Locally Advanced & Inflammatory Breast Cancer

Cancer Connect

Medically reviewed by Dr. C.H. Weaver M.D. 10/2020

Individuals with locally advanced and inflammatory breast cancer are treated with multimodality therapy delivered with curative intent consisting of the following.

  1. Breast-conserving surgery or total mastectomy with axillary lymph node dissection.
  2. Systemic treatment with chemotherapy and precision cancer medicines
  3. Radiation therapy.
  4. Hormone therapy.

Initial surgery is generally limited to biopsy to permit the determination of estrogen receptor (ER) and progesterone receptor (PR) levels and NGS testing for human epidermal growth factor receptor 2 (HER2/neu) over expression and other biomarkers.

Patients responding to preoperative systemic therapy are subsequently treated with total mastectomy followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered for selected patients with a good partial or complete response to preoperative chemotherapy. Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy is administered to patients with ER-positive or ER-unknown tumors. (1-5)

All patients are considered candidates for clinical trials to evaluate the most appropriate way to administer the various components of new multimodality regimens.

Locally advanced breast or stage IIIB breast cancer refers to cancer that has spread locally from the breast, but not to distant sites in the body.

Inflammatory Breast Cancer

Inflammatory breast cancer (IBC) is a more aggressive type of breast cancer with symptoms that differ from other types of breast cancer. The redness, warmth, and swelling that often accompanies IBC is caused by the blockage of lymph vessels by cancer cells. At the time of diagnosis, most women with IBC will have lymph node metastases and roughly one third will have distant metastases.

IBC is less common than non-inflammatory breast cancer, but its poor prognosis highlights the importance of raising awareness about this cancer. IBC accounts for an estimated two percent breast cancer diagnoses in the U.S., but seven percent of breast cancer deaths and the incidence of IBC appears to be increasing.

Risk factors for IBC are poorly understood, and currently it is not possible to estimate a woman’s risk for this type of cancer. IBC tends to occur at a younger age than other types of breast cancer, however, prompting interest in the role of genetic predisposition and early-life exposures. Rates of IBC increase rapidly up to age 50 and then stabilize. IBC is also more common in African-American women than in White women. (7-10)

Diagnosis of Inflammatory Breast Cancer

The diagnosis of IBC is based on the rapid development of symptoms characteristic of IBC, coupled with the presence of cancer cells on a breast biopsy. (8) Symptoms of IBC include the following: (7)

  • Redness, warmth, and swelling in the breast (often without a distinct lump)
  • Breast skin that appears pink, reddish purple, or bruised
  • Breast skin that has ridges or appears pitted, like the skin of an orange
  • An increase in breast size
  • Heaviness, burning, aching, or tenderness in the breast
  • A nipple that becomes inverted
  • Swollen lymph nodes under the arm or above the collarbone

These symptoms can also be caused by conditions other than cancer, and it is important for you to discuss them with your healthcare provider.

Women who have had mastitis (a breast infection that most commonly occurs in breastfeeding women) will notice that the symptoms just mentioned are similar to the symptoms of mastitis. However, unlike mastitis, inflammatory breast cancer is generally not accompanied by a fever and will not respond to treatment with antibiotics. If you’re being treated for mastitis but notice that your symptoms are not improving, you may wish to talk with your doctor about a breast biopsy or a referral to a breast specialist.

Treatment of Inflammatory Breast Cancer

Treatment of IBC generally begins with neoadjuvant therapy administered to both eliminate areas of cancer that have already spread beyond the breast, and also to reduce the amount of cancer in the breast prior to local therapy delivered to the breast and surrounding tissues (surgery and radiation).

Neoadjuvant therapy refers to treatment that is used prior to surgery. Neoadjuvant therapy is used to shrink the cancer to make more complete surgical removal of the cancer possible. Furthermore, instead of waiting for recovering from surgery, full-body anticancer therapy immediately kills cancer cells throughout the body. Neoadjuvant chemotherapy including the agents Adriamycin® (doxorubicin), cyclophosphamide, and paclitaxel (Taxol®) (AC-T) is commonly used in the treatment of breast cancer.

The researchers concluded that continuous administration of neoadjuvant chemotherapy improves rates of complete disappearance of cancer at the site of origin and in the lymph nodes among patients with locally advanced or inflammatory breast cancer, particularly among those with ER-negative cancer and improves survival. (13,14)

Depending on the nature of the cancer and response to initial chemotherapy, locoregional therapy consists of surgery to remove the breast and nearby lymph nodes coupled with radiation therapy, or radiation therapy alone. Patients often then receive additional systemic therapy, which may consist of additional chemotherapy, hormonal therapy, targeted therapy, or a combination of these approaches. (7)

Survival with IBC is worse than with other types of breast cancer, with an estimated 50% of women surviving for at least five years. The addition of chemotherapy to locoregional therapy with surgery and/or radiation has allowed some women with IBC to become long-term survivors. Ten-year survival with current chemotherapy has been reported to be 40% with 35% of patients surviving cancer free. (12)

Precision Cancer Medicines

Advances in treatment have been modest with chemotherapy however precision cancer medicines that target specific cancer causing mutations and immunotherapy appear to be improving treatment outcomes.

  • HER2neu: Many inflammatory cancers over express (make too much of) HER2 and are referred to as HER2-positive. The HER2 pathway is a biological pathway involved in cellular replication and growth. HER2-positive breast cancers can be treated with medicines like Herceptin® (trastuzumab) and Tykerb (lapatinib). Tykerb targets two proteins—EGFR and HER2—that are abnormally expressed in many (but not all) cases of IBC. Inhibiting these proteins can slow or stop cancer growth and has been shown to improve outcomes administered alone or in combination. (15-17)

Strategies to Improve Treatment of Inflammatory Breast Cancer

PD-1 Checkpoint Inhibitors: The cancer immunotherapy strategy known as programmed cell death 1 (PD-1) has generated great excitement for its ability to help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 are called checkpoint inhibitors and may enhance the ability of the immune system to fight cancer.

Keytruda is a fully humanized monoclonal antibody checkpoint inhibitor that binds with high-affinity to the PD-1 receptor. Neoadjuvant Keytruda was reported to be significantly more effective than chemotherapy at eradicating cancer confined to the breast prior to surgery. (18) These results are consistent with the ​I-SPY 2 clinical trial which demonstrated that Keytruda in combination with standard therapy as neoadjuvant treatment for patients with locally advanced TNBC increased the pathologic complete response (pCR) nearly threefold in patients with TNBC .(19)

This was confirmed in the KEYNOTE 522 clinical trial which enrolled 1,174 patients with locally advanced TNBC to receive treatment with standard chemotherapy with or without the addition of Keytruda followed by definitive surgery and radiation therapy. After completion of local therapy patients were treated with additional Keytruda.

Analyses revealed that Keytruda treated patents were less likely to have evidence of cancer in their surgically removed breast tissue and more likely to survive without evidence of cancer recurrence. Overall 65% off Keytruda treated patients had a pathologic complete remission compared to only 51 % of women not treated with Keytruda and 91% survived without evidence of cancer compared to 85% at the time of this analyses. PDL-1-positive patients had a higher response to chemotherapy and combination treatment with Keytruda without unexpected side effects. (20)

The Inflammatory Breast Cancer Research Foundation

Officially established as the Inflammatory Breast Cancer Research Foundation (IBCRF) in 1999, the volunteer-powered, 501(c)(3) nonprofit organization was formed to advance research into the causes of IBC and effective treatments and to increase awareness of symptoms for earlier and more-accurate detection. Maintaining both missions is essential, explains IBCRF executive director and 13-year IBC survivor Ginny Mason: “Research and education must be combined. The two need to happen together for progress to be made,” she says of the interdependence between growing awareness and research.

The structure of the IBCRF indeed speaks to the fact that the scope of its influence on research is only as strong as the IBC community, which supports these efforts with volunteer work, monetary donations, and a willingness to make contributions spanning from information about personal IBC experiences to tissue samples for research purposes. Fortunately, the strength of this community is proving to be formidable.

The IBCRF’s efforts to raise awareness about IBC are guided by the motto You don’t have to have a lump to have breast cancer; and its educational materials—including brochures, bookmarks, and T-shirts—all spread the word that symptoms other than a lump can signal breast cancer. Possible signs of IBC that advocates urge people to look out for include swelling and itching of the breasts and nipple retraction. The foundation also spreads its message of awareness through various avenues on the Internet and offers information through a toll-free number: (877) STOP-IBC. And to stay in step with current research, the IBCRF maintains a presence at conferences where IBC is—or should be—a noteworthy topic.

Integral to the IBCRF’s goal to increase IBC research are efforts to directly encourage researchers to include IBC biospecimen samples and patients in their studies. The foundation has taken a giant step to facilitate this research with the creation of the IBCRF BioBank, which Ginny says is the most significant accomplishment to date and one that, in its proactive nature, propels research advocacy to a new level. Drawing on existing relationships within the advocacy community to generate contributions (an outstanding example of the interdependence between research and awareness), the BioBank is a secure, privacy-protected collection of biological specimens from patients diagnosed with IBC. Also included are clinical data and information from a comprehensive questionnaire as well as specimens from individuals not diagnosed with IBC, which may serve as controls in research studies. All specimens and accompanying information are protected under rigorous industry standards of confidentiality and management. Visit www.ibcresearch.org/biobank for more information about this exciting initiative.

Of the way the IBCRF BioBank has accelerated research advocacy, Ginny explains, “Prior to its creation, we were knocking on doors, looking for researchers who might be interested.” Now, in what she describes as “an incredible turn of events,” researchers, aware of the depth of information and access to biological specimens, are actually seeking out the IBCRF, which is now well respected within the research community as a voice for the disease.

The campaign to promote and expand the BioBank, and with it IBC research and awareness, remains a major focus of the foundation. As enrollment grows, a new computerized database will continue to enhance the BioBank’s ability to effectively make accessible its ever-increasing contents. It’s also important to note that this technological upgrade was funded by an award from the National Breast Cancer Coalition Fund—the 2006 Best Practices in Breast Cancer Advocacy—in recognition of IBC’s innovative and high-impact strategies, such as the BioBank.

With its research advocacy and its education and awareness campaign—and with the success of each resting on the support and the participation of those affected by IBC—the IBCRF is bringing IBC forward from relative obscurity in the breast cancer community. As the disease gains attention in research settings, medical offices, and on a personal level, those diagnosed, along with their loved ones, are not only gaining a community of support but are also taking an active role in research, thereby influencing the focus and the nature of these critical studies.

The IBCRF is a 501(c)(3) nonprofit organization incorporated in Alaska, without a walk-in office. Because the IBCRF president, secretary, and treasurer reside in Washington State, the organization maintains a Washington mailing address (use of the Washington address was filed for with the state of Alaska). The organization also has a Medical Advisory Board that provides guidance and consultation for the medical information on its Web site as well its BioBank project.

References:

  1. National Cancer Institute Fact Sheet. Inflammatory Breast Cancer: Questions and Answers. Available here (Accessed April 30, 2007).
  2. Merajver SD, Sabel MS. Inflammatory Breast Cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:971-982.
  3. Hance KW, Anderson WF, Devesa SS, Young HA, Levine PH. Trends in Inflammatory Breast Carcinoma Incidence and Survival: The Surveillance, Epidemiology, and End Results Program at the National Cancer Institute. Journal of the National Cancer Institute. 2005;97:966-75.
  4. Cristofanilli M, Buzdar AU, Hortobágyi GN. Update on the Management of Inflammatory Breast Cancer. The Oncologist. 2003;8:141-148.
  5. Giordano SH, Hortobagyi GN. Inflammatory Breast Cancer: Clinical Progress and the Main Problems that Must be Addressed. Breast Cancer Research. 2003;5:284-288.
  6. Cristofanilli M, Boussen H, Baselga J, et al. A Phase II combination study of lapatinib and paclitaxel as a neoadjuvant therapy in patients with newly diagnosed inflammatory breast cancer. Proceedings from the 2006 annual San Antonio Breast Cancer Symposium. Oral presentation December 14, 2006. Abstract #1.

Final References:

  1. Petrelli F, Coinu A, Lonati V, et al.: Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs 27 (7): 702-8, 2016. [PUBMED Abstract]
  2. Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994. [PUBMED Abstract]
  3. Brito RA, Valero V, Buzdar AU, et al.: 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. J Clin Oncol 19 (3): 628-33, 2001. [PUBMED Abstract]
  4. Olivotto IA, Chua B, Allan SJ, et al.: Long-term survival of patients with supraclavicular metastases at diagnosis of breast cancer. J Clin Oncol 21 (5): 851-4, 2003. [PUBMED Abstract]
  5. Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40 (4): 321-9.
  6. National Cancer Institute FactSheet. Inflammatory Breast Cancer: Questions and Answers. National Cancer Institute Web site. Available here.
  7. Merajver SD, Sabel MS. Inflammatory breast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004:971-82.
  8. Hance KW, Anderson WF, Devesa SS, Young HA, Levine PH. Trends in inflammatory breast carcinoma incidence and survival: The surveillance, epidemiology, and end results program at the National Cancer Institute. Journal of the National Cancer Institute. 2005;97(13):966-75.
  9. Cristofanilli M, Buzdar AU, Hortobágyi GN. Update on the management of inflammatory breast cancer. The Oncologist. 2003;8(2):141-48.
  10. Giordano SH, Hortobágyi GN. Inflammatory breast cancer: Clinical progress and the main problems that must be addressed. Breast Cancer Research. 2003;5(6):284-88.
  11. Cristofanilli M, Boussen H, Baselga J, et al. A Phase II combination study of lapatinib and paclitaxel as a neoadjuvant therapy in patients with newly diagnosed inflammatory breast cancer. Paper presented at: 2006 Annual San Antonio Breast Cancer Symposium; oral presentation December 14, 2006; San Antonio, Texas. Abstract 1.
  12. Veyret C, Levy C, Chollet P, et al. Inflammatory breast cancer outcome with epirubicin-based induction and maintenance chemotherapy. Ten year results from the French Adjuvant Study Group GETIS 02 Trial. Cancer. 2006; published online in advance of print on October 19, 2006.
  13. Ellis GK, Barlow WE, Russell CA, et al. SWOG 0012, a Randomized Phase III Comparison of Standard Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel Versus Weekly Doxorubicin and Daily Oral Cyclophosphamide plus G-CSF Followed by Weekly Paclitaxel as Neoadjuvant Therapy for Inflammatory and Locally Advanced Breast Cancer. Proceedings from the 42nd Annual Meeting of the American Society of Clinical Oncology. June 2006. Atlanta, Georgia. Abstract LBA537.
  14. Cance W, Carey L, Calvo B, et al. Long-term outcome of neoadjuvant therapy for locally advanced breast carcinoma: effective clinical downstaging allows breast preservation and predicts outstanding local control and survival.Annals of Surgery. 2002;236:295-303.​
  15. Kaufman B, Trudeau M, Awada A et al. Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study. Lancet Oncology [early online publication]. April 27, 2009.
  16. Boussen H, Cristofanilli M, Zaks T, et al. Phase II study to evaluate the efficacy and safety of neoadjuvant lapatinib plus paclitaxel in patients with inflammatory breast cancer. Journal of Clinical Oncology [early online publication]. June 7, 2010.
  17. Kaufman B, Trudeau M, Johnston S, et al. Clinical activity of lapatinib monotherapy in patients with HER2+ relapsed/refractory inflammatory breast cancer (IBC): Final results of the expanded HER2+ cohort in EGF103009. Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #636
  18. Merck’s KEYTRUDA® (pembrolizumab) in Combination with Chemotherapy Met Primary Endpoint of Pathological Complete Response (pCR) in Pivotal Phase 3 KEYNOTE-522 Trial in Patients with Triple-Negative Breast Cancer (TNBC)
  19. Adams S, et al. Safety and clinical activity of atezolizumab (anti-PD-L1) in combination with nab-paclitaxel in patients with triple-negative breast cancer. Proceedings from the 2015 annual San Antonio Breast Cancer Symposium. Presented December 10, 2015. Abstract number: 850477.
  20. Schmid P, Cortés J, Dent R, et al: KEYNOTE-522: Phase III study of pembrolizumab + chemotherapy vs placebo + chemo as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early triple-negative breast cancer. ESMO Congress 2019. Abstract LBA8_PR. Presented September 29, 2019.
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