Click to edit Master title style Edit Master

Click to edit Master title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level Inflammatory Breast Cancer What you need to know • By hossam a. mohamed 1

Outline Click to edit Master title style • • Edit Master text styles IBC definition - how is it different from locally • Second level • Third level advanced breast cancers (LABC) • Fourth level • Fifth level • IBC clinical diagnosis • Imaging • Pathology • IBC treatment protocols - order of treatment! • FAQs 2

IBC has been described for 200 years Click to edit Master title style • • Edit described Master textin styles First 1814 by Sir Charles Bell as • Second level “a purple color on the skin over the tumor, • Third level accompanied by shooting pain” • Fourth level • Fifth level • The term “IBC” was proposed by Lee and Tannenbaum in 1924, after this disease had many previous names • lactation cancer, carcinoma mastitoides, mastitis carcinomatosa, acute encephaloid cancer, acute mammary carcinoma, acute brawny cancer, acute scirrhous carcinoma, and carcinoma telangiectaticum 3

What is inflammatory breast cancer? Click to edit Master title style • • An. Editaggressive Master textsubset styles of breast cancer diagnosed clinically (no current molecular definition!) • Second level • 2 -5% of total BC incidence, but ~10% of mortality • 2 types of IBC • Primary IBC - IBC developing in a previously normal breast • Third level • Fourth level • Fifth level (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 cancer • A palpable lump is present in only a third of IBC patients at diagnosis • Hence the IBC Network’s slogan -“No lump still cancer” slogan 4

Click to edit Master title style • Edit Master text styles How is IBC different from other locally advanced breast cancers? • Second level • Third level • Fourth level • Fifth level 5

1) IBC visual symptoms are distinctive Click to edit Master title style • Edit Master text styles • Classical signs of primary IBC • Second • Warm, rapidlylevel enlarging swollen breast (due to the • Third level • blockage of lymph vessels with tumor clumps) • Fourth level Redness (or pinkness) • Fifth levelcovering 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 d’orange (orange peel) appearance of the skin overlying the breast • Breast can be painful • Nipple changes (e. g. retraction, flattening, crusting) • NOTE: Not all these symptoms must be present for a diagnosis of IBC 6

2) IBC has particular imaging differences Click to edit Master title style • • Edit No Master palpable lump in 2/3 rds of women text styles frequent ‘webby’ appearance • Second level • Mammograms miss >50% of IBC cases • Third level • Fourth level • Fifth level -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 7

3) Demographics of IBC patients (vs non-IBC Click to edit Master style breasttitle cancers) Early stage BC IBC • Edit Master text styles • Second level • Third level • Fourth level • Fifth level Information from SEER national database • Younger median age at diagnosis • IBC - 58 yrs old • n. IBC - 63 -68 yrs old • Black and Asian women are diagnosed younger • 15 -20% of IBC occurs in women with a family history of breast cancer 8

IBC vs LABC Differences Summary Click to edit Master title style • • IBC is different because: Edit Master text styles level & behaves differently - must be aware of 1. • It. Second presents • Third level symptoms and rapidly changing breast appearance • Fourth level • Fifth level 2. It is more difficult to detect by routine imaging (mammograms), and. . . 3. Often presents in young women prior to the recommended age for beginning screening mammography. 4. Requires multidisciplinary specialty care by expert team - several critical differences in management (see later section). 9

Reasons for IBC misdiagnosis Click to edit Master title style • Possible IBC mimics: • Edit text styles • In. Master fection (“that may heal itself”) • Second level breast abscess, TB, syphilis. . . • Mastitis, • Third level • Post radiation dermatitis level • Other • Fourth cancers (leukemia, lymphoma, sarcoma), cysts • Fifth level • Insect bites • Duct ectasia • Trauma e. g. a bruise • Normal calcifications • Less plausible, but actual incorrect diagnoses received by IBC women: • “Menopause in 1 breast” • Pituitary gland infection • Shoulder impingement • A pulled muscle • Pregnancy-related changes 10

Click to edit Master title style • Edit Master text styles • Second level • Third level IBC Clinical Diagnosis • Fourth level • Fifth level 11

Key reference - International IBC consensus Click to edit Masterpaper title style • Edit Master text styles • Second level • Third level • Fourth level • Fifth level Link to article fulltext

Imaging used in IBC diagnosis Click to edit Master title style • • Breast Edit Master text styles level mammogram (may not observe a lump) - only 43% of • • Second Diagnostic • Third level IBC • detected on a mammogram (Dushkin & Cristofanilli, JNCCN, 2011) Fourth level • Most common finding = skin thickening • Fifth level • Ultrasound of breast and nodes • MRI • Metastatic Workup - done because of substantial risk of regional and distant metastatic disease • PET/CT highly recommended if not possible then CT of chest, abdomen, pelvis • Bone scan 13

IBC pathology concepts Click to edit Master title style • • IBC must be confirmed by a core biopsy so that enough tissue is Edit Master text styles obtained for biomarker analysis (ER, PR, HER 2) • Second level • Third level at least 2 skin punch biopsies to determine • Recommend • Fourth level presence of lymphovascular • Fifth level emboli (see later slides). Try to sample the areas that are most discolored. • ER, PR, and HER 2 • Testing must be done to determine potential treatment • ER and PR tested via immunohistochemistry (IHC) • HER 2 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. 14

Examples of ER and HER 2 staining patterns Click to edit Master title style • Edit Master text styles • Second level Estrogen receptor • Third level staining = brown, in the nucleus • Fourth level • Fifth level HER 2 staining is brown and on cell surface 15

IBC pathology concepts Click to edit Master title style • • Edit IBCMaster is not a histologic subtype of breast cancer! text styles • Pathology report may not state “inflammatory • Second level • Third level • Fourthcancer” level breast since pathologically it is not • Fifth level possible to differentiate IBC from other invasive breast cancers • Potential 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 16

Dermal lymphovascular emboli Click to edit Master title style • Dermal lymphovascular • Edit Master text styles • Second level • Third level emboli frequently seen • Fourth level Fifth level 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 17

IBC staging per AJCC guidelines - TNM Click to edit Master title style • • Edit IBCMaster staging uses the established AJCC criteria for text styles breast cancer • Second level • TNM system • T = tumor size. • Third level • Fourth level • Fifth level IBC is always T 4 d regardless of size of redness • N = nodal status. N 1 -N 3 depending on the number and location of clinically positive nodes. • M = distant metastatic sites (eg lung, liver, bone, brain etc) 18

IBC staging specifics Click to edit Master title style • • By definition, T 4 tumors (including IBC) are stage III. Edit Master text styles Second level • • Non-metastatic IBC (ie breast and lymph nodes only) is • Third level always stage IIIB or IIIC (IIB = T 4 N 0 M 0, T 4 N 1 M 0, or • Fourth level • Fifth level= T 4 N 3 M 0) T 4 N 2 M 0, IIIC • 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”) 19

What is the distribution of IBC staging at Click to edit Master title style diagnosis? • Edit Master. IBC text styles Non IBC • Second level • Third level !!!!! IIIB • IIIC Fourth level • Fifth level IV I II IV Unknown 9% 18% 3 % 4% 30% 53% 17% In situ 27% 39% 20

IBC molecular subtypes Click to edit Master title style Master text styles • • Edit. Similar to breast cancer as a whole, IBC can • Second level be • Third ER, level. PR and/or HER 2+. • Difference in proportions: • Fourth level • Fifth level IBC non. IBC ER/PR+ - ~ 50% ER/PR+ - ~ 60 -70% HER 2+ - ~ 40% HER 2+ - ~ 15 -20% TNBC - ~ 30% TNBC - 15 -20% 21

Hormone receptor subtypes have different Click to edit Master title style outcomes in IBC • Data from MD Anderson • Edit Master text styles 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) • Second level • Third level • Fourth level • Fifth level • 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) 22

NBC subtypes are all present in similar ratios in Click to edit Master titleas style TN-IBC well • • Recently, TNBC has been subtyped into various different subtypes with Edit Master text styles • differences outcomes. • Second in level • Third level has a worse outcome, researchers wanted to know whether Because TN-IBC • Fourthof level the distribution subtypes is different in TN-IBC and non-IBC TNBC. • Fifth level • Answer: No statistical differences seen IBC Non IBC 26. 0 17. 3 8. 7 Reference: http: //breast-cancerresearch. com/content/15/6/R 112 0. 0 BL 1 BL 223 IM M MSL LAR

IBC Metastasis Click to edit Master title style Editis. Master text styles • • IBC characterized by a high rate of recurrence - ~50 -60% by 5 years. • Second level • Early • spread of tumor cells via lymphatics and secondarily via the blood Third level • Fourth level • 2 types of recurrences • Fifth level • Local - including skin (higher than LABC) • Distant - many organs (bone, lung, liver, brain are most common) • IBC vs LABC • More bone and soft tissue (skin and lymph nodes) locations of metastasis in IBC • Other visceral (i. e. organ) metastasis similar to non-IBC, and follow similar patterns by histology. 24

Click to edit Master title style • Edit Master text styles • Second level IBC Treatment Protocols • Third level • Fourth level • Fifth level 25

Big picture of IBC consensus treatment strategy III + selected Click to(stage edit Master title stylestage IV) Systemic therapytext styles • Edit Master Partial/com • Second level Chemotherapy +/- level HER 2 • Third targeted therapy • Fourth level plete response • Fifth level Loco-regional therapy Modified radical mastectomy + Axillary dissection Chest wall + regional nodal radiation 5 -6 weeks 4 -6 months (or until maximal response) ? ? ? if not operable (if operable) Further chemotherapy/individ ualized treatment Adjuvant treatments if ER/PR/HER 2+ 26

Systemic therapy: Chemotherapy Click to edit Master title style • • IBC is essentially a systemic disease at diagnosis Edit Master text styles • Neoadjuvant chemotherapy is essential starting point • Second level • Third level • Purpose: reduce disease in breast to make it operable, and eradicate already • Fourth level escaped micro-metastases • Fifth level • Note: “clean” margins are difficult to know prior to detailed pathological analysis. • Goal of neoadjuvant chemotherapy: pathological complete response (p. CR) • Various chemotherapy regimens are reasonable • Most should contain an anthracycline (doxorubicin or epirubicin) and taxane (paclitaxel or docetaxel). Examples of regimens: FEC-Paclitaxel, dd. AC-Taxol etc (see NCCN guidelines for details) • Consider clinical trials if available • If patient’s tumor is not responding to standard regimen, changing to alternative non-cross-resistant drugs recommended (personalized management). 27

Systemic therapy: HER 2 targeted therapy (for Click to edit Master title style HER 2+ patients ONLY!) • • Edit HER 2 -overexpressing patients, defined as IHC 3+ Master text styles • Second level>2. 2 should receive Trastuzumab + or FISH • Third level Pertuzumab in combination with a taxane. (2013 • Fourth level • Fifth level FDA approval) • TCH-P (Taxotere, Carboplatin, Herceptin, Pertuzumab) is an effective anthracycline-free option that has been shown to have benefit in IBC and non. IBC patients • After surgery, patients should continue Trastuzumab for a total of 1 year 28

Loco-regional treatment: Surgery Click to edit Master title style • • Edit After Master completion of chemotherapy, stage III and selected stage IV patients undergo text styles surgery • Second level • to remove any residual disease in the breast and nodes • Third level Stage IV patients • Fourth levelwith detectable/uncontrolled distant metastases still present after chemotherapy may • Fifth levelnot 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 mastectomy • Breast 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. 29

Reconstruction considerations Click to edit Master title style • Immediate reconstruction is not recommended for various reasons • Edit Master text styles • Second level rate - optimal treatment involves radiation in a timely manner. • Elevated recurrence • Third level Fourth level • Expanders • and non-skin-sparing mastectomies do not go together! Skin must be left behind to • Fifth level 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 postradiation. 30

Loco-regional treatment: Radiation Click to edit Master title style • • Post-mastectomy Edit Master textradiation styles is important component of multidisciplinary care. • Second level • At minimum, 60 Gy standard fractionation is used. MD Anderson data has • Thirdincreasing level shown • that the total dose to 66 Gy has benefit in IBC patients. • Fourth level Modulating intensity • Fifth level 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 50 yrs of age, triple negative disease) • Alternatively, use of chemotherapy as a radiosensitizer (such as Xeloda) or a clinical trial may be warranted in this setting • Use 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. 31

Adjuvant treatments Click to edit Master title style • • HER 2+ patients - should receive Trastuzumab for the remainder of 1 year total Edit Master text styles • duration • Second level ER+/PR+ patients • Third level - highly recommended endocrine therapy • • Fourth level Various choices as in • Fifth level 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) 32

FAQs Click to edit Master title style • • Is. Editthere a link to BRCA 1/2 mutation? Should IBC patients be Master text styles tested forlevel one of these mutations? • Second • Answer: Yes, BRCA 1/2 mutations are found in IBC, at a • Third level • Fourth level • Fifth level 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/coveragecriteria/brca-testing/). • Can men get IBC? • Answer: Yes. There is not a large literature, but ~0. 5% of male breast cancer is IBC. 33

IBC Research Themes - Basic/translational Click to edit Master title style • Edit Master text styles • • Second level • Third level Basic/translational laboratory research • • • Fourth level • Fifth level In depth genomic, transcriptomic, proteomic analysis by subtypes Investigation into microenvironmental factors that contribute to risk/outcomes • • • e. g. normal tissue/stromal/immune factors; role of pregnancy and breastfeeding Novel targets especially in TN-IBC; stem-cell biology; anti-metastatic strategies Ways to radio/chemo-sensitize IBC cells 34

IBC Research Themes - Clinical/Epidemiological Click to edit Master title style • • Edit Clinical Master text styles level • • Second What to do for chemo-resistant disease? • Third level • Fourth level for anti-angiogenic therapies? • Is there a role • Fifth level • Recurrence prevention strategies in stage 3 NED patients after trimodality therapy • • • Peptide vaccines/immunotherapy? Statins? Epidemiology • Who is at risk? Lifestyle factors? Geographic issues 35

FAQs (cont. ) Click to edit Master title style • • Edit Can. Master you text lookstyles at my biopsy and tell me if I have IBC? • Second level • Answer: Unfortunately not. Your doctor should use • Third level • Fourth level • Fifth level 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. 36

FAQs (cont. ) Click to edit Master title style Editrecurrences Master textofstyles • • Can IBC change hormone receptor status? Why? • Second level • Answer: • Third. Yes, level it does happen perhaps 20 -40% of the time in breast cancer. There a few • Fourth levelpotential reasons including testing inaccuracy and Fifth level Biological reasons include initial tumor heterogeneity underlying • biology. (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 development is likely multi-factorial, so viral infection is unlikely to be a major driver. 37

Histologic Evaluation Image-guided core needle biopsy +/- skin punch biopsy Grade 3 invasive ductal carcinoma Dermal lymphatic invasion

Initial Evaluation Peau d’orange (dermal lymphatic invasion) Unresectable disease 1. Neoadjuvant systemic therapy for cytoreduction 2. Modified radical mastectomy 3. Chest wall and regional nodal radiotherapy* *Morris, Journal of Surgical Oncology 1983; Dawood et al. Annals of Oncology 2011

What is the Role of Surgery in IBC Survival in 28 patients with IBC (23 patients with stage III disease) with and without surgery, 1969 -1980 Hagelberg, Jolly, Anderson, Am Journal of Surgery 1984

Multivariate Analysis Fields et al, Cancer 1989

What is the Role of Surgery in IBC Response to chemotherapy, receipt of surgery and outcomes in 178 IBC patients 1974 -1993, median follow-up 89 months (22 -223 months) Fleming et al, Ann Surg Oncol 1989

Mastectomy (total, simple) + Axillary lymph node dissection What is a Modified Radical Mastectomy

Why Mastectomy The cancer is often present throughout the breast at the time of diagnosis

Why Axillary Lymph Node Dissection? Axillary lymph nodes are almost always involved at diagnosis and it may be unsafe to not to remove them

Drain s Round Blake Round Jackson-Pratt Flat Jackson-Pratt

Why Should Immediate Reconstruction Not Be Done in IBC? The amount of involved skin can go beyond what is clinically visible

Patterns of Breast Reconstruction in Patients Diagnosed with Inflammatory Breast Cancer: the Dana Farber Cancer Institute’s Inflammatory Breast. Experience Cancer Program • F. Nakhlis, M. M. Regan, Y. S. Chun, L. S. Dominici, J. R. Bellon, L. • Warren, E. D. Yeh, H. A. Jacene, K. Hirko, A. Hazra, J Hirshfield- Bartek, T. A. King, B. Overmoyer • SABCS 2015 Poster

Backgroun d • Immediate reconstruction is not advised in IBC patients due to lack of safety data for skin-sparing mastectomy • Data on breast reconstruction outcomes in IBC patients are scant • Our experience with breast reconstruction in IBC patients was reviewed

Method s • Retrospective analysis of IRB-approved DFCI IBC database • Patients included in the analysis • • Stage III IBC Sufficient response to preoperative chemotherapy to achieve resectability No preoperative radiotherapy No loco-regional progression or distant metastasis during preoperative chemotherapy

Result s Stage III IBC patients* (1997 -2014), n=167 Immediate reconstruction, n=12 Delayed reconstruction, n=18 No reconstruction, n=135 *In two patients breast reconstruction took place but no information about reconstruction details and follow-up is available

Immediate Reconstruction, n=12* Reconstructive Option Number of Patients Tissue expander 3 Single stage implant 3 DIEP flap 1 TRAM flap 4 Latissimus Dorsi flap 1 *Eleven out of 12 patients with immediate reconstruction underwent surgery outside of DFCI

Delayed Reconstruction, n=18 Reconstructive Option Number of Patients Tissue expander 1 TRAM flap 9 DIEP flap 5 Latissimus Dorsi and tissue expander 1 Latissimus Dorsi flap 2

Complications After Delayed Reconstruction Complication Delayed Reconstruction (N=18) Reoperation for flap donor site wound dehiscence 1 (6%) Reconstruction loss 1 (6%) Total Complications 2 (12%)

Future Direction • Exploration of the role of local therapy (surgery and radiation) in stage IV IBC • Axillary and extra-axillary lymphatic drainage in IBC and the potential for sentinel node mapping

Unique Features of IBC • Predilection for skin involvement, particularly dermal lymphatics • High rate of nodal involvement • Axillary, supraclavicular and internal mammary • These features help define the radiation fields

Tri-modality Therapy • Systemic therapy • Kills cells that may have spread from the breast to other parts of the body • Helps decrease the burden of disease in the breast, and nearby lymph nodes • Surgery • Removes residual gross disease in the breast and axilla • Radiation treats the residual skin/chest wall and nodes that aren’t operated upon

What is the Process of Radiation? CT-Simulation • Standard CT • Lasers to make sure patient is straight • Tiny (freckle-like) tattoos to help with reproducibility

Immobilization

Chest Wall Tangents

Digitally Reconstructed Radiograph Axillary Nodes Heart

Nodal Field

Bolus • Tissue equivalent plastic that ‘fools’ the radiation to deposit its dose at the surface • Commonly used after mastectomy (not typically to the intact breast)

Dynamic Multi-Leaf Collimator

Isodose Curves

Side Effects of Treatment: Short Term • Skin • Redness • Possible peeling/blistering • Chest • Tenderness • Pruritus • Fatigue

Side Effects: Long Term • Cardiac • Long-term coronary artery disease

Heart Movement with Respiration

Chest Monitoring During Radiation

Respiratory Trace During Radiation Chest Excursion Window Time (sec)

Side Effects: Long Term • Cardiac • Long-term coronary artery disease • Pulmonary • Pneumonitis • Lymphedema • Impact on Reconstruction

Future Directions • Ongoing studies looking at improving effectiveness of radiation • In large part, this will come from improvements in systemic therapy • Concurrent veliparib (PARP-inhibitor) • Phase I study from U of M • Soon to be launched Phase II randomized trial Radiation with or without veliparib

Conclusions • Radiation, when combined with surgery and systemic therapy is increasingly effective at achieving long-term local control • Efforts are ongoing to ensure maximal safety, with minimal long-term sequelae