Inflammatory Breast CancerWhat you need to know

OutlineIBC definition - how is it different from locally advanced breast cancers (LABC)IBC clinical diagnosis ImagingPathologyIBC treatment protocols - order of treatment!FAQs

IBC has been described for 200 yearsFirst described in 1814 by Sir Charles Bell as a purple color on the skin over the tumor, accompanied by shooting pain

The term IBC was proposed by Lee and Tannenbaum in 1924, after this disease had many previous nameslactation cancer, carcinoma mastitoides, mastitis carcinomatosa, acute encephaloid cancer, acute mammary carcinoma, acute brawny cancer, acute scirrhous carcinoma, and carcinoma telangiectaticum

What is inflammatory breast cancer?An aggressive subset of breast cancer diagnosed clinically (no current molecular definition!)2-5% of total BC incidence, but ~10% of mortality2 types of IBCPrimary IBC - IBC developing in a previously normal breast (MOST CASES) Secondary IBC - IBC features (and biopsy-proven invasive cancer) on the chest wall post mastectomy for non-IBC or a recurrence with inflammatory features in a breast that already had cancerA palpable lump is present in only a third of IBC patients at diagnosisHence the IBC Networks slogan -No lump still cancer slogan

How is IBC different from other locally advanced breast cancers?

1) IBC visual symptoms are distinctiveClassical signs of primary IBC Warm, rapidly enlarging swollen breast (due to the blockage of lymph vessels with tumor clumps)Redness (or pinkness) covering 1/3 or more of the breast, with a history of no more than 6 months (Impt: neglected non-IBC can invade skin and appear like IBC)Peau dorange (orange peel) appearance of the skin overlying the breastBreast can be painfulNipple changes (e.g. retraction, flattening, crusting)NOTE: Not all these symptoms must be present for a diagnosis of IBC

2) IBC has particular imaging differencesNo palpable lump in 2/3rds of women - frequent webby appearance Mammograms miss >50% of IBC cases - but key observations include skin thickening, stromal coarsening, diffusely increased breast density (vs calcifications or a discrete lump in most breast cancers)High rate of abnormal/enlarged lymph nodes in axilla or superclavicular region - most easily detected by ultrasound

3) Demographics of IBC patients (vs non-IBC breast cancers)Younger median age at diagnosisIBC - 58yrs oldnIBC - 63-68yrs oldBlack and Asian women are diagnosed younger15-20% of IBC occurs in women with a family history of breast cancer

Early stage BCIBCInformation from SEER national database

IBC vs LABC Differences SummaryIBC is different because:It presents & behaves differently - must be aware of symptoms and rapidly changing breast appearanceIt is more difficult to detect by routine imaging (mammograms), and...Often presents in young women prior to the recommended age for beginning screening mammography.Requires multidisciplinary specialty care by expert team - several critical differences in management (see later section).

Reasons for IBC misdiagnosisPossible IBC mimics:Infection (that may heal itself)Mastitis, breast abscess, TB, syphilis...Post radiation dermatitisOther cancers (leukemia, lymphoma, sarcoma), cystsInsect bitesDuct ectasiaTrauma e.g. a bruiseNormal calcifications

Less plausible, but actual incorrect diagnoses received by IBC women:Menopause in 1 breastPituitary gland infectionShoulder impingementA pulled musclePregnancy-related changes

IBC Clinical Diagnosis

Key reference - International IBC consensus paper

Link to article fulltext

Imaging used in IBC diagnosisBreastDiagnostic mammogram (may not observe a lump) - only 43% of IBC detected on a mammogram (Dushkin & Cristofanilli, JNCCN, 2011)Most common finding = skin thickeningUltrasound of breast and nodesMRIMetastatic Workup - done because of substantial risk of regional and distant metastatic diseasePET/CT highly recommended if not possible then CT of chest, abdomen, pelvisBone scan

IBC pathology conceptsIBC must be confirmed by a core biopsy so that enough tissue is obtained for biomarker analysis (ER, PR, HER2)Recommend at least 2 skin punch biopsies to determine presence of lymphovascular emboli (see later slides). Try to sample the areas that are most discolored.ER, PR, and HER2Testing must be done to determine potential treatment ER and PR tested via immunohistochemistry (IHC)HER2 tests either by IHC or FISH (fluorescence in situ hybridization).If results fall inside of a grey zone, then the other test is performed by reflex.

Examples of ER and HER2 staining patterns

HER2 staining is brown and on cell surface

Estrogen receptor staining = brown, in the nucleus

IBC pathology conceptsIBC is not a histologic subtype of breast cancer!Pathology report may not state inflammatory breast cancer since pathologically it is not possible to differentiate IBC from other invasive breast cancersPotential histologies include invasive ductal carcinoma (~75%), lobular, mixed ductal + lobular, medullary, small cell, large cell So: IBC = invasive breast cancer in the setting of the clinical symptoms described previously

Dermal lymphovascular emboliDermal lymphovascular emboli frequently seen in IBC (50-75%) and larger than LABC, but NOT REQUIRED for diagnosis, and the presence of emboli is not SUFFICIENT for an IBC diagnosis either.

Tumor emboli

IBC staging per AJCC guidelines - TNMIBC staging uses the established AJCC criteria for breast cancerTNM systemT = tumor size. IBC is always T4d regardless of size of rednessN = nodal status. N1-N3 depending on the number and location of clinically positive nodes.M = distant metastatic sites (eg lung, liver, bone, brain etc)

IBC staging specificsBy definition, T4 tumors (including IBC) are stage III. Non-metastatic IBC (ie breast and lymph nodes only) is always stage IIIB or IIIC (IIB = T4N0M0, T4N1M0, or T4N2M0, IIIC = T4N3M0)De novo metastatic IBC is stage IV

Stage IIIB/C patients who later develop distant metastases are not technically stage IV in cancer statistics. However, many clinicians tell patients they are now stage IV when discussing the goals and duration of treatment (palliative/controlling disease vs curative intent)

What is the distribution of IBC staging at diagnosis?

IBCNon IBC

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IBC molecular subtypesSimilar to breast cancer as a whole, IBC can be ER, PR and/or HER2+. Difference in proportions:

IBCER/PR+ - ~ 50%HER2+ - ~ 40%TNBC - ~ 30%nonIBCER/PR+ - ~ 60-70%HER2+ - ~ 15-20%TNBC - 15-20%

Hormone receptor subtypes have different outcomes in IBCData from MD Anderson registry, patients given optimal treatment based on what was known at the time (ie Trastuzumab when it became available, taxanes added to chemotherapy once data showed superiority)TN-IBC has significantly worse outcome in IBC!Note that unlike non-IBC, ER/PR+ patients still do quite poorly (~compared to 90+% alive at 5 yrs)

TNBC subtypes are all present in similar ratios in TN-IBC as wellRecently, TNBC has been subtyped into various different subtypes with differences in outcomes.Because TN-IBC has a worse outcome, researchers wanted to know whether the distribution of subtypes is different in TN-IBC and non-IBC TNBC.Answer: No statistical differences seen

Reference: http://breast-cancer-research.com/content/15/6/R112

IBC MetastasisIBC is characterized by a high rate of recurrence - ~50-60% by 5 years.Early spread of tumor cells via lymphatics and secondarily via the blood2 types of recurrencesLocal - including skin (higher than LABC)Distant - many organs (bone, lung, liver, brain are most common) IBC vs LABCMore bone and soft tissue (skin and lymph nodes) locations of metastasis in IBCOther visceral (i.e. organ) metastasis similar to non-IBC, and follow similar patterns by histology.

IBC Treatment Protocols

Big picture of IBC consensus treatment strategy (stage III + selected stage IV)Chemotherapy +/- HER2 targeted therapyModified radical mastectomy + Axillary dissection4-6 months (or until maximal response)

Partial/complete response5-6 weeksChest wall + regional nodal radiation

???(if operable)if not operableFurther chemotherapy/individualized treatment

Loco-regional therapySystemic therapyAdjuvant treatments if ER/PR/HER2+

Systemic therapy: ChemotherapyIBC is essentially a systemic disease at diagnosisNeoadjuvant chemotherapy is essential starting point Purpose: reduce disease in breast to make it operable, and eradicate already escaped micro-metastasesNote: clean margins are difficult to know prior to detailed pathological analysis. Goal of neoadjuvant chemotherapy: pathological complete response (pCR)Various chemotherapy regimens are reasonableMost should contain an anthracycline (doxorubicin or epirubicin) and taxane (paclitaxel or docetaxel). Examples of regimens: FEC-Paclitaxel, ddAC-Taxol etc (see NCCN guidelines for details)Consider clinical trials if availableIf patients tumor is not responding to standard regimen, changing to alternative non-cross-resistant drugs recommended (personalized management).

Systemic therapy: HER2 targeted therapy (for HER2+ patients ONLY!)HER2-overexpressing patients, defined as IHC3+ or FISH >2.2 should receive Trastuzumab + Pertuzumab in combination with a taxane. (2013 FDA approval)TCH-P (Taxotere, Carboplatin, Herceptin, Pertuzumab) is an effective anthracycline-free option that has been shown to have benefit in IBC and nonIBC patientsAfter surgery, patients should continue Trastuzumab for a total of 1 year

Loco-regional treatment: SurgeryAfter completion of chemotherapy, stage III and selected stage IV patients undergo surgery to remove any residual disease in the breast and nodesStage IV patients with detectable/uncontrolled distant metastases still present after chemotherapy may not benefit from surgery. Personalized treatment is necessary in this situation.

If surgery is planned, it should be performed ideally within 4-6 weeks of last chemotherapy dose.

Surgery - non skin-sparing modified radical mastectomyBreast conservation (e.g. lumpectomy) is not recommended. IBC involves the skin, so it must be removed. The entire breast may contain dispersed disease so it must be carefully examined pathologically.Axillary dissection must be done for adequate staging and removal of any resistant disease. Note: Sentinel node biopsy is not recommended and frequently fails in IBC patients due to the involvement of regional lymphatics.

Reconstruction considerationsImmediate reconstruction is not recommended for various reasonsElevated recurrence rate - optimal treatment involves radiation in a timely manner.

Expanders and non-skin-sparing mastectomies do not go together! Skin must be left behind to cover an expander, and this skin might harbor residual IBC, leading to rapid recurrence.Placing expanders at time of mastectomy dictates a schedule for filling and future surgeries to complete reconstruction. This schedule compromises the overall care for several potential reasons:Poor radiation coverage of the chest wall and nodes is a consequence of expanders being in place.Complications from larger surgery such as poor wound healing/failed reconstruction can unnecessarily delay radiation (a key component of local control)

Delayed reconstruction (by autologous methods) may be considered in IBC patients who are still disease-free 2 years post surgery. Implants are not usually possible due to skin changes post-radiation.

Loco-regional treatment: Radiation Post-mastectomy radiation is important component of multidisciplinary care.At minimum, 60Gy standard fractionation is used. MD Anderson data has shown that increasing the total dose to 66Gy has benefit in IBC patients.Modulating intensity of radiation via daily vs twice-a-day schedule: Twice a day schedule worth considering in patients with above-average recurrence risk (poor response to chemotherapy, younger than 50yrs of age, triple negative disease)Alternatively, use of chemotherapy as a radiosensitizer (such as Xeloda) or a clinical trial may be warranted in this settingUse of bolus to deposit dose in skin is useful.Patients should be discouraged from using creams that have sunscreen - rather they should be given guidance on appropriate skin care throughout radiation.

Adjuvant treatmentsHER2+ patients - should receive Trastuzumab for the remainder of 1 year total durationER+/PR+ patients - highly recommended endocrine therapyVarious choices as in non-IBC breast cancer:Pre-menopausal - 10 years of tamoxifen OR aromatase inhibitor + ovarian suppression (or removal) for 5+ years (longer treatment with AIs not supported by long-term data yet). Post-menopausal - Aromatase inhibitors for 5 years (or tamoxifen if AIs are not tolerated)Menopausal status should be confirmed in women who were pre/peri-menopausal prior to chemotherapy by hormone testing, since chemotherapy induced amenorrhea can persist in spite of functioning ovaries. Important reason: Aromatase inhibitors are ineffective if the ovaries are still functional (regardless of menstrual cycling status)

FAQsIs there a link to BRCA1/2 mutation? Should IBC patients be tested for one of these mutations?Answer: Yes, BRCA1/2 mutations are found in IBC, at a similar rate as non-IBC. Genetic counseling is highly recommended to make testing decisions, using similar criteria as non-IBC (info > https://www.healthpartners.com/public/coverage-criteria/brca-testing/).

Can men get IBC?Answer: Yes. There is not a large literature, but ~0.5% of male breast cancer is IBC.

IBC Research Themes - Basic/translationalBasic/translational laboratory researchIn depth genomic, transcriptomic, proteomic analysis by subtypesInvestigation into microenvironmental factors that contribute to risk/outcomese.g. normal tissue/stromal/immune factors; role of pregnancy and breast-feeding Novel targets especially in TN-IBC; stem-cell biology; anti-metastatic strategiesWays to radio/chemo-sensitize IBC cells

IBC Research Themes - Clinical/EpidemiologicalClinicalWhat to do for chemo-resistant disease?Is there a role for anti-angiogenic therapies?Recurrence prevention strategies in stage 3 NED patients after trimodality therapyPeptide vaccines/immunotherapy?Statins?

EpidemiologyWho is at risk? Lifestyle factors? Geographic issues

FAQs (cont.)Can you look at my biopsy and tell me if I have IBC?Answer: Unfortunately not. Your doctor should use the clinical criteria discussed in the consensus paper mentioned, and confirm the presence of invasive breast cancer to make a diagnosis of IBC.

Can you get IBC on both breasts at once?Answer: Yes, there have been some cases of bilateral IBC at the same time.

FAQs (cont.)Can recurrences of IBC change hormone receptor status? Why?Answer: Yes, it does happen perhaps 20-40% of the time in breast cancer. There are a few potential reasons including testing inaccuracy and underlying biology. Biological reasons include initial tumor heterogeneity (ie ER+ just means >= 1% of cells are positive) and differential response to chemotherapy/targeted therapy of different clones.

Is IBC caused by a virus?Answer: The role of viruses is unclear. There have been reports of viral DNA found in various breast cancers, but causality is difficult to prove. Some of the viruses (eg EBV) are highly prevalent in the US population, and yet only 1-5% of breast cancers are IBC. IBC development is likely multi-factorial, so viral infection is unlikely to be a major driver.

Resources for more informationUniversity of Texas MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic - http://www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-types/inflammatory-breast-cancer/index.htmlNational Cancer Institute - http://www.cancer.gov/cancertopics/factsheet/Sites-Types/IBCMayo Clinic - http://www.mayoclinic.org/diseases-conditions/inflammatory-breast-cancer/basics/definition/con-20035052The IBC Network Foundation - www.theibcnetwork.org

How to contact usThe IBC Network FoundationTerry Arnold - terry@theibcnetwork.orgAngela Alexander - thecancergeek@gmail.com

Social media accountsTwitter: @TalkIBCFacebook: www.facebook.com/TalkIBCFacebook support group for patients/survivors: https://www.facebook.com/groups/inflammatorybreastcancer