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Inflammatory Breast Cancer

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    Inflammatory Breast Cancer

    Silvana Martino, M.D.
    Director of Breast Cancer Research and Education
    The Angeles Clinic Foundation

    This is a particularly aggressive form of breast cancer. Its name is derived from the fact that inflammatory breast cancer looks similar to a breast that is infected. It is often confused with conditions such as cellulitis, mastitis or infected cysts.

    A common set of events are often described by a woman with this entity. Their breast became swollen, red and hot. They saw a physician who diagnosed an infection and started the patient on antibiotics. The antibiotics did not resolve the condition and a second antibiotic was tried. The breast may have improved somewhat but not completely. At this point, the doctor became concerned and a mammogram was done. At this point, the diagnosis was made. It was inflammatory breast cancer.

    There are two aspects to making the diagnosis of inflammatory breast cancer; (1) the appearance of the breast and (2) the pathological features described from a skin biopsy. The classical appearance of the breast includes a red rash on the skin of the breast. The rash may extend beyond the breast. The breast may look and feel swollen. At times, the patient feels that the breast has grown in size. There is not always a palpable mass within the breast. Often, but not always, the breast feels hot to the touch.

    To make the diagnosis, a breast biopsy is needed, along with a biopsy of the skin overlying the breast. Tumor cells within the lymphatic vessels of the skin confirm that it is inflammatory breast cancer. At times, the demonstration of this finding on skin biopsy by itself is confused and considered sufficient to make a diagnosis of inflammatory breast cancer. This is not correct. This type of skin involvement on skin biopsy can be seen in other forms of breast cancer. It is the clinical picture including the appearance of the breast which is most important in making the diagnosis.

    Unlike most other versions of breast cancer, which can occur in both men and women, I have never seen inflammatory breast cancer in a man. Also, I have never seen it occur bilaterally.

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    This cancer can be both hormone positive or negative as well as HER2 positive or negative.

    Because inflammatory breast cancer generally involves all or most of the breast, surgical treatment is generally a mastectomy. There are occasions when typical breast cancer (noninflammatory) recurs on the skin or chest wall and also looks like an inflammatory process. Some physicians will use the term “inflammatory” to describe this process, but this should not be confused with true inflammatory breast cancer.
    Gregory D. Pawelski

    Vitamin D to Tumors for Possible Inflammatory Breast Cancer Treatment

    The shortened daylight of a Maine winter may make for long, dark nights -- but it has shone a light on a novel experimental approach to fighting inflammatory breast cancer (IBC), an especially deadly form of breast cancer.

    The new approach enlists the active form of Vitamin D3, called calcitriol, which is delivered therapeutically by quantum dots. Quantum dots are an engineered light-emitting nanoscale delivery vehicle. This new preliminary work shows the dots can be used to rapidly move high concentrations of calcitriol to targeted tumor sites where cancer cells accumulate, and also through the lymph system where the cancer spreads. With this approach, the calcitriol can fight on multiple fronts and the targeted location can be visualized with an imaging system tracking the quantum dots.

    The research was presented at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.

    University of Delaware cancer researcher Anja Nohe was living in Maine when she first received funding from the Maine Cancer Foundation to determine the effect of calcitriol on breast cancer cells. Reading cancer literature helped her make connections between cancer, vitamin D, and the daylight regime of higher latitudes. "By talking with talented colleagues about these ideas, the foundation was set for the current project," she says. After moving to the University of Delaware, she began working with Kenneth Van Golen, "an expert in the biology of IBC," to evaluate calcitriol.

    Compared to other forms of breast cancer, IBC is especially difficult to treat. It has a five-year survival rate of 40% versus 87% for all other breast cancers. A big part of what makes IBC treatment difficult is its multi-site growth pattern. Current aggressive treatments such as combinations of chemotherapy, surgery and radiation, have failed to significantly improve IBC survival rates.

    This early experimental work on mice is encouraging because data show calcitriol can inhibit invasion and migration of SUM149 cells, an IBC cell line. "New IBC therapies are urgently needed, which is why the goal of my work is to find a successful treatment for inflammatory breast cancer, especially one with fewer side effects," Nohe says.

    Citation: Biophysical Society (2013, February 1). Quantum dots deliver vitamin D to tumors for possible inflammatory breast cancer treatment. ScienceDaily.
    Gregory D. Pawelski


      What's all involved with inflammatory breast cancer?

      Beth Overmoyer, M.D.
      Inflammatory Breast Cancer Program
      Dana Farber Cancer Institute

      The treatment of inflammatory breast cancer requires a “tri-modality” approach, meaning that all disciplines of physicians (medical oncologist, surgeon, radiation oncologist) are needed to coordinate the optimal care of the patient. The entire breast is involved at the initial presentation of IBC, as is the skin, since the IBC tumor emboli involve the lymphatic vessels of the skin resulting in the changes seen (erythema, edema, swelling). Because of this extensive “local” disease involvement, initial treatment with surgery is not appropriate because the surgeon will “cut through cancer”. Instead, chemotherapy is given to result in killing the cancer in the breast and allowing the surgeon to operate. In addition, IBC has a very high chance of metastasis; therefore chemotherapy is used as initial treatment to kill circulating cancer cells in the bloodstream prior to developing metatastasis. A medical oncologist is the physician who oversees the administration of the chemotherapy.

      After completing the course of chemotherapy, the breast should appear normal and surgery is performed. This is a mastectomy with removal of the axillary lymph nodes because of the extent of the disease involvement in the breast at the initial presentation. Lastly, the radiation oncologist oversees the administration of radiation therapy to the chest wall and regional lymph nodes; because there are always dormant (not-dividing) cancer cells in the lymphatics of the skin after mastectomy. The skin is therefore treated with the radiation therapy.

      If a person (man or woman) notices the onset of redness (erythema) of the breast associated with thickening of the skin of the breast, they should be concerned that this is either an infection or IBC. For this reason, the person should see their healthcare provider as soon as possible, be placed on antibiotics and undergo breast imaging and a referral to a breast surgeon. I recommend not waiting to see if the antibiotics work prior to undergoing the breast imaging (ultrasound, mammogram) and the surgical consultation. If there is anything unusual seen on the imaging, such as lymph node enlargement, then a biopsy of the breast should be performed. A biopsy of the skin is easily performed also, but it can be negative in 25% of the cases with IBC, therefore a negative skin biopsy should not exclude this disease, and a breast biopsy is still necessary. The surgeon will follow the response of the breast to antibiotics and coordinate the biopsies if any abnormal finding is seen on imaging or if the antibiotic treatment does not result in complete resolution of the skin changes in the breast.

      IBC is more commonly found to be HER2+ or triple negative (TN) compared with non-IBC. The prognosis for IBC that is ER+ is more favorable than if ER negative, most likely because the cancer can be treated with endocrine therapy (tamoxifen, aromatase inhibitors) following the completion of chemotherapy. HER2+ IBC also has a more favorable outcome, because medication specifically directed toward the treatment of HER2+ disease (trastuzumab, pertuzumab) has been shown to be very successful. Within IBC, TN disease remains problematic because of the limited therapies available, namely only chemotherapy.

      The optimal chemotherapeutic treatment for IBC is not known. Therefore, there is a difference in the treatment of IBC when it presents only with breast and lymph node involvement (Stage III) compared with distant metastasis (Stage IV). When patients present with TN IBC and do not have distant metastasis, then combination chemotherapy using an anthracycline (doxorubicin, epirubicin) and a taxane (paclitaxel, docetaxel) currently offers the best outcome. The specific combination of chemotherapy does not seem to be as important as ensuring that a combination of these two classes of chemotherapy are administered prior to surgery. There are some important clinical trials that have included the platinum agents (cisplatin, carboplatin) which may be important in the treatment of TN IBC, although those studies included all types of breast cancer, not just IBC, and so proving a specific benefit for IBC may be difficult. When IBC presents as Stage III disease, the chemotherapy regimens chosen are those accepted for the treatment of curable breast cancer, and so proof of benefit is necessary prior to choosing the regimen.

      Once IBC metastasizes, or grows through chemotherapy administered for TN disease, the disease is not curable, and the goal is disease control. This allows for more variation in treatment options. Since TN IBC has no known “target” for treatment, as does HER2+ or ER+ disease, then chemotherapy is the mainstay of standard therapy, however enrollment onto clinical trials investigating novel “targeting” agents may be very beneficial. The choice of second-line chemotherapy for TN IBC depends upon how long it has been since the end of the first-line chemotherapy. If it has been more than one year, the option to return to the original chemotherapy exists. However, standard chemotherapy using cisplatin, ixabepilone with capecitabine, or an older regimen CMF (cyclophosphamide, 5-flurouracil, and methotrexate) can be used as second-line therapy. We do not know which therapy is the “best” regimen, since there is no way to predict which treatment will result in a disease response. Tests for the sensitivity of chemotherapy performed in several laboratories across the country have not been shown to be effective in predicting disease response in humans. Enrollment onto a clinical trial should always be considered when TN IBC progresses because conventional chemotherapy is not sufficient to control this disease.

      There is much exploration in the detection of specific molecular pathways that specifically support the survival of IBC. Basic science investigation has demonstrated a important pathway known as the JAK2/STAT3 pathway that appears to be necessary in the survival of IBC cells, and there are trials that are investigating a JAK2 inhibitor as therapy. ALK is another target that is being investigated in IBC. EGFR (epidermal growth factor receptor) is being evaluated as a target using an antibody against EGFR, panitumumab. Angiogenesis continues to be an important therapeutic target for IBC, and several studies are ongoing using bevacizumab, and sorafinib as well as others. PI3 kinase inhibitors, such as BKM120, are also actively being investigated. The majority of the targeted therapy studies most commonly include all advanced breast cancer, not just limited to IBC, which again makes interpretation of the benefits and how they relate specifically to IC very difficult. Ongoing basic science continues to identify targets specific to IBC and then translate them into clinical investigation, but the progress is slow.

      IBC, similar to non-IBC, can metastasize to every part of the body, with more common sites depending upon the biologic markers of the cancer. For example, TN IBC, like TNBC in general, has a greater tendency to metastasize to lungs and liver, compared with ER+ disease, which has a greater probability of metastasizing to the bones. In this way, IBC acts similarly to non-IBC, meaning sites of metastasis are dependent upon the molecular biology of the disease. However, IBC does have a propensity to metastasize to the brain and to local organs through lymphatic dissemination. Pleural effusions are more common, as are involvement with distant lymph nodes, such as hilar and mediastinal lymph nodes, as well as the contralateral axillary lymph node groups. IBC also more commonly metastasizes to the other breast through extension of lymphatic involvement in the skin. These are not frequent occurrences, but occur more frequently with IBC than with non-IBC.

      The initial evaluation of IBC prior to starting therapy is crucial because sites of distant disease can go undetected if complete staging studies are not performed. Patients should undergo mammogram, and ultrasound as well as MRI imaging of the breast prior to therapy, since these images, specifically the MRI, may be very useful prior to surgery to confirm the disease response and the ability to undergo a mastectomy. PET/CT imaging is also often used to successfully determine the extent of distant metastasis in bone and lymph nodes, though it does not replace the need for specific CT of the chest, abdomen and pelvis. Tumor markers are not helpful in this setting because changing therapy based upon a rise in tumor marker has not been shown to be of benefit.

      During pre-operative therapy, the physical examination of the breast will show the disease response to treatment. Imaging the breast during this time is not necessary unless there is concern that the disease is not responding or even progressing. MRI of the breast prior to mastectomy is often performed, as previously stated.

      Following the completion of pre-operative chemotherapy, mastectomy, and radiation, if metastatic disease is not present, then follow-up imaging only includes mammogram, ultrasound and MRI (if indicated) of the contralateral, non-affected breast. Routine imaging using PET or CT has not been found to be of benefit unless it is directly ordered to evaluate a symptom or sign of recurrent disease. A physical examination with blood tests as needed to follow toxicity of medication such as endocrine therapy, should be performed every 3-6 mo during the first 5 years after treatment, and then every year thereafter. Patients with IBC need to be comfortable in contacting their medical oncologist with any change in symptoms or on physical exam, so that further evaluation is instituted. Imaging or biopsy may then be necessary to determine whether the disease has recurred.

      Pet Scans in Oncology

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      Gregory D. Pawelski