, after a mean survival of 11.8 months and 5 (20%) remain alive, with a mean survival of 44.8 months. Of those who died, 85% were stage IV at presentation. All five survivors were stage IIIb at presentation. Patients underwent a variety of multimodal therapies. Survival was significantly associated with earlier stage at diagnosis and estrogen receptor positivity. CONCLUSIONS: IBC is characterized by rapid progression and dismal outcome. Earlier stage at diagnosis and positive estrogen receptor status suggest a more favorable prognosis. Neoadjuvant chemotherapy, as part of a multimodal approach, has significantly improved the outcome for IBC, but this is limited to patients with stage IIIb disease. Most of our patients presented with stage IV disease. If improvement is to be realized at the community level, limited health care resources must be directed toward aggressive physician and public education.

1998: Chang, S., et al. (1998). Inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program of the National Cancer Institute, 1975-1992. Cancer, 82(12), 2366-72.

BACKGROUND: Little is known about the cause of inflammatory breast carcinoma (IBC), the most aggressive form of breast cancer. To the authors’ knowledge, no studies have investigated whether IBC risk factors are different from those for breast carcinoma overall, and there has been only one report of IBC incidence and survival patterns. METHODS: The authors used data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute for the period 1975-1992 to calculate age-adjusted incidence and survival rates for 913 white and 121 African American women with IBC involving dermal invasion of lymphatic ducts and 166,375 white and 13,674 African American women with other types of breast carcinoma (non-IBC). RESULTS: Between 1975-1977 and 1990-1992, IBC incidence doubled, increasing among whites from 0.3 to 0.7 cases per 100,000 person-years and among African Americans from 0.6 to 1.1 cases. However, rates for African Americans varied due to the small numbers of IBC cases. The twofold increase in IBC incidence was higher than that observed for non-IBC during the same period (27% for African Americans and 25% for whites). IBC patients were significantly younger at diagnosis than non-IBC patients; and among both IBC and non-IBC patients, African Americans were younger than whites. Overall survival was significantly worse for IBC patients than for non-IBC patients and for African Americans than for whites. Among whites, 3-year survival improved more for IBC patients than for non-IBC patients between 1975-1979 and 1988-1992, increasing from 32% to 42% for IBC patients (P=0.0001) and from 80% to 85% for non-IBC patients (P=0.0001). CONCLUSIONS: The disparities observed in incidence trends and age at diagnosis, particularly according to race, highlight the need for further investigation of the differences between IBC and non-IBC incidence.

1999: Curcio, LD., et al. (1999). Beyond palliative mastectomy in inflammatory breast cancer–a reassessment of margin status. Annals of Surgical Oncology, 6(3), 249-54.

BACKGROUND: Inflammatory breast cancer is a locally advanced tumor with an aggressive local and systemic course. Treatment of this disease has been evolving over the last several decades. The aim of this study was to assess whether current therapies, both surgical and chemotherapeutic, are providing better local control (LC) and overall survival (OS). We also attempted to identify clinical and pathologic factors that may be associated with improved OS, disease-free survival (DFS), and LC. METHODS: A 25-year retrospective review performed at the City of Hope National Medical Center identified 90 patients with the diagnosis of inflammatory breast cancer. RESULTS: Of the 90 patients identified with inflammatory breast cancer, 33 received neoadjuvant therapy (NEO) consisting of chemotherapy followed by surgery with radiation (n = 26) and without radiation (n = 7). Fifty-seven patients received other therapies (nonNEO). Treatments received by the nonNEO group consisted of chemotherapy, radiation, mastectomy, adrenalectomy, and oophorectomy, alone or in combination. The median follow-up was 28.9 months for the NEO group and 17.6 months for the nonNEO group. Borderline significant differences in the OS distributions between the two groups were found (P = .10), with 3- and 5-year OS for the NEO group of 40.0% and 29.9% and for the nonNEO group of 24.7% and 16.5%, respectively. DFS and LC were comparable in the two groups. Lower stage was associated with an improved OS (P < .05). The 5-year OS for stage IIIB was 30.9%, compared to 7.8% for stage IV. In those patients with stage III disease who were treated with mastectomy and rendered free of disease, margin status was identified by univariate analysis to be a prognostic indicator for OS (P < .05). The 3-year OS, DFS, and LC for patients with negative margins were 47.4%, 37.5%, and 60.3%, respectively, compared to 0%, 16.7%, and 31.3% in patients with positive margins. CONCLUSIONS: This study suggests that in patients with inflammatory breast cancer and nonmetastatic disease, an aggressive surgical approach may be justified with the goal of a negative surgical margin. Achievement of this local control is associated with a better overall outcome for this subset of patients. The ability to obtain negative margins may further identify a group of patients with a less aggressive tumor biology that may be more responsive to other modalities of therapy.

1999: Kurebayashi, J., et al. (1999). Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Japanese Journal of Cancer Research, 90(9), 977-81.

Vascular endothelial growth factor (VEGF)-A is known to play an important role in tumor angiogenesis. Three additional members of the VEGF family, VEGF-B, -C and -D, have recently been discovered. VEGF-C and VEGF-D are ligands for VEGF receptor-3, which is expressed in the endothelium of lymphatic vessels. The expression of VEGF-C is known to be associated with the development of lymphatic vessels. Therefore, it is conceivable that VEGF-C and VEGF-D might play a role in the development of lymphatic vessels in solid tumors. To obtain some clue as to this role, we developed a semi-quantitative reverse transcription-polymerase chain reaction method to investigate the mRNA expression levels of each VEGF family member in breast cancer. All the VEGF family members were expressed at different levels in seven human breast cancer cell lines explored. Although VEGF-A and VEGF-B expressions were detected in both node-positive and node-negative breast tumors, VEGF-C expression was detected only in node-positive tumors. VEGF-D expression was detected only in an inflammatory breast cancer and a tumor which developed an inflammatory skin metastasis. These findings suggest a possible relationship between the expression level of VEGF-C and/or VEGF-D and the development of lymphatic tumor spread.

1999: van Golen, KL., et al. (1999). A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clinical Cancer Research, 5(9), 2511-9.

Inflammatory breast cancer is a rapidly growing, distinct form of locally advanced breast cancer that carries a guarded prognosis. To identify the genes that contribute to this aggressive phenotype, we compared under- and overexpressed sequences in an inflammatory breast tumor cell line with those of actively replicating normal human mammary epithelial cell lines using differential display. Of the 17 transcripts isolated and characterized from these experiments, overexpression of RhoC GTPase and loss of expression of a novel gene on 6q22, LIBC (lost in inflammatory breast cancer), were highly correlated (P<0.0095 and P<0.0013, respectively) with the inflammatory phenotype when a panel of archival inflammatory breast cancers was compared with noninflammatory stage III breast cancers by in situ hybridization. This study suggests two new molecular markers specific for inflammatory breast cancer.

1999: Alpaugh, ML. (1999). A novel human xenograft model of inflammatory breast cancer. Cancer Research, 59(20), 5079-84.

The step of intravasation or lymphovascular invasion can be a rate-limiting step in the metastatic process. Inflammatory breast carcinoma manifests an exaggerated degree of lymphovascular invasion in situ; hence, a study of its molecular basis might shed light on the general mechanism of lymphovascular invasion exhibited by all metastasizing cancers. To this end, we have established the first human transplantable inflammatory breast carcinoma xenograft (MARY-X) in scid/nude mice. MARY-X, like its human counterpart, exhibited striking erythema of the overlying skin. MARY-X was estrogen receptor, progesterone receptor, Her-2/neu negative and p53, epidermal growth factor receptor positive. The primary tumor of origin of MARY-X exhibited identical markers, except that about 50% of its cells exhibited Her-2/neu amplification. Comparative studies of MARY-X with noninflammatory xenografts indicated 10-20-fold overexpression of E-cadherin and MUC1, findings that were reflected in actual cases of human inflammatory breast cancer.