TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.

Clinical outcomes after 1 versus 2-3 lines of neoadjuvant therapy in stage III inflammatory breast cancer.

PURPOSE: Many stage III inflammatory breast cancer (IBC) patients experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to allow surgery, while some require additional NAC. We evaluated the pathologic complete response (pCR), breast cancer-free survival (BCFS) and overall survival (OS) among patients requiring 1 vs. 2-3 lines (L) of NAC prior to surgery. METHODS: Stage III IBC patients from 2 institutions who received 1L or 2-3L of NAC prior to surgery were identified. Hormone receptor and HER2 status, grade, and pCR were evaluated. BCFS and OS were evaluated by the Kaplan-Meier method. Multivariable Cox models were utilized to estimate the hazard ratio (HR). RESULTS: 808 eligible patients (1997-2020) were identified (median age 51 years, median follow-up 69 months). 733 (91%) had 1L and 75 (9%) had 2-3L of NAC. Grade III, triple-negative and HER2-positive disease were more prevalent in 2-3L patients. 178 (24%) 1L and 14 (19%) 2-3L patients had pCR. 376 1L patients and 41 2-3L patients had recurrences. The 5-year BCFS was worse for the 2-3L group (33 vs. 46%, HR = 1.37; 95% CI 0.99-1.91). However, in 192 patients with a pCR, BCFS was similar (76 vs. 83% in 1L vs. 2-3L, respectively). There were 308 deaths (276 among 1L and 32 among 2-3L patients). The 5-year OS in 1L vs. 2-3L was 60 vs. 53% (HR = 1.32, 95% CI 0.91-1.93). CONCLUSIONS: Among stage III IBC patients, pCR rates were similar, irrespective of the NAC lines number, and BCFS and OS were comparable with pCR after 1L and 2-3L.

Preoperative Risk Factors for Lymphedema in Inflammatory Breast Cancer.

BACKGROUND: Prophylactic lymphatic bypass or LYMPHA (LYmphatic Microsurgical Preventive Healing Approach) is increasingly offered to prevent lymphedema following breast cancer treatment, which develops in up to 47% of patients. Previous studies focused on intraoperative and postoperative lymphedema risk factors, which are often unknown preoperatively when the decision to perform LYMPHA is made. This study aims to identify preoperative lymphedema risk factors in the high-risk inflammatory breast cancer (IBC) population. METHODS: Retrospective review of our institution's IBC program database was conducted. The primary outcome was self-reported lymphedema development. Multivariable logistic regression analysis was performed to identify preoperative lymphedema risk factors, while controlling for number of lymph nodes removed during axillary lymph node dissection (ALND), number of positive lymph nodes, residual disease on pathology, and need for adjuvant chemotherapy. RESULTS: Of 356 patients with IBC, 134 (mean age: 51 years, range: 22-89 years) had complete data. All 134 patients underwent surgery and radiation. Forty-seven percent of all 356 patients (167/356) developed lymphedema. Obesity (body mass index > 30) (odds ratio [OR]: 2.7, confidence interval [CI]: 1.2-6.4, p = 0.02) and non-white race (OR: 4.5, CI: 1.2-23, p = 0.04) were preoperative lymphedema risk factors. CONCLUSION: Patients with IBC are high risk for developing lymphedema due to the need for ALND, radiation, and neoadjuvant chemotherapy. This study also identified non-white race and obesity as risk factors. Larger prospective studies should evaluate potential racial disparities in lymphedema development. Due to the high prevalence of lymphedema, LYMPHA should be considered for all patients with IBC.

Intraoperative Pathology Assessment May Lead to Overtreatment of the Axilla in Clinically Node-Negative Breast Cancer Patients Undergoing Upfront Mastectomy.

BACKGROUND: Randomized trials have established the safety of observation or axillary radiation (AxRT) as an alternative to axillary lymph node dissection (ALND) in patients with limited nodal disease who undergo upfront surgery. Variability remains in axillary management strategies in cN0 patients undergoing mastectomy found to have one to two positive sentinel lymph nodes (SLNs). We examined the impact of intraoperative pathology assessment in axillary management in a national cohort of AMAROS-eligible mastectomy patients. METHODS: The National Cancer Database was used to identify AMAROS-eligible cT1-2N0 breast cancer patients undergoing upfront mastectomy and SLN biopsy (SLNB) and found to have one to two positive SLNs, from 2018 to 2019. We constructed a variable defining intraoperative pathology as 'not performed/not acted on' if ALND was either not performed or performed at a later date than SLNB, or 'performed/acted on' if SLNB and ALND were completed on the same day. Adjusted multivariable analysis examined predictors of treatment with both ALND and AxRT. RESULTS: Overall, 8222 patients with cT1-2N0 disease underwent upfront mastectomy and had one to two positive SLNs. Intraoperative pathology was performed/acted on in 3057 (37.2%) patients. These patients were significantly more likely to have both ALND and AxRT than those without intraoperative pathology (41.0% vs. 4.9%; p < 0.001). On multivariate analysis, the strongest predictor of receiving both ALND and AxRT was use of intraoperative pathology (odds ratio 8.99, 95% confidence interval 7.70-10.5; p < 0.001). CONCLUSIONS: We advocate that consideration should be made for omission of routine intraoperative pathology in mastectomy patients likely to be recommended postmastectomy radiation to minimize axillary overtreatment with both ALND and AxRT in appropriate patients.

Incidence, characteristics, and management of central nervous system metastases in patients with inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have a high risk of central nervous system metastasis (mCNS). The purpose of this study was to quantify the incidence of and identify risk factors for mCNS in patients with IBC. METHODS: The authors retrospectively reviewed patients diagnosed with IBC between 1997 and 2019. mCNS-free survival time was defined as the date from the diagnosis of IBC to the date of diagnosis of mCNS or the date of death, whichever occurred first. A competing risks hazard model was used to evaluate risk factors for mCNS. RESULTS: A total of 531 patients were identified; 372 patients with stage III and 159 patients with de novo stage IV disease. During the study, there were a total of 124 patients who had mCNS. The 1-, 2-, and 5-year incidence of mCNS was 5%, 9%, and 18% in stage III patients (median follow-up: 5.6 years) and 17%, 30%, and 42% in stage IV patients (1.8 years). Multivariate analysis identified triple-negative tumor subtype as a significant risk factor for mCNS for stage III patients. For patients diagnosed with metastatic disease, visceral metastasis as first metastatic site, triple-negative subtype, and younger age at diagnosis of metastases were risk factors for mCNS. CONCLUSIONS: Patients with IBC, particularly those with triple-negative IBC, visceral metastasis, and those at a younger age at diagnosis of metastatic disease, are at significant risk of developing mCNS. Further investigation into prevention of mCNS and whether early detection of mCNS is associated with improved IBC patient outcomes is warranted.

Rates of pathologic nodal disease among cN0 and cN1 patients undergoing routine axillary ultrasound and neoadjuvant chemotherapy.

PURPOSE: Routine axillary ultrasound (AxUS) in patients receiving neoadjuvant chemotherapy (NAC) remains controversial. Here, we report rates of AxUS-detected nodal disease among patients with normal clinical exams, and rates of pathologic nodal disease after NAC based on method of nodal disease detection. METHODS: Clinicopathologic findings were prospectively collected for stage I-III breast cancer patients selected for NAC. All patients had pre-treatment AxUS, suspicious nodes were biopsied. The following four patient cohorts were examined: patients with suspicious exam or AxUS but negative biopsy (Suspicious cN0); those with normal exam and normal AxUS (Not Suspicious cN0); those with normal exam but suspicious AxUS and positive biopsy (AxUS-detected cN1); and those with abnormal exam and positive biopsy (exam-detected cN1). Sentinel (SLN) and non-sentinel lymph nodes (non-SLN) were evaluated by immunohistochemistry; nodal metastases of any size were considered positive. RESULTS: 500 patients were included. Of 310 patients with normal axillary exams, 160 had suspicious AxUS, 65 were biopsy-negative (Suspicious cN0) and 95/310 (30.6%) were biopsy-positive (AxUS-detected cN1). Of 190 with abnormal axillary exams, 166 were biopsy-proven node-positive (exam-detected cN1) and 24 were AxUS or biopsy-negative (Suspicious cN0). Rates of pathologic nodal disease were 20/150 (13.3%) among Not Suspicious cN0 patients, 12/89 (13.5%) among Suspicious cN0 (p = 0.97). Rates of residual nodal disease were 55/95 (57.9%) among AxUS-detected cN1 patients, 102/166 (61.4%) among exam-detected cN1 (p = 0.57). CONCLUSION: AxUS detected nodal disease in 30.6% of patients with normal clinical exams selected for NAC. Rates of pathologic nodal disease were similar among AxUS-detected and exam-detected cN1 patients.

Inflammatory Breast Cancer: Is There a Role for Deescalation of Surgery?

Inflammatory breast cancer (IBC) is a rare and aggressive presentation of breast cancer, characterized by higher propensity for locoregional recurrence and distant metastasis compared with non-IBC. Because of extensive parenchymal and overlying dermal lymphatic involvement by carcinoma, IBC is unresectable at diagnosis. Trimodality therapy (neoadjuvant chemotherapy followed by modified radical mastectomy and adjuvant comprehensive chest wall and regional nodal radiotherapy) has been a well-accepted treatment algorithm for IBC. Over the last few decades, several innovations in systemic therapy have resulted in rising rates of pathologic complete response (pCR) in both the affected breast and the axilla. The latter may present an opportunity for deescalation of lymph node surgery in patients with IBC, as those with an axillary pCR may be able to avoid an axillary dissection. To this end, feasibility data are necessary to address this question. There are very limited data on the safety of breast conservation of IBC; therefore, mastectomy remains the standard of care for this disease. There are also no data addressing the safety of immediate reconstruction in patients with IBC. Considering that some degree of deliberate skin-sparing to facilitate immediate breast reconstruction would be expected, given the extensive skin involvement by disease at diagnosis, the safest oncologic strategy to breast reconstruction in IBC would be the delayed approach.

Atypical Lobular Hyperplasia and Classic Lobular Carcinoma In Situ Can Be Safely Managed Without Surgical Excision.

BACKGROUND: Based on modern series demonstrating low upgrade rates for pure lobular neoplasia (LN) diagnosed on core needle biopsy (CNB), our institution no longer recommends routine excision, provided imaging is concordant. This study describes outcomes in patients managed without surgical excision. METHODS: From an institutional database, we identified all patients with a diagnosis of pure atypical lobular hyperplasia and/or classic lobular carcinoma in situ on CNB managed without surgical excision (i.e., conservative management) from 2015 to 2019. The primary outcome of interest was failure of conservative management, defined as development of ipsilateral same-quadrant ductal carcinoma in situ or invasive breast cancer within 2 years of CNB, or need for ipsilateral same-quadrant excisional biopsy. We also evaluated rates of ipsilateral same-quadrant CNB during follow-up. RESULTS: Among 96 pure LN lesions on CNB since 2015, 80 (83%) were managed without surgical excision. Median follow-up was 27 months (IQR: 16-28), with only 2 (2%) patients lost to follow-up. No patients developed an ipsilateral, same-quadrant breast cancer. The 3-year risk of conservative management failure was 6.2% (95% CI 2.3-15.7%). All failures were a result of need for excisional biopsy due to progressive imaging abnormalities at the initial CNB site, with benign final pathology. The 3-year risk of ipsilateral same-quadrant CNB was 9.2% (95% CI 3.8-21.5%). CONCLUSION: Non-surgical management of pure LN is safe, and the likelihood of requiring subsequent surgical excision or repeat CNB during follow-up is low. These data provide reassurance that routine excision of pure LN in the setting of radiologic-pathologic concordance is not required.

Presence of Non-classic LCIS Is Not a Contraindication to Breast Conservation in Patients with Concomitant Invasive Breast Cancer or DCIS.

BACKGROUND: Non-classic lobular carcinoma in situ (NC-LCIS) represents a spectrum of lesions, histologically distinct from classic LCIS (C-LCIS) and ductal carcinoma in situ (DCIS). Several studies have reported on the safety of breast conservation (BCS) in patients with DCIS or invasive breast cancer and concomitant C-LCIS, yet there are no data addressing this question for patients with concomitant NC-LCIS. We evaluated local recurrence (LR) after BCS in patients with DCIS or invasive cancer and concomitant NC-LCIS. PATIENTS AND METHODS: We searched institutional databases using natural language processing to identify patients with DCIS or invasive breast cancer and concomitant NC-LCIS treated with BCS between 2000 and 2015. Charts were reviewed to collect demographics, disease and treatment details, and recurrence events. All results represent descriptive analyses. RESULTS: We identified 71 patients with DCIS (n = 13) or invasive cancer (n = 58) and concomitant NC-LCIS treated with BCS. Median patient age was 59 years (33-77 years), and median invasive tumor size was 1.2 cm (0.1-6.9 cm); 62% of DCIS and 79% of invasive cancer patients had hormone receptor (HR)-positive disease. Among DCIS patients, seven (54%) received radiation and none hormonal therapy. Among those with invasive cancer, 52 (90%) received radiation, 17 (29%) received chemotherapy and 44 of 55 with HR-positive disease (78%) received hormonal therapy. At median follow-up of 79 months (1-265 months), the LR rate was 8% and 2% among patients with DCIS and invasive cancer, respectively. CONCLUSION: NC-LCIS is rarely present in association with DCIS or invasive cancer, and it does not appear to impact LR outcomes following BCS.

How Often Does Retrieval of a Clipped Lymph Node Change Adjuvant Therapy Recommendations? A Prospective, Consecutive, Patient Cohort Study.

BACKGROUND: Prior studies examining sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) for cN1 patients have demonstrated that 20% of biopsied, clipped lymph nodes (cLNs) are nonsentinel lymph nodes (non-SLNs). Our goal was to determine how often the cLN was a non-SLN among both cN0 and cN1 patients and how often cLN pathology impacted management. METHODS: Overall, 238 patients treated with NAC and surgery January 2019 to June 2020 were prospectively examined. Patients underwent routine axillary ultrasound, biopsy of suspicious nodes, and clip placement. Radioactive iodine-125 seed localization of the cLN was performed in cN1 patients only. Isolated tumor cells (ITCs) were considered node positive (ypN+) for both cN0 and cN1 cohorts. Chart review was performed to determine if cLNs were non-SLN and their ypN status. RESULTS: Of 118 cN0 patients, 115 of 118 (97%) underwent successful SLNB, 33 of whom had a cLN present; 21 of 33 (64%) cLNs were non-SLNs. Overall, 9 of 118 (8%) were ypN+; no cLN was ypN+ without additional +SLNs. Of 120 cN1 patients, 104 of 120 (87%) converted to cN0, 98 of 104 (94%) of which had attempted SLNB, and 95 of 98 (97%) successfully mapped. The cLN was a non-SLN in 18 of 95 (19%). Overall, 58 of 104 (56%) cN1 patients were ypN+. One patient had a positive cLN in the absence of +SLNs. This patient underwent axillary lymph node dissection (ALND); adjuvant treatment recommendations were unchanged. CONCLUSIONS: The cLN was a non-SLN in 19% of cN1 patients. cLN pathology did not impact adjuvant therapy recommendations, calling into question the utility of routinely clipping biopsied lymph nodes.

The Incidence of Adjacent Synchronous Invasive Carcinoma and/or Ductal Carcinoma In Situ in Patients with Intraductal Papilloma without Atypia on Core Biopsy: Results from a Prospective Multi-Institutional Registry (TBCRC 034).

BACKGROUND: Available retrospective data suggest the upgrade rate for intraductal papilloma (IP) without atypia on core biopsy (CB) ranges from 0 to 12%, leading to variation in recommendations. We conducted a prospective multi-institutional trial (TBCRC 034) to determine the upgrade rate to invasive cancer (IC) or ductal carcinoma in situ (DCIS) at excision for asymptomatic IP without atypia on CB. METHODS: Prospectively identified patients with a CB diagnosis of IP who had consented to excision were included. Discordant cases, including BI-RADS > 4, and those with additional lesions requiring excision were excluded. The primary endpoint was upgrade to IC or DCIS by local pathology review with a predefined rule that an upgrade rate of ≤ 3% would not warrant routine excision. Sample size and confidence intervals were based on exact binomial calculations. Secondary endpoints included diagnostic concordance for IP between local and central pathology review and upgrade rates by central pathology review. RESULTS: The trial included116 patients (median age 56 years, range 24-82) and the most common imaging abnormality was a mass (n = 91, 78%). Per local review, 2 (1.7%) cases were upgraded to DCIS. In both of these cases central pathology review did not confirm DCIS on excision. Additionally, central pathology review confirmed IP without atypia in core biopsies of 85/116 cases (73%), and both locally upgraded cases were among them. CONCLUSION: In this prospective study of 116 IPs without atypia on CB, the upgrade rate was 1.7% by local review, suggesting that routine excision is not indicated for IP without atypia on CB with concordant imaging findings.

Discrepancy between FDG-PET/CT and contrast-enhanced CT in the staging of patients with inflammatory breast cancer: implications for treatment planning.

PURPOSE: Optimizing treatment strategies for patients with inflammatory breast cancer (IBC) relies on accurate initial staging. This study compared contrast-enhanced computed tomography (ce-CT) and FDG-PET/CT for initial staging of IBC to determine the frequency of discordance between the two imaging modalities and potential impact on management. METHODS: 81 patients with IBC underwent FDG-PET/CT and ce-CT prior to starting treatment. FDG-PET/CT and ce-CT scans were independently reviewed for locoregional and distant metastases and findings recorded by anatomic site as negative, equivocal, or positive for breast cancer involvement. Each paired ce-CT and FDG-PET/CT case was classified as concordant or discordant for findings. Discordant findings were subclassified as (a) related to the presence or absence of distant metastases; (b) affecting the locoregional radiation therapy plan; or (c) due to incidental findings not related to IBC. RESULTS: There were 47 discordant findings between ce-CT and FDG-PET/CT in 41 of 81 patients (50.6%). Thirty (63.8%) were related to the presence or absence of distant metastases; most commonly disease detection on FDG-PET/CT but not ce-CT (n = 12). FDG-PET/CT suggested alterations of the locoregional radiation therapy plan designed by CT alone in 15 patients. FDG-PET/CT correctly characterized 5 of 7 findings equivocal for metastatic IBC on ce-CT. CONCLUSIONS: This study demonstrates differences between ce-CT and FDG-PET/CT for initial staging of IBC and how these differences potentially affect patient management. Preliminary data suggest that FDG-PET/CT may be the imaging modality of choice for initial staging of IBC. Prospective trials testing initial staging with FDG-PET/CT versus important clinical end-points in IBC are warranted.

Extent of axillary surgery in inflammatory breast cancer: a survival analysis of 3500 patients.

PURPOSE: Inflammatory breast cancer (IBC) is an aggressive variant for which axillary lymph node (LN) dissection following neoadjuvant chemotherapy (NACT) remains standard of care. But with increasingly effective systemic therapy, it is unclear whether more limited axillary surgery may be appropriate in some IBC patients. We sought to examine whether extent of axillary LN surgery was associated with overall survival (OS) for IBC. METHODS: Female breast cancer patients with non-metastatic IBC (cT4d) diagnosed 2010-2014 were identified in the National Cancer Data Base. Cox proportional hazards modeling was used to estimate the association between extent of axillary surgery (≤ 9 vs ≥ 10 LNs removed) and OS after adjusting for covariates, including post-NACT nodal status (ypN0 vs ypN1-3) and radiotherapy receipt (yes/no). RESULTS: 3471 patients were included: 597 (17.2%) had cN0 disease, 1833 (52.8%) had cN1 disease, and 1041 (30%) had cN2-3 disease. 49.9% of cN0 patients were confirmed to be ypN0 on post-NACT surgical pathology. Being ypN0 (vs ypN1-3) was associated with improved adjusted OS for all patients. Radiotherapy was associated with improved adjusted OS for cN1 and cN2-3 patients but not for cN0 patients. Regardless of ypN status, there was a trend towards improved adjusted OS with having ≥ 10 (vs ≤ 9) LNs removed for cN2-3 patients (HR 0.78, 95% CI 0.60-1.01, p = 0.06) but not for cN0 patients (p = 0.83). CONCLUSIONS: A majority of IBC patients in our study presented with node-positive disease, and for those presenting with cN2-3 disease, more extensive axillary surgery is potentially associated with improved survival. For cN0 patients, however, more extensive axillary surgery was not associated with a survival benefit, suggesting an opportunity for more personalized care.

Genomic profiling of pleomorphic and florid lobular carcinoma in situ reveals highly recurrent ERBB2 and ERRB3 alterations.

Pleomorphic LCIS (P-LCIS) and florid LCIS (F-LCIS) are morphologic variants distinguished from classic LCIS by marked nuclear pleomorphism and/or an expansile growth pattern with or without necrosis. Given the rarity of these LCIS variants, little data exist regarding their molecular pathogenesis, natural history, and optimal management. The purpose of this study was to genomically profile LCIS variants to gain further insight into their biology. Nineteen cases of pure LCIS variants (17 P-LCIS, 2 F-LCIS) diagnosed on core needle biopsy at our institution from 2006 to 2017 were included, five of which were upgraded to invasive cancer at excision. Macrodissected lesions were analyzed by a hybrid-capture next generation sequencing assay that surveyed exonic sequences of 447 genes for mutations and copy number variations (CNVs) and 191 regions across 60 genes for structural rearrangements. LCIS variants were all confirmed as E-cadherin negative by immunohistochemistry. Receptor profiles among the 17 P-LCIS cases included HR+/HER2- (nine cases), HR+/HER2+ (three cases), HR-/HER2+ (two cases), and HR-/HER2- (three cases). The two F-LCIS cases were HR+/HER2- and HR+/HER2+. All LCIS variants had genetic alterations consistent with a lobular phenotype including 1q gain (16 cases), 16q loss (18 cases), and CDH1 mutations (18 cases). Highly recurrent ERBB2 alterations were noted including mutations (13 cases) and amplifications (six cases). Other significant alterations included mutations in PIK3CA (six cases), RUNX1 (four cases), ERBB3 (four cases), and CBFB (three cases), as well as amplification of CCND1 (five cases). A TP53 mutation was identified in one case of HR-/HER2+ P-LCIS with signet ring cell features that lacked 1q gain and 16q loss. P-LCIS and F-LCIS contain genetic alterations characteristic of lobular neoplasia; however, these LCIS variants are distinguished from classical LCIS reported in the literature by their highly recurrent ERBB2 alterations.

Characteristics associated with inflammatory breast cancer (IBC): An epidemiologic study from a dedicated IBC program.

There are scant data identifying epidemiologic characteristics among individuals diagnosed with inflammatory breast cancer (IBC), which is considered the most aggressive subtype of breast cancer. The purpose of this study was to evaluate the epidemiologic features among patients seen at a dedicated IBC program, to elucidate the potential causes of this disease and guide prevention strategies. We reviewed retrospective data from 447 patients enrolled in an IRB-approved IBC registry through Dana-Farber Cancer Institute from 1997 to 2016. The data examined included the following: demographics, medical, reproductive and family history, duration of symptoms prior to the diagnosis of IBC, pathologic characteristics, and clinical outcome. JMP statistical software was used to compile the data. Descriptive statistics were used to evaluate the data. The majority of patients (66.0%) were overweight or obese (body mass index [BMI] ≥25) at the time of diagnosis. Fifty patients (11.1%) had "secondary" IBC, defined as developing IBC after a previous history of non-IBC breast cancer in an ipsilateral breast. Of those patients with secondary IBC, 60% were also overweight or obese at the time of IBC diagnosis. Approximately 58% of IBC patients had a family history of breast or ovarian cancer, including first- and second-degree relatives. This analysis suggested a high frequency of familial breast/ovarian cancer among IBC patients which supports further evaluating genetic risks. This may have implications for screening and prevention strategies as well as insight into additional contributing risk factors. The prevalence of a high BMI among both pre- and postmenopausal women with IBC, including those diagnosed with secondary IBC, warrants focusing on strategies targeting the obesity crisis as a potential means of reducing the risk of developing this disease.

Patterns of breast reconstruction in patients diagnosed with inflammatory breast cancer: The Dana-Farber Cancer Institute's Inflammatory Breast Cancer Program experience.

Inflammatory breast cancer (IBC) exhibits dermal lymphatic involvement at presentation, and thus, the standard surgical approach is a nonskin-sparing modified radical mastectomy (MRM) without breast reconstruction (BR). In this study, we evaluated immediate and delayed BR receipt and its outcomes in IBC. Using an IRB-approved database, we retrospectively evaluated stage III IBC patients who received trimodality therapy (preoperative systemic therapy, followed by MRM and postmastectomy chest wall/regional nodal radiation). Patients with an insufficient response to preoperative systemic therapy and/or who required preoperative radiotherapy were excluded. BR receipt, timing, and morbidity were evaluated. Among 240 stage III IBC patients diagnosed between 1997 and 2016, 40 (17%) underwent BR. Thirteen (33%) had immediate, and 27 (67%) had delayed BR. Four patients had complications (1 [8%] immediate BR and 3 [11%] delayed BR); only 1 BR (delayed) was unsuccessful. From the MRM date, the median time to recurrence was 35 months (<1-212) and median overall survival was 87 months (<1-212). In this cohort of stage III IBC patients, only 11% pursued delayed BR following trimodality therapy, possibly attributable to the observed high recurrence rates hindering BR. Further studies addressing BR outcomes in IBC are needed for better counseling patients regarding their reconstructive options.

Premalignant Disorders of the Breast in Pregnancy and Lactation.

Papillomas, atypical hyperplasias, and lobular carcinoma in situ of the breast are not malignant tumors, but present serious management challenges when they are diagnosed in a breast biopsy . Upgrading after excision and increased possibility of future cancer are risks that accompany these lesions. While some features have been defined as high-risk for upgrading, many practitioners now recommend conservative non-surgical treatment and vacuum-assisted biopsy . However, the challenge gets worse when the patient is pregnant or breastfeeding because of the limitations in imaging and treatment in relation to the fetus. This chapter deals with these problems, although the best management strategy cannot be defined because of lack of evidence at present.

Impact of Age on Locoregional and Distant Recurrence After Mastectomy for Ductal Carcinoma In Situ With or Without Microinvasion.

BACKGROUND: Locoregional recurrence (LRR) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) is increased in young women. We examined the impact of age on LRR and distant disease after mastectomy for DCIS ± microinvasion. METHODS: We identified consecutive patients with DCIS ± microinvasion treated with mastectomy from 1995 to 2017. LRR was defined as recurrence at the ipsilateral chest wall or regional nodes. RESULTS: Overall, 3121 cases were identified, of which 421 (13.5%) had DCIS + microinvasion. Median age was 49 years and median follow-up was 6.4 years; 821 were followed for 10 or more years. Thirty-four LRRs were observed: 33 (97%) were invasive, and 23 (68%) were in the chest wall alone. Cumulative 10-year LRR incidence was 1.4%. Age < 50 years, high grade, and DCIS + microinvasion were associated with LRR (p ≤ 0.001); however, margin status was not (p = 0.14). Adjusting for grade and DCIS + microinvasion, age < 50 years (hazard ratio [HR] 14.7, 95% confidence interval [CI] 3.5-61.5; p < 0.001) was associated with LRR. Compared with women ≥ 50 years of age, women age < 40 years had the highest risk (HR 27.0, 95% CI 6.0-121), and women age 40-49 years had intermediate risk (HR 11.8, 95% CI 2.8-50.5). The cumulative 10-year LRR incidence was 4.2% for women < 40 years of age, 2.0% for women 40-49 years of age, and 0.2% for women ≥ 50 years of age. Women age < 40 years had a 10-year distant disease rate of 1.6% versus women age 40-49 years (0.7%) and women age ≥ 50 years (0.7%) (log-rank p = 0.051). Grade, DCIS + microinvasion, and margins were unassociated with distant disease. CONCLUSIONS: LRR after mastectomy for DCIS ± microinvasion is uncommon, but is more frequent among women < 50 years of age, particularly in those < 40 years of age. The 10-year LRR rate in this youngest group remains low at 4.2%. Young age is an independent risk factor for LRR after BCS or mastectomy.

Evaluating the Rate of Upgrade to Invasive Breast Cancer and/or Ductal Carcinoma In Situ Following a Core Biopsy Diagnosis of Non-classic Lobular Carcinoma In Situ.

BACKGROUND: A diagnosis of non-classic lobular carcinoma in situ (NC-LCIS) encompasses a variety of lesions with poorly characterized natural history. We evaluated upgrade rates and factors associated with upgrade to malignancy following a core biopsy diagnosis of NC-LCIS, and its natural history. METHODS: Upon Institutional Review Board approval, pathology databases were searched for NC-LCIS core biopsy diagnoses (carcinoma in situ [CIS], CIS with ductal and lobular features [CIS/DLF], pleomorphic LCIS [P-LCIS], variant LCIS [V-LCIS], LCIS with necrosis). Cases with available core and excision pathology were included, while cases with concurrent ipsilateral invasive carcinoma (IC), ductal carcinoma in situ (DCIS), and/or atypical ductal hyperplasia were excluded. RESULTS: Overall, 121 NC-LCIS cases were identified from 1998 to 2017. We excluded 46 cases with concurrent cancer; 75 patients with 76 NC-LCIS core biopsy diagnoses followed by excision formed our study cohort. Median age was 56 years (range 41-83), and all imaging findings were classified as Breast Imaging Reporting and Data System 4; calcifications were the most common biopsy indication (80%). Excision yielded malignancy in 27 (36%) patients (IC 17, 63%; DCIS alone 10, 37%). We were unable to identify radiologic or pathologic features predictive of upgrade. Of 49 pure NC-LCIS cases, 15 (31%) had mastectomy, 9 (18%) had excision and radiation, and 25 (51%) had excision alone. At a median follow-up of 58 months (range 1-224), 1/25 (4%) patients with excision alone developed ipsilateral DCIS 14 months later. CONCLUSIONS: In this series of NC-LCIS, 36% of cases were upgraded, supporting routine excision. We were unable to identify predictors of upgrade. Among 25 patients with pure NC-LCIS, only one patient developed a future ipsilateral cancer. Further study of the natural history of NC-LCIS is warranted.

Impact of Residual Nodal Disease Burden on Technical Outcomes of Sentinel Lymph Node Biopsy for Node-Positive (cN1) Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

BACKGROUND: Recent trials have demonstrated the feasibility of sentinel lymph node biopsy (SLNB) for cN1 breast cancer patients after neoadjuvant chemotherapy (NAC). This study evaluated the technical outcomes of SLNB by residual nodal disease volume. METHODS: From a prospective database, cT1-3 cN1 patients receiving NAC and surgery from 2016 to 2017 were identified. Performance measures of post-NAC physical exam and imaging-based axillary assessment were compared. For the patients who converted to cN0 and underwent SLNB, adequate mapping (defined as ≥ 3 SLN) and the false-negative rate (FNR) of intraoperative SLN evaluation were assessed by residual nodal disease volume (ypN1-3 vs ypN0[i+]/ypN1mi vs ypN0). RESULTS: Of 156 cT1-3 cN1 patients, 96 converted to cN0 and underwent SLNB. Adequate mapping was achieved for 64 patients (66.7%) and was not associated with nodal volume (p = 0.12). The FNR of the intraoperative SLN evaluation was 37.8%, and smaller nodal volume was associated with FNR (p < 0.01). Of 36 patients (37.5%) who achieved an axillary pathologic complete response, 24 (66.7%) had three or more negative SLNs and were safely spared axillary lymph node dissection (ALND). The positive predictive values of physical exam versus imaging-based post-NAC nodal assessment were respectively 88% and 69.8%. CONCLUSIONS: This study showed SLNB to be an effective tool for minimizing axillary surgery in cN1 patients treated with NAC. However, important technical limitations exist, such as inability to identify three SLNs in more than two-thirds of patients and high-false negative rates for intraoperative SLN evaluation, particularly for patients with small residual nodal volumes. Preoperative counseling should include realistic assessment of the potential need for ALND in this population.