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Background The purpose of this study was to determine the prognostic role of hormone receptor (HR) on inflammatory breast cancer (IBC) to elucidate its aggressive biological behavior. Methods We evaluated the expression of estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemical staining and determined the predictive and prognostic role of HR expression on 189 patients with HR+/HER2– IBC and 677 patients with HR+/HER2– stage III non-IBC. Furthermore, we performed gene expression (GE) analyses on 137 patients with HR+/HER2– IBC and 252 patients with HR+/HER2– non-IBC to detect genes that are specifically overexpressed in IBC. Results The expression of ER% was significantly associated with longer distant disease-free survival and overall survival. However, there was no significant relationship between ER% and neoadjuvant chemotherapy outcome. In the GE study, 84 genes were identified as significantly distinguishing HR+ IBC from non-IBC. Among the top 15 canonical pathways expressed in IBC, the ERK/MAPK, PDGF, insulin receptor, and IL-7 signaling pathways were associated with the ER signaling pathway. Upregulation of the MYC gene was observed in three of these four pathways. Furthermore, HR+/HER2– IBC had significantly higher MYC amplification, and the genetic alteration was associated with poor survival outcome. Conclusions Higher ER expression was significantly associated with improved survival in both HR+/HER2– IBC and HR+/HER2– stage III non-IBC patients. HR+/HER2– IBC had several activated pathways with MYC upregulation, and the genetic alteration was associated with poor survival outcome. The results indicate that MYC may be a key gene for understanding the biology of HR+/HER2– IBC.

Purpose To perform a planned interim analysis of acute (within 12 months) and late (after 12 months) toxicities and cosmetic outcomes after proton accelerated partial breast irradiation (APBI). Methods and Materials A total of 100 patients with pTis or pT1-2 N0 (≤3cm) breast cancer status after segmental mastectomy were enrolled in a single-arm phase 2 study from 2010 to 2019. The clinically determined postlumpectomy target volume, including tumor bed surgical clips and operative-cavity soft-tissue changes seen on imaging plus a radial clinical expansion, was irradiated with passively scattered proton APBI (34 Gy in 10 fractions delivered twice daily with a minimum 6-hour interfraction interval). Patients were evaluated at protocol-specific time intervals for recurrence, physician reports of cosmetic outcomes and toxicities, and patient reports of cosmetic outcomes and satisfaction with the treatment or experience. Results Median follow-up was 24 months (interquartile range [IQR], 12-43 months). Local control and overall survival were 100% at 12 and 24 months. There were no acute or late toxicities of grade 3 or higher; no patients experienced fat necrosis, fibrosis, infection, or breast shrinkage. Excellent or good cosmesis at 12 months was reported by 91% of patients and 94% of physicians; at the most recent follow-up, these were 94% and 87%, respectively. The most commonly reported late cosmetic effect was telangiectasis (17%). The total patient satisfaction rate for treatment and results at 12 and 24 months was 96% and 100%, respectively. Patients’ mean time away from work was 5 days (IQR, 2-5 days), and the median out-of-pocket cost was $700 (IQR, $100-$1600). The mean left-sided heart dose was 2 cGy (range, 0.2-75 cGy), and the mean ipsilateral lung dose was 19 cGy (range, 0.2-164 cGy). Conclusions Proton APBI is a maturing treatment option with high local control, favorable intermediate-term cosmesis, high treatment satisfaction, low treatment burden, and exceptional heart and lung sparing.

Inflammatory breast cancer (IBC) is a highly metastatic and lethal breast cancer. As many as 25-30% of IBCs are triple negative (TN) and associated with low survival rates and poor prognosis. We found that the microenvironment of IBC is characterized by high infiltration of tumor associated macrophages (TAMs) and by over-expression of the cysteine protease cathepsin B (CTSB). TAMs in IBC secrete high levels of the cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared to non-IBC patients. Herein, we tested the roles of IL-8 and MCP-1/CCL2 in modulating proteolytic activity and invasiveness of TN-non-IBC as compared to TN-IBC and addressed the underlying molecular mechanism(s) for both cytokines. Quantitative real time PCR results showed that IL-8 and MCP-1/CCL2 were significantly overexpressed in tissues of TN-IBCs. IL-8 and MCP-1/CCL2 induced CTSB expression and activity of the p-Src and p-Erk1/2 signaling pathways relevant for invasion and metastasis in TN-non-IBC, HCC70 cells and TN-IBC, SUM149 cells. Dasatinib, an inhibitor of p-Src, and U0126, an inhibitor of p-Erk1/2, down-regulated invasion and expression of CTSB by HCC70 and SUM149 cells, a mechanism that is reversed by IL-8 and MCP-1/CCL2. Our study shows that targeting the cytokines IL-8 and MCP-1/CCL2 and associated signaling molecules may represent a promising therapeutic strategy in TN-IBC patients.

Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer–associated genes is unknown. In a population-based case-control study, we examined the association between RT; variants in ATM, BRCA1/2, or CHEK2*1100delC; and CBC risk. We analyzed 708 cases of women with CBC and 1399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2000 and aged younger than 55 years at diagnosis and screened for variants in breast cancer–associated genes. Rate ratios (RR) and 95% confidence intervals (CIs) were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (eg, BRCA1/2 pathogenic variant carriers without RT: RR = 3.52, 95% CI = 1.76 to 7.01; BRCA1/2 pathogenic variant carriers with RT: RR = 4.46, 95% CI = 2.96 to 6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT: RR = 0.38, 95% CI = 0.09 to 1.55; carriers of ATM rare missense variants of uncertain significance with RT: RR = 2.98, 95% CI = 1.31 to 6.80). Further mechanistic studies will aid clinical decision-making related to RT.

Importance The 21-gene assay recurrence score is increasingly used to personalize treatment recommendations for systemic therapy in postmenopausal women with estrogen receptor (ER)– or progesterone receptor (PR)–positive, node-positive breast cancer; however, the relevance of the 21-gene assay to radiotherapy decisions remains uncertain. Objective To examine the association between recurrence score and locoregional recurrence (LRR) in a postmenopausal patient population treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone. Design, Setting, and Participants This cohort study was a retrospective analysis of the Southwest Oncology Group S8814, a phase 3 randomized clinical trial of postmenopausal women with ER/PR-positive, node-positive breast cancer treated with tamoxifen alone, chemotherapy followed by tamoxifen, or concurrent tamoxifen and chemotherapy. Patients at North American clinical centers were enrolled from June 1989 to July 1995. Medical records from patients with recurrence score information were reviewed for LRR and radiotherapy use. Primary analysis included 316 patients and excluded 37 who received both mastectomy and radiotherapy, 9 who received breast-conserving surgery without documented radiotherapy, and 5 with unknown surgical type. All analyses were performed from January 22, 2016, to August 9, 2019. Main Outcomes and Measures The LRR was defined as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. Time to LRR was tested with log-rank tests and Cox proportional hazards regression for multivariate models. Results The final cohort of this study comprised 316 women with a mean (range) age of 60.4 (44-81) years. Median (interquartile range) follow-up for those without LRR was 8.7 (7.0-10.2) years. Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (hazard ratio [HR], 2.36; 95% CI, 1.02-5.45;P = .04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051). Conclusions and Relevance This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.

Indoleamine 2,3-dioxygenase 1 (IDO1), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDO1 was expressed at higher levels in F4/80+Gr1intCD11b+ myeloid-derived suppressor cells (MDSCs) that were prominent in 344SQ_R. The INCB023843 reduced IDO1 expression and percentages of these MDSCs while increasing CD8+ T cells infiltration, hence reactivating antitumor T-cell responses in 344SQ_R. Therefore, IDO1 inhibition holds promise for treating lung cancer that does not respond to anti-PD1 therapy.

Inflammatory breast cancer (IBC) is a rare form of breast cancer that accounts for only 2% to 4% of all breast cancer cases. Despite its low incidence, IBC contributes to 7% to 10% of breast cancer caused mortality. Despite ongoing international efforts to formulate better diagnosis, treatment, and research, the survival of patients with IBC has not been significantly improved, and there are no therapeutic agents that specifically target IBC to date. The authors present a comprehensive overview that aims to assess the present and new management strategies of IBC.

Purpose Physical examination and diagnostic imaging are often less precise in determining the extent of disease in invasive lobular carcinoma (ILC) relative to nonlobular histologies. Anecdotally, surgical axillary evaluation frequently reveals positive lymph nodes in clinically N0 patients with ILC; however, few studies quantify the likelihood of finding unsuspected disease at the time of surgery. In this study, we evaluate whether the presence of lobular histology increases the incidence of surgical upstaging to pathologic stage IIIA or greater in patients with a clinically node-negative axilla and positive sentinel lymph node (SLN) biopsy. Methods and materials We examined patients from our institution between 1997 and 2009 treated specifically with mastectomy, SLN biopsy, and completion axillary lymph node dissection due to a positive SLN. For analysis, patients were grouped according to the presence of any lobular component on surgical pathology. The number of total positive lymph nodes, cancer stage, age, final tumor size, and ER/PR/HER2 status were assessed based on tumor histology. Results We evaluated 345 previously untreated women with clinical T0-T2 and N0 disease at the time of surgery. A total of 110 patients (32%) had a component of ILC on surgical pathology. In addition, 295 patients (85.5%) had ER + breast carcinoma, 243 (70.4%) had PR + disease, 56 (16.2%) were HER2 + , and 28 (8.1%) were triple negative. At the time of surgery, women with lobular disease were observed to have a greater number of positive lymph nodes (2.79 vs 2.26; P = .009) and were more frequently upstaged to at least pathologic stage IIIA compared with nonlobular patients (30.9% vs 17.4%; P = .007). Conclusions In this cohort, patients with a component of lobular carcinoma were more often surgically upstaged to pathologic stage IIIA or higher, which is a classical indication for postmastectomy radiation therapy. Our findings suggest that ILC is often more extensive than it appears clinically and has significant implications for management of patients with lobular carcinoma after the discovery of a positive SLN.

Purpose Locoregional control for inflammatory breast cancers and chest wall recurrences is suboptimal, which has motivated interest in radiosensitization to intensify therapy. Preclinical studies have suggested a favorable therapeutic index when poly (ADP-ribose) polymerase inhibitors are used as radiosensitizers; clinical investigation is necessary to establish appropriate dosing and confirm safety. Patients and Methods We conducted a multi-institutional phase I study of veliparib and concurrent radiotherapy (RT) to the chest wall and regional lymph nodes in 30 patients with inflammatory or locally recurrent breast cancer after complete surgical resection. RT consisted of 50 Gy to the chest wall and regional lymph nodes plus a 10-Gy boost. A Bayesian time-to-event continual reassessment method escalated dose through four levels, with a 30% targeted rate of dose-limiting toxicity (DLT) measured during the 6 weeks of treatment plus 4 weeks of follow-up. DLTs were defined as confluent moist desquamation > 100 cm2, nonhematologic toxicity grade ≥ 3, toxicity that requires an RT dose delay > 1 week, absolute neutrophil count < 1,000/mm3, platelet count < 50,000/mm3, or hemoglobin < 8.0 g/dL if possibly, probably, or definitely related to study treatment. Results Five DLTs occurred: Four were moist desquamation (two each at 100 and 150 mg twice a day), and one was neutropenia (at 200 mg twice a day). The crude rate of any grade 3 toxicity (regardless of attribution) was 10% at year 1, 16.7% at year 2, and 46.7% at year 3. At year 3, six of 15 surviving patients had severe fibrosis in the treatment field. Conclusion Although severe acute toxicity did not exceed 30% even at the highest tested dose, nearly half of surviving patients demonstrated grade 3 adverse events at 3 years, which underscores the importance of long-term monitoring of toxicity in trials of radiosensitizing agents.

Inflammatory breast cancer (IBC) is a rare and aggressive disease that accounts for ~2-4% of all breast cancers. However, despite its low incidence rate, IBC is responsible for 7-10% of breast cancer-related mortality in Western countries. Thus, the discovery of robust biological targets and the development of more effective therapeutics in IBC are crucial. Despite major international efforts to understand IBC biology, genomic studies have not led to the discovery of distinct biological mechanisms in IBC that can be translated into novel therapeutic strategies. In this Review, we discuss these molecular profiling efforts and highlight other important aspects of IBC biology. We present the intrinsic characteristics of IBC, including stemness, metastatic potential and hormone receptor positivity; the extrinsic features of the IBC tumour microenvironment (TME), including various constituent cell types; and lastly, the communication between these intrinsic and extrinsic components. We summarize the latest perspectives on the key biological features of IBC, with particular emphasis on the TME as an important contributor to the aggressive nature of IBC. On the basis of the current understanding of IBC, we hope to develop the next generation of translational studies, which will lead to much-needed survival improvements in patients with this deadly disease.

National and international experts in inflammatory breast cancer (IBC) from high-volume centers treating IBC recently convened at the 10th Anniversary Conference of the Morgan Welch Inflammatory Breast Cancer Research Program at The University of Texas MD Anderson Cancer Center in Houston Texas. A consensus on the clinical management of patients with IBC was discussed, summarized, and subsequently reviewed. All participants at the conference (patients, advocates, researchers, trainees, and clinicians) were queried using the MDRing electronic survey on key management issues. A summary of the expert consensus and participant voting is presented. Bilateral breast and nodal evaluation, breast magnetic resonance imaging, positron emission tomography/computed tomography, and medical photographs were endorsed as optimal. Neoadjuvant systemic therapy, modified radical mastectomy and level I and II ipsilateral axillary node dissection, post-mastectomy radiotherapy, adjuvant targeted therapy and hormonal therapy as indicated, and delayed reconstruction were agreed-upon fundamental premises of standard non-protocol-based treatment for IBC. Consideration for local-regional therapy in de novo stage IV IBC was endorsed to provide local control whenever feasible. Variation across centers and special circumstances were discussed.

Controversy exists regarding the role of locoregional therapy for stage IV inflammatory breast cancer (IBC). This study aims to determine indicators of prognosis, including primary tumor resection, for stage IV IBC patients. Using the National Cancer Data Base, female patients diagnosed 2010–2013 with unilateral a priori metastatic T4d invasive adenocarcinoma of the breast were identified. We conducted propensity score matched analysis to balance confounders of surgery versus no-surgery. Stratified log-rank test and double-robust estimation under the Cox model were used to assess the effect of surgery, and margins, on overall survival (OS) in the propensity score matched cohort. Of 1266 patients, 41% underwent surgery. In the unmatched cohort, median OS of the surgery and no-surgery groups was 36 and 20 months, respectively (p

Background Most inflammatory breast cancer (IBC) patients have axillary disease at presentation. Current standard is axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NACT). Advances in NACT have improved pathologic complete response (pCR) rates increasing interest in performing sentinel lymph node (SLN) biopsy (SLNB). Previous studies on SLNB for IBC patients did not assess nodal response with imaging or use dual tracer mapping. We sought to prospectively determine false negative rates of SLNB in IBC patients using dual tracer mapping, and to correlate pathology with preoperative axillary imaging. Patients and Methods Patients with IBC were prospectively enrolled. Patients underwent axillary staging with physical examination and axillary ultrasound before and after NACT. All patients underwent SLNB using blue dye and radioisotope, followed by ALND. Results Sixteen patients were prospectively enrolled. Clinical N stage was N0 in 1 patient, N1 in 8, and N3 in 7. SLN mapping was successful in only 4 patients (25%) with 12 (75%) not draining either tracer to a SLN. Three of the 4 (75%) who mapped had an axillary pCR. The patient who mapped but did not have an axillary pCR had a positive SLNB with additional axillary nodal disease identified on ALND. All patients who successfully mapped had presumed residual nodal disease on preoperative axillary ultrasound. Conclusion SLNB was unsuccessful in most IBC patients. A small subset who have pCR might undergo successful SLNB, but preoperative axillary imaging failed to identify these patients. ALND should remain standard practice for IBC patients.

The purpose of this narrative review is to summarize the contributors to misdiagnosis or delayed diagnosis of inflammatory breast cancer (IBC) and strategies for expedient diagnosis.Patients with IBC often report the disease as initially being misdiagnosed, most commonly as mastitis.We reviewed the literature on this challenging diagnosis by using sequential PubMed search criteria including IBC breast symptoms, IBC diagnosis, and IBC imaging modalities to augment the authors' knowledge of IBC. Other references were added from the manuscripts identified in the PubMed searches and from manuscript reviewers.Several factors contribute to the delayed diagnosis of IBC. One important factor is that IBC is uncommon, and many generalists may not be aware of it in the differential diagnosis of breast skin symptoms. Several features of IBC contribute to the low sensitivity of mammography for its detection, and so the diagnosis is based on clinical factors and is thereby subjective. The presentation can be highly varied; classic textbook images that do not capture the range of presenting signs and symptoms across skin tones may contribute to missed diagnoses in patients with atypical presentations. In fact, the staging system of the American Joint Committee on Cancer, which requires erythema of the breast skin for diagnosis, may exclude patients with obvious global breast skin findings that are not explicitly red. We present an adapted algorithm for working up the undiagnosed inflammatory breast to ensure the timely and accurate diagnosis of IBC. We assert that frank, non-erythematous global skin signs in an enlarged breast with diffuse breast malignancy are sufficient to diagnose IBC if the timing of these signs and findings on biopsy are consistent. We further provide images of atypical IBC identified by global breast skin signs, including peau d'orange, consistent with IBC in the absence of frank erythema.

Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are medications that have been used for decades to lower cholesterol and to prevent or treat cardiovascular diseases. Since their approval by the US Food and Drug Administration in the 1980s, other potential uses for statins have been speculated on and explored. Basic science and clinical research suggest that statins are also effective in the management of breast cancer. Specifically, in various breast cancer cell lines, statins increase apoptosis and radiosensitivity, inhibit proliferation and invasion, and decrease the metastatic dissemination of tumors. Clinical trials in breast cancer patients support these laboratory findings by demonstrating improved local control and a mortality benefit for statin users. A role for statins in the management of aggressive breast cancers with poor outcomes - namely, inflammatory breast cancer and triple-negative breast cancer - is particularly implicated. However, data exist showing that statins may actually promote invasive breast disease after long-term use and thus should be prescribed cautiously. Furthermore, a general consensus on the type of statin that should be administered, for how long, and when in relation to time of diagnosis is lacking. Given their low toxicity profile, affordability, and ease of use, consideration of statins as a therapy for breast cancer patients is imminent. In this review, we summarize current evidence regarding statins and clinical breast cancer outcomes, as well as discuss potential future studies that could shed light on this increasingly relevant topic.

PURPOSE/OBJECTIVE(S) To report outcomes for women with pT1-2N1M0 breast cancer undergoing mastectomy and sentinel lymph node biopsy (SLNB) without completion axillary dissection, and to investigate the effect of post-mastectomy radiation therapy (PMRT). MATERIALS/METHODS Data from 5 North American institutions were pooled to include women with pT1-2N1M0 breast cancer from 1997-2015 who underwent mastectomy with a positive SLNB and ≤ 5 lymph nodes (LNs) resected. All patients were clinically N0 and none received neoadjuvant chemotherapy. Competing-risks regression was performed to identify factors associated with overall recurrence (OR), inclusive of locoregional (LR) and distant recurrence (DM). RESULTS Among 871 patients included, median age at diagnosis was 57 years, 92% were ER/PR-positive, 85% HER2-negative, and 60% received adjuvant chemotherapy. The 500 (57%) patients who received PMRT were significantly younger, had larger tumors, more positive LN, lymphovascular invasion (LVI), extracapsular extension (ECE), HER2-positive disease, and more frequently received adjuvant chemotherapy (all P < 0.05) compared to those not receiving PMRT. Median number of lymph nodes sampled in each group was 3 (range: 1-5). At a median follow up of 5.2 years, the 5-year cumulative incidence rates of LR, DM, OR, and breast cancer mortality (BCM) were 2%, 4%, 5%, and 3%, respectively. The 5-year rates of disease-free survival (DFS) and overall survival (OS) were 87% and 91%. LR was the only endpoint with a statistically significant difference between those receiving PMRT (0.4%) as compared to those without PMRT (3.9%), P < 0.001. On univariable competing risks regression, tumor size, nodal ratio, grade, LVI, and ER/PR status were significantly associated with OR and were included in multivariable analysis. On multivariable competing risks regression, larger tumor size (HR 1.47, 95% CI 1.19-1.81, P < 0.001), grade III (HR 1.81, 95% CI 1.07-3.05, P = 0.03), higher nodal ratio (HR 2.86, 95% CI 1.01-7.69, P = 0.049), and LVI (HR 2.04, 95% CI 1.27-3.28, P = 0.003) were significantly associated with increased risk of OR. PMRT was associated with decreased risk of OR (HR 0.60, 95% CI 0.26-1.00, P = 0.05), though this effect did not reach statistical significance. CONCLUSION In selected patients undergoing mastectomy and SLNB without completion axillary dissection for pT1-2N1 breast cancer, larger tumor size, higher grade, increased nodal ratio and the presence of LVI are associated with increased risk of overall recurrence. Further studies are needed to identify which subset of patients may benefit most from PMRT.

Purpose/Objective(s) Breast cancer patients with clinical N3c (cN3c) disease at diagnosis have poor outcomes relative to other breast cancer patients. Radiotherapy (RT) has an important role in the management of these patients as the supraclavicular (SCV) nodes are not routinely surgically dissected. However, outcomes and prognostic factors in the era of modern neoadjuvant chemotherapy (NAC) are not well-described. Materials/Methods We reviewed breast cancer patients with non-metastatic cN3c disease treated at our institution from 2014-2019 with curative intent NAC, surgery, and adjuvant RT. All patients received nodal RT including the SCV, infraclavicular, and internal mammary nodes. Institutional guidelines recommend a 10 Gy boost to clinically resolved N3 nodal basins and 16 Gy to unresolved N3 nodes. Variables including initial and boost dose, pathologic response, and type of nodal dissection were collected. Local (LC) and regional control (RC), freedom from distant metastases (FFDM), and overall survival (OS) were analyzed with the Kaplan Meier method. A saturated multivariable Cox proportional hazards model of OS with backward elimination identified clinical variables associated with OS at P Results A total of 176 consecutive patients were analyzed. The median follow-up time was 2.83 years. The median age was 54 years, 76 (43%) were ER+/HER2-, 20 (11%) ER+/HER2+, 26 (15%) ER-/HER2+, and 54 (31%) ER-/HER2-. 102 (57%) had T3/4 disease, 41 (23%) underwent lumpectomy, 142 (81%) had pathologic confirmation of N3c, and 10 (6%) had a neck dissection. The median initial radiation dose was 50 Gy (range, 44-56.25), SCV boost 10 Gy (range, 6-16), and 156 (89%) received cumulative SCV dose ≥60 Gy. The 3-year OS, FFDM, RC, and LC were 79%, 64%, 93%, and 96%, respectively. For cumulative SCV dose of ≥60 Gy vs. Conclusion In a large, modern cohort of non-metastatic cN3c breast cancer patients treated with multimodality therapy, cumulative SCV dose ≥60 Gy was found to be associated with improved OS. Although optimal radiation dosing cannot be established from this data, a SCV radiation boost should be considered in cN3c patients treated with curative intent respecting normal tissue constraints.

Background We conducted a prospective phase II study to examine the response rate of gross chemo-refractory breast cancer treated with concurrent capecitabine (CAP) and radiotherapy (RT). Methods Breast cancer patients with inoperable disease after chemotherapy, residual nodal disease after definitive surgical resection, unresectable chest wall or nodal recurrence after a prior mastectomy, or oligometastatic disease were eligible. Response by RECIST criteria was assessed after 45Gy. Conversion to operable (CTO), locoregional control, and grade>3 toxicities were assessed. The first nine patients received CAP 825 mg/m 2 BID continuously. Due to toxicity, subsequent patients received CAP only on radiation days. Kaplan-Meier analysis was used to estimate overall survival (OS) and locoregional recurrence-free survival (LRFS). Results From 2009-2012, 32 patients were accrued; 26 received protocol-specified treatment. Median follow-up was 12.9 months (interquartile range 7.1–42.9). Nineteen patients (73%) had partial or complete response. Fourteen patients (53.9%) experienced grade 3 non-dermatitis toxicity (7/9 continuous dosing). Three/four inoperable patients converted to operable. One-year actuarial OS in the treated cohort was 54%. The trial was stopped early after interim analysis suggested futility independent of response. Treatment was deemed futile (i.e., CTO but M1 disease immediately post-op) in 9/10 patients with triple-negative (TN) versus 6/16 with non-TN disease (p=0.014). Median OS and 1-yr LRFS among non-TN vs. TN patients was 22.8 vs. 5.1 months, and 63% vs. 20% (p=0.007). Conclusions Capecitabine can be safely administered on radiation days with careful clinical monitoring and was associated with encouraging response in this chemo-refractory cohort. However, patients with TN breast cancer had poor outcomes even when response was achieved. Further study in non-TN patients may be warranted.

Purpose To determine the associated toxicity, tolerance, and safety of partial-breast reirradiation. Methods and Materials Eligibility criteria included in-breast recurrence occurring >1 year after whole-breast irradiation, Results Between 2010 and 2013, 65 patients were accrued, and the first 55 eligible and with 1 year follow-up were analyzed. Median age was 68 years. Twenty-two patients had ductal carcinoma in situ, and 33 had invasive disease: 19 ≤1 cm, 13 >1 to ≤2 cm, and 1 >2 cm. All patients were clinically node negative. Systemic therapy was delivered in 51%. All treatment plans underwent quality review for contouring accuracy and dosimetric compliance. All treatment plans scored acceptable for tumor volume contouring and tumor volume dose-volume analysis. Only 4 (7%) scored unacceptable for organs at risk contouring and organs at risk dose-volume analysis. Treatment-related skin, fibrosis, and/or breast pain AEs were recorded as grade 1 in 64% and grade 2 in 7%, with only 1 ( Conclusion Partial-breast reirradiation with 3-dimensional conformal radiation therapy after second lumpectomy for patients experiencing in-breast failures after whole-breast irradiation is safe and feasible, with acceptable treatment quality achieved. Skin, fibrosis, and breast pain toxicity was acceptable, and grade 3 toxicity was rare.

// Xiaoping Wang 1, 2, 3, * , Monica E. Reyes 1, 2, 3, * , Dongwei Zhang 1, 2, 3, * , Yohei Funakoshi 1, 2, 3 , Adriana P. Trape 1, 2, 3 , Yun Gong 1, 4 , Takahiro Kogawa 1, 2, 3 , Bedrich L. Eckhardt 1, 2, 3 , Hiroko Masuda 1, 2, 3 , David A. Pirman Jr 5 , Peiying Yang 6 , James M. Reuben 1, 7 , Wendy A. Woodward 1, 8 , Chandra Bartholomeusz 1, 2, 3 , Gabriel N. Hortobagyi 3 , Debu Tripathy 3 and Naoto T. Ueno 1, 2, 3 1 Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 6 Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 7 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 8 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA * These authors contributed equally to this work Correspondence to: Naoto T. Ueno, email: nueno@mdanderson.org Xiaoping Wang, email: xiwang@mdanderson.org Keywords: inflammatory breast cancer, EGFR, COX-2, nodal, cancer stem-like cells Received: October 19, 2016 Accepted: June 17, 2017 Published: July 04, 2017 ABSTRACT Inflammatory breast cancer (IBC) is the most lethal and aggressive type of breast cancer, with a strong proclivity to metastasize, and IBC-specific targeted therapies have not yet been developed. Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in IBC. However, the mechanism behind the therapeutic effect of EGFR targeted therapy is not well defined. Here, we report that EGFR regulates the IBC cell population that expresses cancer stem-like cell (CSC) markers through COX-2, a key mediator of inflammation whose expression correlates with worse outcome in IBC. The COX-2 pathway promoted IBC cell migration and invasion and the CSC marker-bearing population in vitro , and the inhibition of this pathway reduced IBC tumor growth in vivo . Mechanistically, we identified Nodal, a member of the TGFβ superfamily, as a potential driver of COX-2-regulated invasive capacity and the CSC phenotype of IBC cells. Our data indicate that the EGFR pathway regulates the expression of COX-2, which in turn regulates the expression of Nodal and the activation of Nodal signaling. Together, our findings demonstrate a novel connection between the EGFR/COX-2/Nodal signaling axis and CSC regulation in IBC, which has potential implications for new combination approaches with EGFR targeted therapy for patients with IBC.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that is defined by negative estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Treating patients with TNBC remains clinically challenging, as patients are not candidates for endocrine or HER2-directed therapy. As a result, chemotherapy with traditional agents such as anthracyclines and taxanes remains the only available option with moderate success. Recent discoveries have revealed that TNBC is a heterogeneous disease at the clinical, histological and molecular levels. The use of biomarkers to identify distinct subsets of TNBC that derive the greatest benefit from presently approved as well as novel therapeutics has become the main focus of current research. The aim of this review is to explore the clinical and biological complexity of TNBC as well as identify novel therapeutic options that target the various molecular subsets of TNBC.

Purpose: The role of regional nodal irradiation (RNI) for patients with breast cancer remains controversial, particularly on the basis of nodal involvement. Using the National Cancer Database, we aimed to validate published data on whether expanding treatment fields from whole-breast irradiation (WBI) to encompass the regional nodes (WBI+RNI) affected overall survival (OS) for patients with node-positive (pN1-3) or high-risk node-negative (pN0) breast cancer treated with breast-conserving surgery and adjuvant chemotherapy. Methods and materials: Women diagnosed with invasive breast cancer between 2004 and 2012 who met the selection criteria for the National Cancer Institute of Canada MA.20 trial were identified and stratified by receipt of RNI. Propensity score matching was used to compare 1:1 matched pairs of patients. Five-year OS was estimated using the Kaplan-Meier method. We used multivariate logistic regression to predict receipt of WBI+RNI and a multivariable Cox model to examine associations between patients' demographic, tumor, and treatment characteristics and OS using double robust estimation. Results: Of 23,567 patients, 6,920 (29%) received WBI+RNI and 16,647 (71%) WBI. Median follow-up was 56 months. Use of WBI+RNI increased from 25.2% in 2004 to 32.2% in 2012 (P 1 involved node, and were not privately insured. For all patients, the 5-year OS rates were 90.8% with WBI+RNI versus 92.6% with WBI (P < .001). In the matched cohort (n = 10,922), the corresponding 5-year OS rates were 92% and 91.9% (P = .45), respectively. On multivariate analysis, WBI+RNI did not affect OS in the matched cohort (hazard ratio, 1.02; 95% confidence interval, 0.89-1.17, P = .76), regardless of pathologic nodal status. Conclusions: In this large retrospective analysis, use of WBI+RNI did not affect 5-year OS rates for women with high-risk, early stage breast cancer undergoing breast-conserving surgery and adjuvant chemotherapy, regardless of nodal status, which confirms the findings of the MA.20 trial.

Summary In the absence of histological criteria that distinguish between inflammatory and non-inflammatory breast cancer, diagnosis of inflammatory breast cancer relies entirely on the existence of clinical criteria as outlined by the TNM classification. This classification restricts patients presenting with clinical criteria characteristic of inflammatory breast cancer to subcategory T4d, which immediately relegates all patients with non-metastatic inflammatory breast cancer to stage 3, regardless of tumour size or nodal spread. Patients who present with metastatic disease are consigned to stage 4, and the TNM classification does not distinguish patients on the basis of the presence of inflammatory criteria. Evidence by our group and others suggests that patients with inflammatory breast cancer have significantly reduced overall survival among those who present with distant metastasis at diagnosis (stage 4). In light of these results, this Personal View addresses whether the current TNM staging classification accurately represents a distinction between patients with inflammatory and those with non-inflammatory breast cancer.

BACKGROUND Guidelines for the treatment of nonmetastatic inflammatory breast cancer (IBC) using trimodality therapy (TT) (chemotherapy, surgery, and radiotherapy) have remained largely unchanged since 2000. However, many patients with nonmetastatic IBC do not receive TT. It is unknown how patient-level (PL) and facility-level (FL) factors contribute to TT use. METHODS Using the National Cancer Data Base, patients with nonmetastatic IBC who underwent locoregional treatment from 2003 through 2011 were identified. The authors correlated PL factors, including demographic and tumor characteristics, with TT use. An observed-to-expected ratio for the number of patients treated with TT was calculated for each hospital by adjusting for significant PL factors. Hierarchical mixed effects models were used to assess the percentage of variation in TT use attributable to PL and FL factors, respectively. RESULTS Of the 542 hospitals examined, 55 (10.1%) and 24 (4.4%), respectively, were identified as significantly low and high outliers for TT use (P

Background In patients with triple-negative breast cancer (TNBC), tumor-infiltrating lymphocytes (TILs) have been reported to be associated with improved survival. Lehmann et al. identified 6 molecular subtypes of TNBC [basal-like (BL) 1, BL2, mesenchymal (M), mesenchymal stem like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR)], and we previously reported that TNBC subtype is a predictor of pathologic complete response (pCR). Recently, the IM gene expression signature has been shown to be indicative of the presence of TILs and has been incorporated into TNBC subtyping as a modifier of the other groups rather than a separate subtype. However, the association between TNBC subtype and the presence of TILs is not known. We hypothesized that the BL2 and LAR subtypes, which have low pCR rates, have low rates of immune infiltration. Inflammatory breast cancer (IBC) is an aggressive cancer that is frequently triple-negative. The association between IBC and the presence of TILs also is not known. In this study, we analyzed the association between TNBC molecular subtype and the IM signature and determined whether the IM signature differed between patients with IBC and non-IBC. Methods We retrospectively analyzed 88 patients with TNBC from the World IBC Consortium dataset for whom IBC status was known (IBC, n=39; non-IBC, n=49) and tumor gene expression data were available. TNBC specimens were classified using the TNBCtype algorithm (Insight Genetics, Inc., TN, USA), which uses a 101-gene signature. For each tumor, the TNBCtype algorithm reports the TNBC molecular subtype (BL1, BL2, M, MSL, or LAR) and the IM status, which is described as positive (IM+) or negative (IM-). Recently, Fisher's exact test was used to analyze differences in subtype distribution between the IM+ and IM- tumors. Results The subtype distribution differed significantly between the IM+ and IM- tumors IM signature in TNBC subtypesSubtypeTotal (n=88)IM+ (n=32)IM- (n=56)BL13015 (50)15 (50)BL2202 (100)M808 (100)MSL3113 (42)18 (58)LAR121 (8)11 (92)Not determined53 (60)2 (40) (p=0.0087). The majority of IM+ cases occurred in the BL1 and MSL subtypes. No IM+ cases were observed in the BL2 or M subtypes, and only 1 was observed in the LAR subtype. IM+ cases occurred at roughly the same frequency in patients with IBC (33%) and non-IBC (37%, p=0.73). Conclusions TNBC molecular subtypes differ in their degree of immune infiltration, and most IM+ TNBCs are of the BL1 and MSL subtypes. Our finding that the proportion of IM+ cases was not different between IBC and non-IBC indicates that TILs are recruited to the tumor microenvironment similarly in IBC and non-IBC tumors. Further, Pietenpol et al recently showed that the MSL signature represents normal stromal cells rather than tumor cells by performing laser-capture microdissection of TNBC specimen. Validation studies are needed to corroborate and further expand upon our findings. Citation Format: Harano K, Wang Y, Lim B, Seitz RS, Morris SW, Bailey DB, Hout DR, Skelton RL, Ring BZ, Masuda H, Rao AUK, Woodward WA, Reuben JM, Ueno NT. Rates of immune infiltration in patients with triple-negative breast cancers by molecular subtype and in patients with inflammatory and non-inflammatory breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-14.

Purpose: Breastfeeding alters the breast microenvironment, and several lines of evidence suggest the breast microenvironment contributes to the clinical phenotype of inflammatory breast cancer. We investigated breastfeeding history as a modifier of locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) in parous women with inflammatory breast cancer. Methods: Parous women with inflammatory breast cancer were identified from a prospective registry at The University of Texas MD Anderson Cancer Center. We compared patient and tumor characteristics, LRR, DM, DFS, and OS patients with (BF+) and without (BF-) a history of breastfeeding. Results: Eighty-two patients were included. At a median follow-up of 50 months, BF+ patients had significantly lower risk of LRR (9.0% vs. 23.6%; p=0.01), a lower risk of DM (26.8% vs. 53.8%; p=0.008), and better DFS (73.1% vs. 48.1%; p=0.006) than BF- patients. On multivariate analysis, BF+ history was associated with significantly lower risk of DM (hazard ratio 0.38, 95% confidence interval 0.15-0.97; p=0.04) and better DFS (hazard ratio 0.37, 95% confidence interval 0.15-0.93; p=0.04) after adjusting for established predictive and prognostic variables. The prognostic significance of breastfeeding may be most pronounced in women with triple-negative IBC. Conclusion: A lack of breastfeeding history in parous women with inflammatory breast cancer may predict worse prognosis. We speculate that breastfeeding-induced alterations in the breast microenvironment may alter the aggressiveness of inflammatory breast cancer.

Recent published guidelines suggest that adequate margins for DCIS should be ≥ 2 mm after breast conserving surgery followed by radiotherapy (RT). Many groups now use this guideline as an absolute indication for additional surgery. This article describes detailed multidisciplinary practices including extensive preoperative/intraoperative pathologic/histologic image-guided assessment of margins, offering some patients with small low/intermediate grade DCIS no RT, the use/magnitude of radiation boost tailoring to margin width, and endocrine therapy for ER-positive DCIS. Use of these protocols over the past 20-years has resulted in 10-year local recurrence rates below 5% for patients with negative margins < 2 mm who received RT. Patients with margins < 2 mm who do not receive RT experience significantly higher local failure rates. Thus, there is not an absolute need to achieve wider negative surgical margins when < 2 mm for patients treated with RT and this should be determined by the multidisciplinary team. Utilization of these multidisciplinary treatment protocols and techniques may not be exportable and extrapolated to all hospitals, breast programs and systems as they can be complex and resource intensive.

International audience; In 2006, a remarkable collaboration between University of Texas MD Anderson Cancer Center clinicians andTexas and New Mexico State legislators led to the formation of a dedicated IBC Research Program and Clinicat MD Anderson. This initiative provided funding and infrastructure to foster coordination of an IBC WorldConsortium of national and international experts, and launch the first ever IBC international conference in2008, which brought together experts from around the world to facilitate collaborations and accelerateprogress. Indeed great progress has been made since then. National and international experts in IBCconvened at the 10th Anniversary Conference of the MD Anderson IBC Clinic and Research Program andpresented the most extensive sequencing analysis to date comparing IBC to non-IBC, gene- andprotein-based immunoprofiling of IBC versus non-IBC patients, and converging lines of evidence on thespecific role of the microenvironment in IBC. Novel models, unique metabolic mechanisms, and prominentsurvival pathways have been identified and were presented. Multiple clinical trials based on the work of thelast decade are in progress or in development. The important challenges ahead were discussed. This progressand a coordinated summary of these works are presented herein.

Background: Patients who have TNBC or triple negative-IBC (TN-IBC) and do not achieve pathological complete response after neoadjuvant chemotherapy are at significant risk for distant relapse and death from recurrent disease. Apart from capecitabine, there are no proven adjuvant therapies that may improve these poor outcomes of patients with chemo-resistant tumors. Therefore, there is an unmet need for effective systemic therapy for this subset of patients with TNBC. Epidemiological evidence reveals that statin use after diagnosis is associated with improved breast cancer relapse-free survival and decreased mortality. However, direct evidence of in vivo mechanisms explaining this association are lacking. Preclinical studies using statins in breast cancer reveal pathways that statins can inhibit proliferation, stem cell self-renewal and metastatic potential. Trial Design: This is a pilot study designed in 2 phases to assess feasibility of completion while providing a signal of efficacy in biomarker changes. In the first phase, we will follow the initial 30 patients who meet eligibility for atorvastatin treatment for the 2-year treatment window, or until disease recurrence. We will collect blood samples prior to, and during atorvastatin treatment for circulating tumor cells (CTCs), cytokine and inflammatory biomarker analyses. We defined a positive outcome as CTCs remaining non-detected at 6 months when baseline CTC is undetected, or a reduction in the number of CTCs at 6 months compared to baseline. If we observe a positive outcome among the initial 30 patients, then we will open the second phase of this study for an additional 50 patients. Here we will follow both patient cohorts who receive and not receive atorvastatin treatment to collect longitudinal data on biomarkers as a function of the natural history of TNBC to better understand the activity of atorvastatin. Trial Eligibility: Patients with stage II-III TNBC who have residual cancer burden (RCB)-II or RCB-III or stage 3 TN-IBC with any amount of residual disease, and are not taking a statin or any other anti-lipidemic agent are candidates for the study. Patients must have adequate hematologic, organ, and cardiac function and must have recovered from the acute effects of any prior treatments. Baseline lipid profile will be assessed by a cardiologist to determine the patients’ eligibility to take atorvastatin based on current ACC/AHA guideline, and to select between moderate (20mg) or high intensity treatment (40mg). Specific Aims: The primary objective is to determine the proportion of patients with undetectable CTCs at 6 months with and without atorvastatin therapy. Secondary objectives include correlation of baseline lipid profiles/lipid profile changes with 2 year-relapse free survival (RFS), CTC counts and inflammatory biomarkers. Statistical Methods: The total estimated enrollment is 80 patients, including at least 5 treated with adjuvant capecitabine and at least 5 without adjuvant capecitabine. The study overall is powered with the assumption that 48 patients will receive atorvastatin and 32 will not, and this will allow us to estimate the percent of patients with negative CTCs at 6 months with a standard error not larger than 7% and 9%, respectively. All other analyses including inflammatory biomarkers and RFS differences between groups are exploratory and considered hypothesis-generating rather than conclusive. Citation Format: Angela Alexander, Takeo Fujii, Michael C Stauder, Wendy A Woodward, James M Reuben, Yu Shen, Diane Liu, Sangeetha M Reddy, Vicente Valero, Susan C Gilchrist, Bora Lim, Anthony Lucci, Naoto T Ueno, Carlos H Barcenas. A pilot study to examine the feasibility of measuring CTC and inflammatory biomarker changes resulting from atorvastatin as adjuvant therapy in TNBC and TN-IBC patients with residual disease after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-02-02.

Background: The American Joint Committee on Cancer (AJCC) recently updated its breast cancer staging system to incorporate biological factors, including estrogen and progesterone receptor (ER, PR), and HER2 status, in the new “prognostic stage” in addition to the traditional TNM anatomic stage. For the clinical anatomic staging, IBCs are classified at T4d; N0-2 as IIIB; and N3 as IIIC. For the clinical prognostic staging, ER+/PR+/HER2+/grade1-2 staged as IIIA; ER+/PR-/HER2-/grade3, ER-/PR+/HER2-/grade3, and all triple-negative cancers staged as IIIC; and all others as IIIB. We undertook this study to validate the clinical prognostic and anatomic stages for inflammatory breast cancer (IBC), an aggressive subgroup. The prognostic staging system, which was developed using non-IBC data, has not been validated in IBC. Methods: We established two cohorts of IBC patients diagnosed without distant metastasis: (1) patients treated at MD Anderson Cancer Center between 1989 and 2017 (MDA-cohort) and (2) patients registered in the SEER database between 2010 and 2015 (SEER-cohort). Survival endpoints including overall survival (OS), and disease-free survival (DFS) were calculated by the Kaplan-Meier method. Breast cancer-specific survival (BCSS) was calculated by the competing risk analysis. The log-rank test was used to compare differences in endpoints between staging groups. The Harrell concordance index (C index) was used to quantify staging models’ predictive performance. A higher C index indicates a better predictive performance. Results: We studied 885 patients in the MDA cohort and 338 in the SEER cohort. In the MDA cohort, the prognostic stage upstaged 248 patients (28%) and downstaged 146 (16%) comparing with the anatomic stage. The prognostic stage showed significant predictive power for BCSS, OS, and DFS (all P Conclusions: The prognostic stage incorporating biological factors provided more accurate prognostication for IBC patients than the anatomic stage. Our results show that the 8th edition AJCC prognostic staging system is optimal for prognostification in IBC. Citation Format: Kumiko Kida, Kenneth R Hess, Bora Lim, Toshiaki Iwase, Sudpreeda Chainitikun, Maryanne E Sapon, Vicente Valero, Anthony Lucci, Carisa Le-Petross, Wendy A Woodward, Savitri Krishnamurthy, Gabriel N Hortobagyi, Debu Tripathy, Naoto T Ueno. Validation of prognostic stage and anatomic stage in the American joint committee on cancer 8th edition for inflammatory breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-10.

New indications have been found for regional nodal irradiation (RNI) in breast cancer treatment, yet the relationship of RNI and lymphedema risk is uncertain. We sought to determine the association of RNI and lymphedema. We searched MEDLINE, EMBASE, and Scopus for articles in English on humans published from 1995 to 2015, using search terms breast neoplasm, treatment, and morbidity. Two investigators independently selected articles and extracted information, including manuscripts reporting incidence of lymphedema by radiation targets. Meta-analyses, review papers, case–control studies, matched-pair studies, repetitive datasets, and retrospective studies were excluded. A total of 2399 abstracts were identified and 323 corresponding articles reviewed. Twenty-one studies met inclusion criteria. Data were pooled using a random effects mixed model. Network meta-analyses were performed to determine the association of radiation targets alone and radiation targets plus extent of axillary surgery on incidence of lymphedema. The addition of RNI to breast/CW irradiation was associated with an increased incidence of lymphedema (OR 2.85; 95% CI 1.24–6.55). In patients treated with sentinel lymph node biopsy or axillary sampling, there was no association of lymphedema with the addition of RNI to breast/CW irradiation (OR 1.58; 95% CI 0.54–4.66; pooled incidence 5.7 and 4.1%, respectively). Among patients treated with axillary lymph node dissection (ALND), treatment with RNI in addition to breast/CW radiation was associated with a significantly higher risk of lymphedema (OR 2.74; 95% CI 1.38–5.44; pooled incidence 18.2 and 9.4%, respectively). RNI is associated with a significantly higher risk of lymphedema than irradiation of the breast/CW, particularly after ALND.

The advent of affordable and rapid next-generation DNA sequencing technology, along with the US Supreme Court ruling invalidating gene patents, has led to a deluge of germline and tumor genetic variant tests that are being rapidly incorporated into clinical cancer decision-making. A major concern for clinicians is whether the presence of germline mutations may increase the risk of radiation toxicity or secondary malignancies. Because scarce clinical data exist to inform decisions at this time, the American Society for Radiation Oncology convened a group of radiation science experts and clinicians to summarize potential issues, review relevant data, and provide guidance for adult patients and their care teams regarding the impact, if any, that genetic testing should have on radiation therapy recommendations. During the American Society for Radiation Oncology workshop, several main points emerged, which are discussed in this manuscript: (1) variants of uncertain significance should be considered nondeleterious until functional genomic data emerge to demonstrate otherwise; (2) possession of germline alterations in a single copy of a gene critical for radiation damage responses does not necessarily equate to increased risk of radiation-induced toxicity; (3) deleterious ataxia-telangiesctasia gene mutations may modestly increase second cancer risk after radiation therapy, and thus follow-up for these patients after indicated radiation therapy should include second cancer screening; (4) conveying to patients the difference between relative and absolute risk is critical to decision-making; and (5) more work is needed to assess the impact of tumor somatic alterations on the probability of response to radiation therapy and the potential for individualization of radiation doses. Data on radiosensitivity related to specific genetic mutations is also briefly discussed.

Background Inflammatory breast cancer (IBC) is a rare yet aggressive variant of breast cancer with a high recurrence rate. We hypothesized that patterns of metastasis differ between IBC and non-IBC. We focused on the patterns of bone metastasis throughout disease progression to determine statistical differences that can lead to clinically relevant outcomes. Our primary outcome of this study is to quantify and describe this difference with a view to applying the findings to clinically relevant outcomes for patients. Subjects, Materials, and Methods We retrospectively collected data of patients with nonmetastatic IBC (n = 299) and non-IBC (n = 3,436). Probabilities of future site-specific metastases were calculated. Spread patterns were visualized to quantify the most probable metastatic pathways of progression and to categorize spread pattern based on their propensity to subsequent dissemination of cancer. Results In patients with IBC, the probabilities of developing bone metastasis after chest wall, lung, or liver metastasis as the first site of progression were high: 28%, 21%, and 21%, respectively. For patients with non-IBC, the probability of developing bone metastasis was fairly consistent regardless of initial metastasis site. Conclusion Metastatic patterns of spread differ between patients with IBC and non-IBC. Selection of patients with IBC with known liver, chest wall, and/or lung metastasis would create a population in whom to investigate effective methods for preventing future bone metastasis. Implications for Practice This study demonstrated that the patterns of metastasis leading to and following bone metastasis differ significantly between patients with inflammatory breast cancer (IBC) and those with non-IBC. Patients with IBC had a progression pattern that tended toward the development of bone metastasis if they had previously developed metastases in the liver, chest wall, and lung, rather than in other sites. Selection of patients with IBC with known liver, chest wall, and/or lung metastasis would create a population in whom to investigate effective methods for preventing future bone metastasis.

Purpose Inflammatory breast cancer (IBC) has been characterized by high locoregional recurrence (LRR) rates even after trimodality therapy. We recently reported excellent locoregional control among patients treated since formal dedication of an IBC-specific clinic and research program in 2006. Institutionally, a standard twice-daily (BID) dose escalation regimen for all patients with IBC was de-escalated in select cases in 2006 after review demonstrated that young age, incomplete response to neoadjuvant therapy, and positive margins identified subsets with maximal benefit from dose escalation. We report local control and toxicity rates specific to BID versus once-daily (QD) radiation therapy approaches. Methods and Materials From a prospectively collected database, we identified 103 patients with nonmetastatic IBC who received trimodality therapy at our institution from 2007 to 2015. Descriptive statistics were used to describe the study cohort and compare retrospectively extracted rates of radiation therapy–associated toxicity. The actuarial rate of LRR-free survival was analyzed using the Kaplan-Meier method. Results The median follow-up is 3.6 years. Thirty-nine patients (37.9%) received postmastectomy radiation therapy (PMRT) to the chest wall and undissected regional lymphatics in QD fractions (median dose, 50.0 Gy in 25 fractions [fx]; median boost dose, 10.0 Gy in 5 fx) and 64 patients (62.1%) received BID PMRT (median dose, 51.0 Gy in 34 fx; median boost dose, 15.0 Gy in 10 fx). Crude rates of toxicity were not different between patients treated with QD or BID PMRT. Two BID patients (3.1%) and no QD patients (0.0%) experienced LRR (P = .53). The 3- and 5-year LRR-free survival were 95.1% and 100.0% for BID and QD patients, respectively (P = .25). Conclusions Tailoring radiation therapy to clinical risk factors was associated with excellent locoregional control. De-escalation of PMRT from BID to QD was not clearly associated with reduced toxicity compared with BID, although retrospective data collection may limit this comparison.

523 Background: Statins have been shown to target pathways related to breast cancer carcinogenesis, specifically in more aggressive breast cancer subtypes such as triple negative breast cancer (TNBC). Given the limited toxicity profile, low cost, and ease of use of statins, an association between statin therapy and improved breast cancer outcomes, particularly in aggressive breast cancers with more limited treatment options, could have important public health implications. Here we examine the association of statin therapy with breast cancer outcomes in women with stage I-III breast cancer, specifically TNBC. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER)-Medicare and Texas Cancer Registry (TCR)-Medicare data. We included women age 66 years or older with histologically confirmed stage I-III breast cancer diagnosed from 2008-2015. We used multivariable Cox proportional hazards regression models to examine the association of statin use with overall survival (OS) and breast cancer specific survival (BCSS) adjusting for age, race, education, state buy-in, residence area, stage, subtype, endocrine therapy, radiation, chemotherapy, surgery, baseline statin use, comorbidity, and baseline hypertension. For BCSS, we accounted for the competing risk of death using the Fine and Grey method. We required all individuals to survive until 12 months post-diagnosis, which we defined as the start of the follow-up period, to account for immortal time bias. Results: We identified 45,063 patients with stage I-III breast cancer meeting inclusion criteria, out of which 22,518 (50.0%) received a statin within one year following diagnosis (statin-users). The 5-year cumulative estimates of breast cancer specific deaths were 5.9% and 6.9% for statin-users and non-users (P

Background: IBC is considered a clinical diagnosis characterized by rapid onset of diffuse skin changes in the setting of a breast cancer diagnosis. A wide variety of visual changes are accurately diagnosed as IBC. Here, we sought to determine whether the most subjectively “classic” appearing presentation (swollen, involved breast with nipple inversion and diffuse skin change) was associated with worse outcomes. Method: We reviewed the images and charts of patients from the prospective IBC registry from the MD Anderson IBC Clinic. Breast medical photographs were reviewed by a non-expert and the visual presentation was scored as classic (as above), not classic, and in between. Comparative analyses were used to assess differences between patient groups using Chi-squared test, or Fisher’s exact test for categorical variables. Wilcoxon rank sum test was used for continuous measures. We used the Kaplan Meier estimator and the log-rank test to investigate association between scoring and survival distributions. Cox proportional hazard regression was employed to assess the impact of important covariates on the overall survival. Results: We analyzed 245 IBC patients with median age 55 (range, 26-81), M0 vs. M1 status (157 and 88 patients, respectively), 68 TNBC vs. 177 non-TNBC patients. The classic presentation was significantly associated with smoking, post-menopausal status, and metastatic disease at presentation (P = 0.002, 0.018, and 0.004, respectively). Presentation was significantly associated with OS in univariate analysis (P < 0.001). 10 year overall survival was 57% vs. 33% for classic (score 3) versus non-classic or in between presentation. The multivariable Cox regression model adjusting for clinical staging (P Conclusions: A visual inspection of presentation photograph for “classic” appearance, obvious swelling, skin change, and nipple inversion, independently predicted poorer OS in IBC. Further work is warranted to understand the differences in classic and non-classic presentations, and the relationship between smoking and breast cancer presentation. Citation Format: Wintana Balema, Diane Liu, Yu Shen, Randa El-Zein, Megumi Kai, Beth Overmoyer, Kathy D Miller, Carisa Le-Petross, Naoto T Ueno, Wendy A Woodward. A picture worth a thousand words - “classic” inflammatory breast cancer (IBC) appearance associated with overall survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-04.

NDRG1 is widely described as a metastasis suppressor in breast cancer. However, we found that NDRG1 is critical in promoting tumorigenesis and brain metastasis in mouse models of inflammatory breast cancer (IBC), a rare but highly aggressive form of breast cancer. We hypothesized that NDRG1 is a prognostic marker associated with poor outcome in patients with IBC. NDRG1 levels in tissue microarrays from 64 IBC patients were evaluated by immunohistochemical staining with NDRG1 (32 NDRG1-low (&le, median), 32 NDRG1-high (&gt, median)). Overall and disease-free survival (OS and DSS) were analyzed with Kaplan&ndash, Meier curves and log-rank test. Univariate analysis showed NDRG1 expression, tumor grade, disease stage, estrogen receptor (ER) status, and receipt of adjuvant radiation to be associated with OS and DSS. NDRG1-high patients had poorer 10-year OS and DSS than NDRG1-low patients (OS, 19% vs. 45%, p = 0.0278, DSS, 22% vs. 52%, p = 0.0139). On multivariable analysis, NDRG1 independently predicted OS (hazard ratio (HR)=2.034, p = 0.0274) and DSS (HR = 2.287, p = 0.0174). NDRG1-high ER-negative tumors had worse outcomes OS, p = 0.0003, DSS, p = 0.0003, and NDRG1-high tumors that received adjuvant radiation treatment had poor outcomes (OS, p = 0.0088, DSS, p = 0.0093). NDRG1 was a significant independent prognostic factor for OS and DSS in IBC patients. Targeting NDRG1 may represent a novel strategy for improving clinical outcomes for patients with IBC.

We sought to determine the rate of postmastectomy radiation therapy (PMRT) among women treated with axillary lymph node dissection (ALND) after positive sentinel lymph node (SLN) biopsy results and to establish the effect of negative ALND results and PMRT on locoregional recurrence (LRR) and overall survival (OS).All patients were treated with mastectomy and ALND after positive SLN biopsy results. All patients had clinical N0 or NX disease at the time of mastectomy and received no neoadjuvant therapy. The presence of lymphovascular space invasion, presence of multifocality, number of positive SLNs and non-SLNs, clinical and pathologic stage, extranodal extension, age, and use of PMRT were evaluated for significance regarding the rates of OS and LRR.A total of 345 patients were analyzed. ALND after positive SLN biopsy results was negative in 235 patients (68.1%), and a total of 112 patients (32.5%) received radiation therapy. On multivariate analysis, only pathologic stage III predicted for lower OS (hazard ratio, 3.32; P.001). The rate of 10-year freedom from LRR was 87.9% and 95.3% in patients with positive ALND results and patients with negative ALND results, respectively. In patients with negative ALND results with ≥3 positive SLNs, the rate of freedom from LRR was 74.7% compared with 96.7% in those with3 positive SLNs (P=.009). In patients with negative ALND results, ≥3 positive SLNs predicted for an increase in LRR on multivariate analysis (hazard ratio, 10.10; P=.034).A low proportion of cT1-2, N0 patients with positive SLNs who undergo mastectomy receive PMRT after ALND. Even in this low-risk cohort, patients with ≥3 positive SLNs and negative ALND results are at increased risk of LRR and may benefit from PMRT.

Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

// Adam R. Wolfe 1, 2 , Nicholaus J Trenton 5 , Bisrat G. Debeb 1, 2 , Richard Larson 1, 2 , Brian Ruffell 6 , Khoi Chu 4 , Walter Hittelman 4 , Michael Diehl 5 , Jim M Reuben 1 , Naoto T. Ueno 1, 3 , Wendy A. Woodward 1, 2 1 MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Bioengineering, Rice University, Houston, TX, USA 6 Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Correspondence to: Wendy A. Woodward, email: wwoodward@mdanderson.org Keywords: inflammatory breast cancer, macrophages, mesenchymal stem cells, IL-6, statins Received: August 23, 2016 Accepted: October 06, 2016 Published: October 15, 2016 ABSTRACT Inflammatory breast cancer (IBC) is a unique and deadly disease with unknown drivers. We hypothesized the inflammatory environment contributes to the IBC phenotype. We used an in vitro co-culture system to investigate interactions between normal and polarized macrophages (RAW 264.7 cell line), bone-marrow derived mesenchymal stem cells (MSCs), and IBC cells (SUM 149 and MDA-IBC3). We used an in vivo model that reproduces the IBC phenotype by co-injecting IBC cells with MSCs into the mammary fat pad. Mice were then treated with a macrophage recruitment inhibitor, anti-CSF1. MSC and macrophages grown in co-culture produced higher levels of pro-tumor properties such as enhanced migration and elevated IL-6 secretion. IBC cells co-cultured with educated MSCs also displayed enhanced invasion and mammosphere formation and blocked by anti-IL-6 and statin treatment. The treatment of mice co-injected with IBC cells and MSCs with anti-CSF1 inhibited tumor associated macrophages and inhibited pSTAT3 expression in tumor cells. Anti-CSF1 treated mice also exhibited reduced tumor growth, skin invasion, and local recurrence. Herein we demonstrate reciprocal tumor interactions through IL-6 with cells found in the IBC microenvironment. Our results suggest IL-6 is a mediator of these tumor promoting influences and is important for the IBC induced migration of MSCs.

BACKGROUND The authors compared longitudinal patient-reported outcomes and physician-rated cosmesis with conventionally fractionated whole-breast irradiation (CF-WBI) versus hypofractionated whole-breast irradiation (HF-WBI) within the context of a randomized trial. METHODS From 2011 to 2014, a total of 287 women with American Joint Committee on Cancer stage 0 to stage II breast cancer were randomized to receive CF-WBI (at a dose of 50 grays in 25 fractions plus a tumor bed boost) or HF-WBI (at a dose of 42.56 grays in 16 fractions plus a tumor bed boost) after breast-conserving surgery. Patient-reported outcomes were assessed using the Breast Cancer Treatment Outcome Scale (BCTOS), the Functional Assessment of Cancer Therapy-Breast, and the Body Image Scale and were recorded at baseline and 0.5, 1, 2, and 3 years after radiotherapy. Physician-rated cosmesis was assessed at the same time points. Outcomes by treatment arm were compared at each time point using a 2-sided Student t test. Multivariable mixed effects growth curve models assessed the effects of treatment arm and time on longitudinal outcomes. RESULTS Of the 287 patients enrolled, 149 were randomized to CF-WBI and 138 were randomized to HF-WBI. At 2 years, the Functional Assessment of Cancer Therapy-Breast Trial Outcome Index score was found to be modestly better in the HF-WBI arm (mean 79.6 vs 75.9 for CF-WBI; P = .02). In multivariable mixed effects models, treatment arm was not found to be associated with longitudinal outcomes after adjusting for time and baseline outcome measures (P≥.14). The linear effect of time was significant for BCTOS measures of functional status (P = .001, improved with time) and breast pain (P = .002, improved with time). CONCLUSIONS In this randomized trial, longitudinal outcomes did not appear to differ by treatment arm. Patient-reported functional and pain outcomes improved over time. These findings are relevant when counseling patients regarding decisions concerning radiotherapy. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2886–2894. © 2016 American Cancer Society

Purpose We previously showed that high-density lipoprotein (HDL) radiosensitizes inflammatory breast cancer (IBC) cells in vitro and is associated with better local control after radiation therapy in IBC patients. The microRNA miR-33 family negatively regulates the adenosine triphosphate binding cassette transporter subfamily A member 1. We hypothesized that variations in miR-33a expression in IBC cancer cells versus non-IBC cells would correlate with radiation sensitivity following exposure to HDL in vitro. Methods and Materials MiR-33a expression was analyzed by reverse transcriptase–polymerase chain reaction in 4 cell lines representing common clinical breast cancer subtypes. Overexpression and knockdown of miR-33a was demonstrated via transfection of an miR-33a mimic or an anti-miR-33a construct in high- and low-expressing miR-33a cell lines. Clonogenic survival in vitro in these cells was quantified at baseline and following HDL treatment. MiR-33a expression on distant relapse-free survival (DRFS) of 210 cases downloaded from the Oxford breast cancer dataset was determined. Results Expression levels of miR-33a were lower in IBC cell lines and IBC tumor samples than in non-IBC cell lines and normal breast tissue. Cholesterol concentrations in the cell membranes were higher in IBC cells than in non-IBC cells. Clonogenic survival following 24 hours of HDL treatment was decreased in response to irradiation in the low-miR-33a–expressing cell lines SUM149 and KPL4, but survival following HDL treatment decreased in the high-miR-33a–expressing cell lines MDA-MB-231 and SUM159. In the high-miR-33a–expressing cell lines, anti-miR-33a transfection decreased radiation resistance in clonogenic assays. Conversely, in the low-miR-33a–expressing cell lines, the miR-33a mimic reversed the HDL-induced radiation sensitization. Breast cancer patients in the top quartile based on miR-33a expression had markedly lower rates of DRFS than the bottom quartile ( P =.0228, log-rank test). For breast cancer patients treated with radiation, high miR-33a expression predicted worse overall survival ( P =.06). Conclusions Our results reveal miR-33a negatively regulates HDL-induced radiation sensitivity in breast cancer.

// Bisrat G. Debeb 1, 5 , Lara Lacerda 1, 5 , Richard Larson 1, 5 , Adam R. Wolfe 1, 5 , Savitri Krishnamurthy 2, 5 , James M. Reuben 3, 5 , Naoto T. Ueno 4, 5 , Michael Gilcrease 2 , Wendy A. Woodward 1, 5 1 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 3 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 4 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 5 MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX 77030, USA Correspondence to: Wendy A. Woodward, email: wwoodward@mdanderson.org Bisrat G. Debeb, email: bgdebeb@mdanderson.org Keywords: HDAC inhibitors, cancer stem cells, pentose phosphate pathway, G6PD Received: September 24, 2015 Accepted: March 16, 2016 Published: April 07, 2016 ABSTRACT Purpose: We recently demonstrated that histone deacetylase (HDAC) inhibitors can “reprogram” differentiated triple-negative breast cancer cells to become quiescent stem-like cancer cells. We hypothesized that the metabolic state of such cells differs from that of their differentiated progeny. Results: In untreated cells, glucose uptake was higher in ALDH + cells than in ALDH – cells ( p = 0.01) but lactate production was not different; treating ALDH – or ALDH + cells with VA or SAHA similarly increased glucose uptake without changing lactate production but upregulated G6PD, a rate-limiting enzyme in pentose phosphate pathway metabolism. NADPH production was higher in HDAC inhibitor-treated stem-like cells than in vehicle-treated cells ( p < 0.05). Two G6PD inhibitors, 6-aminonicotinamide and dehydroepiandrosterone, decreased mammosphere formation efficiency and ALDH activity and 6-aminonicotinamide reduced the VA-induced increase in ALDH + cells. Finally, patients expressing high G6PD mRNA had significantly worse overall survival ( p < 0.001), and patients with high G6PD protein showed a similar trend towards worse disease-specific survival ( p = 0.06). Methods: Glucose consumption, lactate and NADPH production, and reactive oxygen species generation were compared in aldehyde dehydrogenase (ALDH)-positive and –negative cells in the presence or absence of the HDAC inhibitors valproic acid (VA) or suberoylanilide hydroxamic acid (SAHA). Glucose-6-phosphate dehydrogenase (G6PD) expression was evaluated in a tissue microarray from 94 patients with node-positive invasive breast carcinoma and in two publically available databases and correlated with overall survival. Conclusions: Energy metabolism in HDAC inhibitor-induced stem-like cancer cells differed sharply from that of differentiated cell types. HDAC inhibitor-induced dedifferentiation promoted metabolic reprogramming into the pentose phosphate pathway, which is targeted effectively by G6PD inhibition. These findings highlight a potential dual-therapy approach to targeting bulk differentiated cells with HDAC inhibitors and CSCs with G6PD inhibitors.

Although there is some evidence in animal studies that cholesterol signaling mediates radiation sensitivity of normal tissues, until recently, no connection had been made between cholesterol signaling and tumor radiosensitivity. Aberrant cholesterol signaling in breast cancer promotes oncogenesis and tumor progression by either altering membrane fluidity, membrane associated rafts, or as a direct activator of transcription. Cholesterol is synthesized de novo by the mevalonate pathway. A causal role for hydroxy-3-methylglutaryl-coenzyme A reductase, a rate-limiting enzyme of the mevalonate pathway, in oncogenic transformation, progression, and sensitivity to treatment offers an opportunity for drugs that inhibit this enzyme (i.e., statins) as well as other cholesterol mediating strategies as radiosensitizing treatments. This review discusses potential mechanisms by which statins alter cholesterol signaling in breast cancer and potentially enhances radiation sensitivity and outcome with a special focus on inflammatory breast cancer.

The AJCC updated its breast cancer staging system to incorporate biological factors in the &ldquo, prognostic stage&rdquo, We undertook this study to validate the prognostic and anatomic stages for inflammatory breast cancer (IBC). We established two cohorts of IBC diagnosed without distant metastasis: (1) patients treated at The University of Texas MD Anderson Cancer Center between 1991 and 2017 (MDA cohort) and (2) patients registered in the national Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 (SEER cohort). For prognostic staging, estrogen receptor (ER)+/progesterone receptor (PR)+/ human epidermal growth factor receptor-2 (HER2)+/grade 1&ndash, 2 was staged as IIIA, ER+/PR&minus, /HER2&minus, /grade 3, ER&minus, /PR+/HER2&minus, /grade 3, and triple-negative cancers as IIIC, and all others as IIIB. Endpoints were breast cancer-specific survival (BCSS), overall survival (OS), and disease-free survival (DFS). We studied 885 patients in the MDA cohort and 338 in the SEER cohort. In the MDA cohort, the prognostic stage showed significant predictive power for BCSS, OS, and DFS (all p &lt, 0.0001), although the anatomic stage did not. In both cohorts, the Harrell concordance index (C index) was significantly higher in the prognostic stage than the anatomic stage for all endpoints. In conclusion, the prognostic stage provided more accurate prognostication for IBC than the anatomic stage. Our results show that the prognostic staging is applicable in IBC.

Purpose: Inflammatory breast cancer (IBC) is an aggressive variant of breast cancer characterized by visible skin symptoms on the breast at the time of presentation. We demonstrated mesenchymal stem cells (MSC) promote skin symptoms in the SUM149 xenograft model. Here, we extend this finding to IBC patient-derived xenograft (PDX) lines and performed RNA-sequencing analysis of tumors from IBC patient-derived xenograft (PDX) lines by presence of skin symptoms. We hypothesize host MSC variation may explain sporadic skin symptoms in IBC PDX tumors across generations. Methods: MSC were co-injected at the time of tumor initiation in PDX tumors (IBC-3, 5, 6, and 7) and skin symptoms assessed visually and at the time of gross resection. A priori analysis plan was to group PDX by treatment group irrespective of PDX line. IBC PDX models spontaneously but inconsistently develop skin symptoms after multiple passages. RNA sequencing was performed on IBC-PDX tumors (n=33) and non-IBC PDX tumors (n=12) across generations from IBC PDX lines 5, 6, and 7 and non-IBC PDX lines 2, 3, and 4. Four samples were discarded due to poor quality. TSNE was applied using the top differential expressed genes. Xenome analysis was performed to examine host stromal expression by skin involvement. Samples from PDX lines 5 were compared with lines 6 and 7 and the top differentially expressed genes were compared with the Molecular Signatures Databases (MSigDB). CIBERSORT was performed to deconvolute cell type composition. Results: Co-injecting MSC with PDX transplant increased skin symptoms (57% of PDX animals (cohort from IBC5, IBC6, IBC7 and non-IBC4) with MSC vs. 0% without (cohort from IBC5, IBC6, IBC7, non-IBC2 and non-IBC4) (P = 0.0007). TSNE analysis of IBC PDX split samples into three subgroups distinguished by PDX lines and skin invasion. Xenome was used to split reads from human or mouse: samples show high percentage of reads coming from human (mean±SD, 97.44%± 8.98%). Seventy-four genes show FDR ≤ 0.2 between PDX line 5 and line 6 and comparing these top 74 genes with MSigDb for interaction revealed pathways such as GPCR, signal transduction, and sensory perception. CIBERSORT revealed no enrichment for MSC in IBC PDX with skin invasion, however significant differences in CD8 expression in these immunosuppressed PDX models casts doubt on the robustness of this finding. Conclusions: Exogenous MSC enhance skin symptoms in a cohort of IBC and non-IBC PDX. Skin symptoms segregate IBC PDX tumors by expression suggesting specific biology drives this presentation. However, we are unable to demonstrate evidence for spontaneous MSC signaling in these models. Future work is warranted to link top skin symptom related signaling to stromal signals and unravel the unexpected CD8 signaling identified in these models. Citation Format: Omar Rahal, Jie Yang, Li Li, Richard Larson, Steven Van Laere, Naoto Ueno, Erik Sulman, Wendy Woodward. Transcriptome analysis of patient derived xenograft mouse models of inflammatory breast cancer to gain insights into the contribution of tumor microenvironment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-06-08.