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Breast cancer mortality after ductal carcinoma in situ is rare, making it difficult to predict which patients are at risk and to identify whether risk factors for this outcome are the same as those for invasive recurrence. We aimed to identify whether risk factors for invasive recurrences are similar to those for breast cancer death after a diagnosis of pure ductal carcinoma in situ.The Surveillance, Epidemiology, and End Results Program was queried for female patients diagnosed with pure ductal carcinoma in situ. Cumulative incidence was estimated by treatment group using competing risks. Competing risks regression was then performed for the development of in-breast invasive recurrence with competing risks of breast and non-breast cancer death. Competing risks regression was then again performed for development of breast cancer mortality with the competing risk of non-breast cancer death.A total of 29,515 patients were identified. Of them, 164 patients suffered breast cancer mortality without an intervening invasive recurrence, and 44 suffered breast cancer mortality after an invasive in-breast recurrence. On competing risks analysis for invasive in-breast recurrence, significant factors included lesion size5 cm (hazard ratio = 1.59, 95% confidence interval 1.24-2.04, P.001), diffuse disease (hazard ratio = 0.0005, 95% confidence interval 0.0003-0.0007, P.001), other race (hazard ratio = 1.29, 95% confidence interval 1.10-1.52, P = .002), Black race (hazard ratio = 1.21, 95% confidence interval 1.01-1.46, P = .04), age at diagnosis (hazard ratio = 0.99, confidence interval 0.98-1.00, P = .02), low-grade disease (hazard ratio = 0.79, 95% confidence interval 0.64-0.96, P = .02), lumpectomy with radiation (hazard ratio = 0.67, 95% confidence interval 0.58-0.77, P.001), and mastectomy (hazard ratio = 0.36, 95% confidence interval 0.30-0.44, P.001). Significant factors for breast cancer mortality included age at diagnosis (hazard ratio = 1.04, 95% confidence interval 1.03-1.05, P.001), Black race (hazard ratio = 2.88, 95% confidence interval 2.08-3.99, P.001), diffuse disease (hazard ratio = 6.02, 95% confidence interval 1.39-26.07, P = .02), lumpectomy with radiation (hazard ratio = 0.51, 95% confidence interval 0.36-0.72, P.001), and mastectomy (hazard ratio = 0.60, 95% confidence interval 0.50-0.92, P = .02).Our results suggested that risk factors for in-breast invasive recurrence after a diagnosis of pure ductal carcinoma in situ differ from risk factors for breast cancer mortality and development of metastatic recurrence. In-breast invasive recurrence is not the only consideration for breast cancer specific mortality in ductal carcinoma in situ patients.

Background Ultrasound-guided percutaneous cryoneurolysis is an analgesic technique in which a percutaneous probe is used to reversibly ablate a peripheral nerve(s) using exceptionally low temperature, and has yet to be evaluated with randomized, controlled trials. Pain after mastectomy can be difficult to treat, and the authors hypothesized that the severity of surgically related pain would be lower on postoperative day 2 with the addition of cryoanalgesia compared with patients receiving solely standard-of-care treatment. Methods Preoperatively, participants at one enrolling center received a single injection of ropivacaine, 0.5%, paravertebral nerve block at T3 or T4, and perineural catheter. Participants subsequently underwent an active or sham ultrasound–guided percutaneous cryoneurolysis procedure of the ipsilateral T2 to T5 intercostal nerves in a randomized, patient- and observer-masked fashion. Participants all received a continuous paravertebral block with ropivacaine, 0.2%, until the early morning of discharge (usually postoperative day 2). The primary endpoint was the average pain level measured using a 0 to 10 numeric rating scale the afternoon of postoperative day 2. Participants were followed for 1 yr. Results On postoperative day 2, participants who had received active cryoneurolysis (n = 31) had a median [interquartile range] pain score of 0 [0 to 1.4] versus 3.0 [2.0 to 5.0] in patients given sham (n = 29): difference –2.5 (97.5% CI, –3.5 to –1.5), P < 0.001. There was evidence of superior analgesia through month 12. During the first 3 weeks, cryoneurolysis lowered cumulative opioid use by 98%, with the active group using 1.5 [0 to 14] mg of oxycodone compared with 72 [20 to 120] mg in the sham group (P < 0.001). No oral analgesics were required by any patient between months 1 and 12. After 1 yr chronic pain had developed in 1 (3%) active compared with 5 (17%) sham participants (P < 0.001). Conclusions Percutaneous cryoneurolysis markedly improved analgesia without systemic side effects or complications after mastectomy. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

A 30-year-old woman with a history of anorexia nervosa was admitted with weight loss, hypoglycaemia and electrolyte disturbances. During her admission, transaminases peaked at ALP 457 U/l, AST 817 U/l and ALT 1066 U/l. Imaging and laboratory findings were unrevealing, and she declined liver biopsy. Nutrition was introduced via a nasogastric tube and she demonstrated improvement in her laboratory values over several weeks. Her transaminitis was determined to be secondary to severe malnutrition, which has been previously described, but cases with such profound transaminitis are less common. Studies have demonstrated hepatic autophagocytosis as the likely cause.

BackgroundFollowing outpatient surgery, it is often difficult to provide adequate analgesia while concurrently minimizing opioid requirements. Ultrasound-guided percutaneous peripheral nerve stimulation has been proposed as an analgesic, but requires physician-level skills, advanced equipment, up to an hour to administer, and is frequently cost prohibitive. In contrast, percutaneous auricular neuromodulation may be placed by nursing staff in a few minutes without additional equipment, theoretically provides analgesia for nearly any anatomic location, lacks systemic side effects, and has no significant risks. We now present a case report to demonstrate proof of concept for the off-label use of an auricular neuromodulation device—originally developed to treat symptoms associated with opioid withdrawal—to instead provide analgesia following outpatient surgery.Case presentationFollowing moderately painful ambulatory orthopedic and breast surgery, seven patients had an auricular neuromodulation device (NSS-2 Bridge, Masimo, Irvine, California, USA) affixed within the recovery room in approximately 5 min and discharged home. Average resting and dynamic pain scores measured on the 0–10 Numeric Rating Scale were a median of 1 over the first 2 days, subsequently falling to 0. Five patients avoided opioid use entirely, while the remaining two each consumed 5 mg of oxycodone during the first 1–2 postoperative days. After 5 days, the devices were removed at home and discarded.ConclusionsThese cases demonstrate that ambulatory percutaneous auricular neuromodulation is feasible and may be an effective analgesic and decreasing or even negating opioid requirements following outpatient surgery. Considering the lack of systemic side effects, serious adverse events, and misuse/dependence/diversion potential, further study with a randomized, controlled trial appears warranted.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a group of preinvasive breast neoplasms. Studies have shown excellent survival among patients with lumpectomy-amenable disease. Patients requiring mastectomy have been less well characterized. We aim to characterize this cohort and identify whether growth distribution pattern is associated with sentinel lymph node involvement at time of surgery or subsequent development of metastatic disease. METHODS: Patients were identified using local cancer registry data and were chart reviewed using electronic medical records. Growth pattern was classified as unifocal, multifocal, or diffuse. Chi-squared, Analysis of Variance (ANOVA), and Kaplan-Meier analyses were performed. RESULTS: Two hundred and twenty-six patients were identified with median age at diagnosis 49 and follow up 7.1 years. 42 had unifocal, 51 had multifocal and 20 had diffuse lesions. 3/20 patients with diffuse type lesions developed subsequent distant metastatic disease, while none of the patients with unifocal or multifocal lesions did. 1/20 patients with diffuse and 2/51 with multifocal disease had sentinel lymph node involvement (SLNI) at surgery. Tumor extent was not associated with sentinel lymph node involvement or distant metastatic disease (P=0.2, Kaplan-Meier analysis) but growth pattern was (P=0.01). It was also associated on Kaplan-Meier with development of distant metastatic disease alone (P=0.01). CONCLUSIONS: Patients with diffuse growth pattern DCIS were more likely to have SLNI or development of distant metastatic disease. Our findings suggest that patients with diffuse type lesions are at greater risk of metastatic disease and therefore breast cancer death from DCIS. Optimal therapy for these patients will need further elucidation.

Purpose:Diffusion-weighted MRI (DW-MRI) is a contrast-free modality that has demonstrated ability to discriminate between predefined benign and malignant breast lesions. However, how well DW-MRI discriminates cancer from all other breast tissue voxels in a clinical setting is unknown. Here we explore the voxelwise ability to distinguish cancer from healthy breast tissue using signal contributions from the newly developed three-component multi-b-value DW-MRI model.Experimental Design:Patients with pathology-proven breast cancer from two datasets (n = 81 and n = 25) underwent multi-b-value DW-MRI. The three-component signal contributions C1 and C2 and their product, C1C2, and signal fractions F1, F2, and F1F2 were compared with the image defined on maximum b-value (DWImax), conventional apparent diffusion coefficient (ADC), and apparent diffusion kurtosis (Kapp). The ability to discriminate between cancer and healthy breast tissue was assessed by the false-positive rate given a sensitivity of 80% (FPR80) and ROC AUC.Results:Mean FPR80 for both datasets was 0.016 [95% confidence interval (CI), 0.008–0.024] for C1C2, 0.136 (95% CI, 0.092–0.180) for C1, 0.068 (95% CI, 0.049–0.087) for C2, 0.462 (95% CI, 0.425–0.499) for F1F2, 0.832 (95% CI, 0.797–0.868) for F1, 0.176 (95% CI, 0.150–0.203) for F2, 0.159 (95% CI, 0.114–0.204) for DWImax, 0.731 (95% CI, 0.692–0.770) for ADC, and 0.684 (95% CI, 0.660–0.709) for Kapp. Mean ROC AUC for C1C2 was 0.984 (95% CI, 0.977–0.991).Conclusions:The C1C2 parameter of the three-component model yields a clinically useful discrimination between cancer and healthy breast tissue, superior to other DW-MRI methods and obliviating predefining lesions. This novel DW-MRI method may serve as noncontrast alternative to standard-of-care dynamic contrast-enhanced MRI.

Mean (95% CI) for all performance measures the U.S. dataset (Supplementary Table S1) and European dataset (Supplementary Table S2). Median (interquartile range) for average signal of the cancer and control regions of interests (ROIs) for both datasets combined (Supplementary Table S3).

Probability density colormaps for the three-component model given C1 and C2 for all voxels per patient for (A.) cancer (cancer ROI) and (B.) healthy breast tissue (control ROI).

Probability density colormaps for the three-component model given C1 and C2 for all voxels per patient for (A.) cancer (cancer ROI) and (B.) healthy breast tissue (control ROI).

Probability density colormaps for the three-component model given C1 and C2 for all voxels per patient for (A.) cancer (cancer ROI) and (B.) healthy breast tissue (control ROI).

PURPOSE Trials for DCIS have not explored whether outcomes for patients with large disease burden requiring mastectomy are comparable to those of patients with lumpectomy-amenable disease. We aim to identify whether patients with DCIS larger than 5 cm and diffuse-type DCIS differ in breast cancer mortality (BCM) from patients with disease less than 5 cm. METHODS Patients diagnosed with DCIS in the SEER program were assessed to identify factors prognostic of breast-cancer-specific survival using competing risks regression. RESULTS 44,849 patients met criteria for the cumulative incidence estimate. On competing risks cumulative incidence approximation, the 10-year estimate for BCM for each group was 1.3%, 1.3%, 2.3%, and 5.1%, respectively, and the difference among groups was significant (p = 0.017). On competing risks regression of patients with known covariates, both diffuse-type disease and disease larger than 5 cm (hazard ratio [HR] = 6.2 and 1.7, p = 0.013 and p = 0.042, respectively) were associated with increased risk of BCM. After matching, DCIS > 5 cm and diffuse disease were associated with increased BCM relative to disease

Background Diffusion-weighted (DW) echo-planar imaging (EPI) is prone to geometric distortions due to B0 inhomogeneities. Both prospective and retrospective approaches have been developed to decrease and correct such distortions. Purpose The purpose of this work was to evaluate the performance of reduced-field-of-view (FOV) acquisition and retrospective distortion correction methods in decreasing distortion artifacts for breast imaging. Coverage of the axilla in reduced-FOV DW magnetic resonance imaging (MRI) and residual distortion were also assessed. Study type Retrospective. Population/phantom Breast phantom and 169 women (52.4 ± 13.4 years old) undergoing clinical breast MRI. Field strength/sequence A 3.0 T/ full- and reduced-FOV DW gradient-echo EPI sequence. Assessment Performance of reversed polarity gradient (RPG) and FSL topup in correcting breast full- and reduced-FOV EPI data was evaluated using the mutual information (MI) metric between EPI and anatomical images. Two independent breast radiologists determined if coverage on both EPI data sets was adequate to evaluate axillary nodes and identified residual nipple distortion artifacts. Statistical tests Two-way repeated-measures analyses of variance and post hoc tests were used to identify differences between EPI modality and distortion correction method. Generalized linear mixed effects models were used to evaluate differences in axillary coverage and residual nipple distortion. Results In a breast phantom, residual distortions were 0.16 ± 0.07 cm and 0.22 ± 0.13 cm in reduced- and full-FOV EPI with both methods, respectively. In patients, MI significantly increased after distortion correction of full-FOV (11 ± 5% and 18 ± 9%, RPG and topup) and reduced-FOV (8 ± 4% both) EPI data. Axillary nodes were observed in 99% and 69% of the cases in full- and reduced-FOV EPI images. Residual distortion was observed in 93% and 0% of the cases in full- and reduced-FOV images. Data conclusion Minimal distortion was achieved with RPG applied to reduced-FOV EPI data. RPG improved distortions for full-FOV images but with more modest improvements and limited correction near the nipple. Evidence level 3 TECHNICAL EFFICACY: Stage 1.

Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/Tis ypN0). SGN-LIV1A is an investigational antibody drug conjugate consisting of an antibody to LIV1A, a zinc transporter highly prevalent in breast cancer, and a highly potent microtubule inhibitor, monomethyl auristatin E. Retrospective IHC analysis of LIV1A expression levels amongst tumor samples from 100 previous ISPY-2 patients showed 88% of breast tumor samples with moderate to high expression of LIV1A (Yau, C. et al SABCS 2018).Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone-receptor positive (HR+) patients had to have MP high molecular profile. Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MR imaging where response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Analysis set was modified intention to treat with patients who switched to non-protocol therapy counted as non-pCR and not as their pCR status at time of surgery. The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within signatures defined by HR & HER2 status & MP result. This investigational arm was eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Regimens may also leave the trial for futility (< 10% probability of success), maximum sample size accrual (10% < probability of success Results: Sixty patients were randomized and evaluable to SGN-LIV1A. The study arm was stopped due to reaching the predetermined time limit for patient accrual of 2 yrs. Final estimated pCR rates are below. The estimated pCR rates were similar between the SGN-LIV1A and control arms for any tumor subtype. Preliminary safety events for SGN-LIV1A include increased rates of transaminitis and hyperglycemia and reduced rates of peripheral neuropathy compared to control. One patient was removed from the analysis as she was determined to have angiosarcoma of the breast. Notably, this patient had a dramatic early response and subsequent pCR to SGN-LIV1A treatment. Conclusion: The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing. A trial of SGN-LIV1A in the treatment of angiosarcoma is under consideration at this time. Final Estimated pCR Rates and Predictive ProbabilitiesEstimated pCR rate(95% prob interval)SignatureSGN-LIV1AControlProbability SGNLIV1A Superior to ControlPredictive Probability of Success in Phase 3HER2-0.16 (0.08-0.24) N= 600.20 (0.16-0.25) N= 3270.180.02HR-/HER2-0.25 (0.12-0.37) N=360.28 (0.21-0.35) N=1460.310.06HR+/HER2-0.09 (0-0.18) N=240.14 (0.09-0.19) N=1810.150.03 Citation Format: Heather Beckwith, Richard Schwab, Christina Yau, Erica Stringer-Reasor, Shi Wei, A. Jo Chien, Kathy S Albain, Kevin Kalinsky, Anne Wallace, Anthony Elias, Douglas Yee, Amy S Clark, Judy C Boughey, Heather Han, Rita Nanda, Claudine Isaacs, Zahi Mitri, Julie E Lang, Alexandra Thomas, Tara Sanft, Angela DeMichele, Jane Perlmutter, Hope S Rugo, Nola M Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, I-SPY 2 Consortium, Amy Wilson, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [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 PD1-10.

Purpose: Diffusion-weighted MRI (DW-MRI) is a contrast-free modality that has demonstrated ability to discriminate between predefined benign and malignant breast lesions. However, how well DW-MRI discriminates cancer from all other breast tissue voxels in a clinical setting is unknown. Here we explore the voxelwise ability to distinguish cancer from healthy breast tissue using signal contributions from the newly developed three-component multi-b-value DW-MRI model. Experimental Design: Patients with pathology-proven breast cancer from two datasets (n = 81 and n = 25) underwent multi-b-value DW-MRI. The three-component signal contributions C1 and C2 and their product, C1C2, and signal fractions F1, F2, and F1F2 were compared with the image defined on maximum b-value (DWImax), conventional apparent diffusion coefficient (ADC), and apparent diffusion kurtosis (Kapp). The ability to discriminate between cancer and healthy breast tissue was assessed by the false-positive rate given a sensitivity of 80% (FPR80) and ROC AUC. Results: Mean FPR80 for both datasets was 0.016 [95% confidence interval (CI), 0.008–0.024] for C1C2, 0.136 (95% CI, 0.092–0.180) for C1, 0.068 (95% CI, 0.049–0.087) for C2, 0.462 (95% CI, 0.425–0.499) for F1F2, 0.832 (95% CI, 0.797–0.868) for F1, 0.176 (95% CI, 0.150–0.203) for F2, 0.159 (95% CI, 0.114–0.204) for DWImax, 0.731 (95% CI, 0.692–0.770) for ADC, and 0.684 (95% CI, 0.660–0.709) for Kapp. Mean ROC AUC for C1C2 was 0.984 (95% CI, 0.977–0.991). Conclusions: The C1C2 parameter of the three-component model yields a clinically useful discrimination between cancer and healthy breast tissue, superior to other DW-MRI methods and obliviating predefining lesions. This novel DW-MRI method may serve as noncontrast alternative to standard-of-care dynamic contrast-enhanced MRI.

Background: Disseminated tumor cells (DTCs) in bone marrow detected after treatment may represent occult residual disease. We enumerated DTCs after neoadjuvant chemotherapy (NACT) in patients (pts) diagnosed with high-risk early stage breast cancer and examined the relationship of these cells with response and survival. Methods: I-SPY SURMOUNT is a sub-study of the I-SPY 2 TRIAL (NCT01042379). Pts enrolled on I-SPY 2, who signed consent for this sub-study, had bone marrow aspirates (BMA) collected after NACT at the time of surgery. DTCs were isolated and enumerated from BMA using immunomagnetic enrichment/flow cytometry (IE/FC). DTCs were defined as EPCAM-positive and CD45-negative nucleated cells. Samples were considered positive using a predetermined threshold of >4 DTCs per mL (Magbanua et al, unpublished data). Pathologic response was assessed using the residual cancer burden (RCB) method at local sites, and pts underwent standard adjuvant therapy if indicated and follow up for recurrence events and death. Relationship of DTCs with clinicopathologic variables was examined using Chi-squared test. Group means were compared using t tests. The log-rank test was used to compare survival curves. Results: A total of 73 patients were enrolled, 51 of whom had successful DTC assessment. The median DTC per mL was 4 (interquartile range 1.2-11.6). 24/51 (47%) were DTC-positive. Clinical characteristics by DTC status are shown in the table. DTC-positive pts were significantly younger (p=0.02) and had larger pretreatment tumors (longest diameter by magnetic resonance imaging) compared to DTC-negative pts (p=0.032). DTCs were not associated with receptor subtype. Thirty pts (41%) achieved a pathologic complete response (pCR). DTCs were not associated with pCR (p= 0.166); however, DTC-positive patients were significantly more likely to have residual cancer (RCB-II/III) after NACT compared to DTC-negative patients (OR 3.3, p=0.037). Median follow up of this cohort was 2.8 years (range: 0.9-4.8). Interim survival analysis showed that DTCs were not significantly correlated with EFS (p=0.6) or DRFS (p=0.41). Conclusions: Detection of DTCs at surgery after NACT is significantly more common in young patients, those with larger tumors, and those with residual disease at surgery. While these associations suggest higher risk for later recurrence, larger studies and longer follow up are necessary to determine if DTCs add prognostic value over pathologic evaluation alone for pts receiving NACT. Citation Format: Mark Jesus M Magbanua, Laura van 't Veer, Amy Clark, A. Jo Chien, Judy Boughey, Heather Han, Anne Wallace, Heather Beckwith, Minetta Liu, Christina Yau, E. Paul Wileyto, Lamorna Brown Swigart, Jane Perlmutter, Lauren Bayne, Shannon Deluca, Stephanie Yee, Erica Carpenter, Laura Esserman, John Park, Lewis Chodosh, Angela DeMichele. Outcomes associated with disseminated tumor cells at surgery after neoadjuvant chemotherapy in high-risk early stage breast cancer: The I-SPY SURMOUNT study [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 PS2-07.

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Primary cutaneous anaplastic large-cell lymphoma and breast implant-associated ALCL (BIA-ALCL) are rare subtypes of anaplastic lymphoma kinase (ALK)-negative ALCLs originating from skin and breast implants, respectively. Herein, we report a unique case of cutaneous ALK-negative ALCL occurring in the skin of left medial breast from a patient with multiple rounds of bilateral breast implants and a history of breast carcinoma. The lymphoma cells are entirely confined to the lymphatic channels in the dermis, and the patient has no other areas of skin abnormality, no lymphadenopathy, peri-implant fluid accumulation, or masses from the bilateral capsules of implants. The differential diagnosis and its relationship with breast implants are further explored.

PURPOSE: To use the National Cancer Database to assess treatment patterns in very young women with ductal carcinoma in situ (DCIS) given their propensity for higher risk features and increased risk of recurrence. METHODS: We used the NCDB to identify female patients who underwent surgery for a first cancer diagnosis of DCIS within three different age groups: ≤30, 31–50, and >50. Demographic information, tumor characteristics, and initial treatment patterns were characterized and compared. Univariable and multivariable logistic regression of individuals with hormone-receptor positive disease who underwent breast conserving surgery (BCS) was conducted to assess for group differences in adjuvant endocrine therapy utilization. Survival analysis was conducted via Kaplan-Meier method and Cox Regression. RESULTS: We identified 236,832 patients meeting inclusion criteria. Individuals in the youngest group were more likely to be a minority, had better Charlson-Deyo scores, lived further from their treatment facility, and were less often insured. This group also had more unfavorable tumor features and were more likely to undergo bilateral mastectomy. In subgroup analysis of patients with hormone-receptor positive disease who underwent BCS, the youngest group was significantly less likely to have received endocrine therapy. There was also a trend towards worse overall survival in the youngest group. CONCLUSION: We report differences in demographics, tumor characteristics, and treatment of very young women with DCIS. Given the known reduction in recurrence with use of adjuvant endocrine therapy, there may be room for increasing therapy rates or otherwise altering guidelines for treatment of young women with hormone-receptor positive DCIS who undergo BCS.

The impact of HER2 status in ductal carcinoma in situ (DCIS) on the risk of progression to invasive ductal carcinoma (IDC) has been debated. We aim to use a national database to identify patients with known HER2 status to elucidate the effect of HER2 overexpression on ipsilateral IDC (iIDC) development. We performed survival analysis on patient-level data using the U.S. NCI's Surveillance Epidemiology and End Results program. We identified patients diagnosed with DCIS who underwent lumpectomy and had known HER2 status. Competing risks analysis was performed. A total of 1,540 patients had known HER2 status and met inclusion criteria. Median age at diagnosis was 60, median follow-up time was 44.5 months. A total of 417 (27.1%) patients were HER2 positive and 1,035 (67.2%) were HER2 negative. Twenty-two (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% for HER2-negative and borderline patients, and 3.9% for HER2-positive patients. On multivariate competing risks regression, two factors were significant for iIDC: radiation (protective) therapy within 24 months (HR, 0.05; P = 0.00006) and HER2 overexpression (increased likelihood; HR, 2.72; P = 0.044). Patients with HER2-positive DCIS were more likely to have recurrences with receptor discordance. HER2 may serve as a prognostic factor for invasive recurrence and was the only lesion-related factor to significantly relate to iIDC development. It may also be associated with receptor discordance of recurrences. Further large studies will be needed to confirm these results.

Background: Patients who achieve a pathological complete response (pCR- defined as no invasive cancer) after neoadjuvant chemotherapy (NAC) for breast cancer (BC) have improved outcomes, but there is still controversy about the significance of residual ductal carcinoma in situ (DCIS) on local recurrence rate (LRR). The I-SPY 2 TRIAL is an adaptive neoadjuvant platform trial evaluating novel experimental regimens in comparison to standard chemotherapy in women with high-risk breast cancer. The purpose of this study is to determine if residual DCIS after NAC in early BC affects LRR in patients with or without residual invasive disease in the I-SPY 2 TRIAL. Methods: 933 I-SPY 2 patients with residual cancer burden (RCB) and follow-up data were included in this analysis. Residual DCIS was defined as any carcinoma in situ > 0% on RCB evaluation. Local recurrence was defined as recurrence in breast, chest wall or locoregional nodes and/or skin and subcutaneous tissue. We stratified our cohort into four groups: those without residual invasive disease (defined as RCB0) ± residual DCIS, and those with residual invasive disease (RCB>0) ± residual DCIS. We estimated LRR within each group using the Kaplan Meier method; and used Cox proportional hazards models to assess LRR differences between groups, with: patients with no residual disease (invasive or in situ) as reference group. Results: Among 933 patients assessed, median follow up time was 3.9 years. RCB 0 status was achieved in 337 patients (36%). Of these, 267 (29%) had no residual DCIS, which represents our reference group, and 70 (7%) had residual DCIS. Among 596 (64%) patients who had RCB>0, 296 (32%) had residual DCIS. For patients with RCB0 without DCIS and RCB0 with DCIS, the LRR at 3 years were similar: 2% vs 3% respectively (Hazard ratio: 1.29 [0.26-6.39]). Results were also similar in the RCB>0 group, with a LRR of 10% at 3 years in those without residual DCIS, and 11% in those with residual DCIS. Both RCB>0 groups had significantly higher LRR when compared to the patients with RCB0 without DCIS (Hazard ratio: 5.25 [2.20-12.5]) and HR 5.85 [2.47-13.9] respectively). Conclusion: There was no association between residual DCIS and LRR after neoadjuvant chemotherapy, regardless of resolution of invasive disease. Further work is needed to determine whether residual DCIS should drive locoregional therapy decisions after neoadjuvant chemotherapy for invasive breast cancer. Citation Format: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Smita M. Asare, Ron Balassanian, Jodi M. Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Gretchen Ahrendt, Akiko Chiba, Cheryl Ewing, Constantine Godellas, Nora Jaskowiak, Brigid Killelea, Helen Krontiras, Rachael Lancaster, Julie Lang, M. Catherine Lee, Arpana Naik, Roshni Rao, Julia Tchou, Shannon Tierney, Eleni Tousimis, Tod Tuttle, Anne Wallace, I-SPY 2 TRIAL Consortium, Bev Parker, Laura J. Esserman, Rita A. Mukhtar. The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL [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 P3-08-16.

Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [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 P2-20-02.

Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify (graduate) regimens with ≥ 85% Bayesian predictive probability of success (i.e., demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with pCR endpoint within signatures defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status. Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or safety concerns as recommended by the independent DSMB. For HER2+ patients, the I-SPY2 control arm was 12 weekly cycles of paclitaxel+trastuzumab (TH, control) followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x4 and surgery. Patritumab is a fully human monoclonal antibody that inhibits HER3. In this experimental arm for HER2+ patients, patritumab was given q3w x 4 cycles (18mg/kg loading dose followed by 9mg/kg/dose) concurrent with paclitaxel and trastuzumab q1w x 12 weeks (PTH, treatment), followed by AC q2-3w. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 weeks after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Analysis was intention to treat. Patients who switched to non-protocol therapy count as non-pCR. Patients on treatment arm therapy at the time of arm closure are non-evaluable. Graduation potential was in 3 of 10 pre-defined signatures: all HER2+, HR-/HER2+, and HR+/HER2+. Results: The PTH regimen was stopped at the recommendation of the Safety Working Group and DSMB based on a safety event (bilateral sensorineural hearing loss, Gr 3) observed in one patient. At the time of arm closure, N=31 patients had received PTH treatment; 4 patients receiving PTH were changed to non-protocol therapy and removed from the analysis. The final estimated pCR report will consider 27 PTH and 31 TH as evaluable patients. Accrual was insufficient to assess graduation, however, there appears to be good signal in the HER2+HR- but not HER2+HR+ signatures. I-SPY 2 TRIAL Est. pCR at time of arm closureSignaturesPTH (Treatment)N= 31TH (Control)N = 31All (HER2+)0.40 (0.22 - 0.59), n=310.23 (0.09 - 0.37), n=31HR-/HER2+0.64 (0.36 - 0.91), n=110.30 (0.12 - 0.47), n=12HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19 HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19The patient who developed Gr3 sensorineural hearing loss 6 days after the 2nd patritumab (and 4th paclitaxel/trastuzumab) treatment, did not recover her hearing after patritumab was stopped, and also reported Gr3 vulvovaginal pain, vulvitis, and vaginal inflammation. Other gynecological symptoms in the PTH arm include: 1 pt with Gr1 vaginal hemorrhage, and 1 pt with Gr2 dyspareunia. There was a higher frequency of Gr3 hypokalaemia (12.5% vs. 3.2%). One pt in the PTH arm reported Gr3 small intestinal obstruction which resolved with conservative management. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial; PTH was stopped due to safety concerns, although there was activity in the HER2+ HR- signature. This is the first report of Gr3 hearing loss associated with patritumab/paclitaxel/trastuzumab, and thus attribution is uncertain. Citation Format: Teresa L Helsten, Shelly S Lo, Christina Yau, Kevin Kalinsky, Anthony D Elias, Anne M Wallace, A. Jo Chien, Janice Lu, Julie E Lang, Kathy S Albain, Erica Stringer-Reasor, Amy S Clark, Judy C Boughey, Erin D Ellis, Douglas Yee, Angela DeMichele, Claudine Isaacs, Jane Perlmutter, Hope S Rugo, Richard Schwab, Nola M. Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, Amy Wilson, Ruby Singhrao, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant I-SPY 2 trial [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 P3-11-02.

Background: I-SPY2 is a multicenter, response-adaptive randomization phase 2 trial to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - weekly paclitaxel + investigational treatment x 12 wks followed by doxorubicin & cyclophosphamide(AC) q3 wks x 4 vs. weekly paclitaxel/AC (control). The primary endpoint is pathologic complete response (pCR). The goal for all investigational arms is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with a pCR endpoint within signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Findings from the graduated, previously reported Pembro4 arm (Nanda et al, ASCO 2017) supported investigation of de-escalating therapy, and determining if pembrolizumab (an anti-PD-1 antibody) alone q3 wks x 4 after weekly paclitaxel x 12 wks + pembrolizumab q3 wks x 4 was sufficient to sustain response without AC. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ were ineligible. MRI scans (at baseline, 3 wks, 12 wks, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients (pts). Pts who receive non-protocol therapy (e.g., carboplatin or AC for the Pembro8-noAC arm) count as non-pCR. Pembro8-noAC was open to HER2- pts for evaluation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2-, and HR-/HER2-. Regimens exit the trial for futility ( Results: Pembro8-noAC was randomized to 73 pts, 3 of whom progressed while receiving pembrolizumab alone on study. Randomization to this arm continued after the first report because the rate of progression during AC over the course of the trial was estimated to be 6.5% based on serial MRI studies. However, notification of the third case prompted the study team to ask the DSMB for the summary response for this arm. Although it did not meet formal stopping rules for either graduation or futility, Pembro8-noAC was not near the target threshold pCR rates of 60% for HR-/HER2- and 30% for HR+/HER2+. As a result of this information, combined with the on-treatment progressions, assignment to Pembro8-noAC was discontinued. Treatment with pembrolizumab alone was no longer allowed due to the potential concern for progression, and investigators were given the option to administer AC with pembrolizumab or proceed with definitive surgery following the 12 weeks of paclitaxel + pembrolizumab. 34 pts had surgery results at the time the study was closed. Of the remaining 39 pts, 34 pts have on-therapy MRI assessments. Estimated pCR rates were based on all pts with information at the time (see table). Immune-related adverse events included grade 3 colitis (n=2), grade 3 pneumonitis (n=1), grade 3 transaminitis (n=1), grade 3 hypothyroidism (n=1), and grade 1-2 adrenal insufficiency (n=5). Conclusion: Although Pembro8-noAC is performing at least as well as standard paclitaxel/AC, the likelihood is very low that the regimen would be successful in a phase 3 trial. Pembrolizumab alone following 12 weeks of paclitaxel + pembrolizumab was not sufficient to sustain a response. This was quickly assessed with a small number of patients. Estimated pCR rateSignature(95% prob interval)Pembro8-noACControlHER2-0.210.2(0.09-0.32)(0.15-0.25)HR-/HER2-0.270.27(0.09-0.45)(0.19-0.35)HR+/HER2-0.150.15(0.01-0.29)(0.09-0.20) Citation Format: Minetta C. Liu, Patricia A Robinson, Christina Yau, Anne M Wallace, A. Jo Chien, Erica Stringer-Reasor, Rita Nanda, Douglas Yee, Kathy S Albain, Judy C Boughey, Heather S Han, Anthony D Elias, Kevin Kalinsky, Amy S Clark, Kathleen Kemmer, Claudine Isaacs, Julie E Lang, Janice Lu, Tara Sanft, Angela DeMichele, Nola M Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Patricia K Haugen, Amy Wilson, Ruby Singhrao, Smita Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [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 P3-09-02.

BackgroundParavertebral nerve blocks (PVBs) are frequently used to treat pain during and following breast surgery, but have various undesirable risks such as pneumothorax. The erector spinae plane block (ESPB) also provides perioperative breast analgesia, but is purported to be easier to administer with a favorable safety profile. However, it remains unknown if the new ESPB provides comparable analgesia as the decades-old PVB technique.MethodsSubjects undergoing unilateral or bilateral non-mastectomy breast surgery were randomized to a single-injection ESPB or PVB in a subject-blinded fashion (ropivacaine 0.5% with epinephrine; 20 mL unilateral or 16 mL/side for bilateral). We hypothesized that (1) analgesia would be non-inferior in the recovery room as measured on a Numeric Rating Scale (NRS) with ESPB, and (2) opioid consumption would be non-inferior in the operating and recovery rooms with ESPB.ResultsBoth pain scores and opioid consumption were higher in subjects with ESPBs (n=50) than PVBs (n=50; median NRS 3.0 vs 0; 95% CI −3.0 to 0; p=0.0011; and median morphine equivalents 2.0 vs 1.5 mg; 95% CI −1.2 to −0.1; p=0.0043). No block-related adverse events occurred in either group.ConclusionsPVBs provided superior analgesia and reduced opioid requirements following non-mastectomy breast surgery. To compare the relatively rare complications between the techniques will require a sample size 1–2 orders of magnitude greater than the current investigation; however, without a dramatic improvement in safety profile for ESPBs, it appears that PVBs are superior to ESPBs for postoperative analgesia after non-mastectomy breast surgery.Trial registration numberNCT03549234.

PURPOSE: Restriction spectrum imaging (RSI) decomposes the diffusion-weighted (DW) MRI signal into separate diffusion components of known apparent diffusion coefficients (ADCs). The number of diffusion components and optimal ADCs for RSI are organ-specific and determined empirically. The purpose of this work was to determine the RSI model for breast tissues. METHODS: The DW-MRI signal was described using a linear combination of multiple exponential components. A set of ADC values was estimated to fit voxel in cancer and control regions of interest (ROIs). Later, the signal contributions of each diffusion component were estimated using these fixed ADC values. Relative fitting residual and Bayesian information criterion (BIC) were assessed. Contrast-to-noise ratio (CNR) between cancer and fibroglandular tissue in RSI-derived signal contribution maps was compared to dynamic contrast enhanced (DCE) imaging. RESULTS: A total of 74 women with breast cancer were scanned at 3.0T MRI. The fitting residuals of conventional ADC and BIC suggest that a three-component model improves the characterization of the diffusion signal over a bi-exponential model. Estimated ADCs of tri-exponential model were D(1,3)=0, D(2,3)=1.5×10(−3) and D(3,3)=10.8×10(−3) mm(2)/s. The RSI-derived signal contributions of the slower diffusion components were larger in tumors than in fibroglandular tissues. Further, the CNR and specificity at 80% sensitivity of DCE and a subset of RSI-derived maps were equivalent. CONCLUSION: Breast DW-MRI signal was best described using a tri-exponential model. Tumor conspicuity in breast RSI model is comparable to that of DCE without the use of exogenous contrast. These data may be used as differential features between healthy and malignant breast tissues.

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY’s prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

ImportancePathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS).ObjectiveTo examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response.Design, Setting, and ParticipantsThe study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence.InterventionsParticipants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery.Main Outcomes and MeasuresThe presence of DCIS and EFS, DRFS, and LRR.ResultsThe study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS.Conclusions and RelevanceThe analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS.Trial RegistrationClinicalTrials.gov Identifier NCT01042379.

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51–52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379

BackgroundParavertebral and serratus plane blocks are both used to treat pain following breast surgery. However, it remains unknown if the newer serratus block provides comparable analgesia to the decades-old paravertebral technique.MethodsSubjects undergoing unilateral or bilateral non-mastectomy breast surgery were randomized to a single-injection serratus or paravertebral block in a subject-masked fashion (ropivacaine 0.5%; 20 mL unilateral; 16 mL/side bilateral). We hypothesized that (1) analgesia would be non-inferior in the recovery room with serratus blocks (measurement: Numeric Rating Scale), and (2) opioid consumption would be non-inferior with serratus blocks in the operating and recovery rooms. In order to claim that serratus blocks are non-inferior to paravertebral blocks, both hypotheses must be at least non-inferior.ResultsWithin the recovery room, pain scores for participants with serratus blocks (n=49) had a median (IQR) of 4.0 (0–5.5) vs 0 (0–3.0) for those with paravertebral blocks (n=51): 0.95% CI −3.00 to −0.00; p=0.001. However, the difference in morphine equivalents did not reach statistical significance for superiority with the serratus group consuming 14 mg (10–19) vs 10 mg (10–16) for the paravertebral group: 95% CI −4.50 to 0.00, p=0.123. Since the 95% CI lower limit of −4.5 was less than our prespecified margin of −2.0, we failed to conclude non-inferiority of the serratus block with regard to opioid consumption.ConclusionsSerratus blocks provided inferior analgesia compared with paravertebral blocks. Without a dramatic improvement in safety profile for serratus blocks, it appears that paravertebral blocks are superior to serratus blocks for postoperative analgesia after non-mastectomy breast surgery.Trial registration numberNCT03860974.

Trials for DCIS have not explored whether outcomes for patients with large disease burden requiring mastectomy are comparable to those of patients with lumpectomy-amenable disease. We aim to identify whether patients with DCIS larger than 5 cm and diffuse-type DCIS differ in breast cancer mortality (BCM) from patients with disease less than 5 cm.Patients diagnosed with DCIS in the SEER program were assessed to identify factors prognostic of breast-cancer-specific survival using competing risks regression.44,849 patients met criteria for the cumulative incidence estimate. On competing risks cumulative incidence approximation, the 10-year estimate for BCM for each group was 1.3%, 1.3%, 2.3%, and 5.1%, respectively, and the difference among groups was significant (p = 0.017). On competing risks regression of patients with known covariates, both diffuse-type disease and disease larger than 5 cm (hazard ratio [HR] = 6.2 and 1.7, p = 0.013 and p = 0.042, respectively) were associated with increased risk of BCM. After matching, DCIS 5 cm and diffuse disease were associated with increased BCM relative to disease 5 cm (HR = 1.69, p = 0.04). Among patients undergoing mastectomy for disease larger than 5 cm or diffuse disease, the 10-year cumulative incidence for BCM was 0.5% among patients undergoing bilateral mastectomy and 2.4% for patients undergoing unilateral mastectomy.Patients with large and diffuse DCIS represent uncommon but poorly studied DCIS subgroups with worse prognoses than patients with disease smaller than 5 cm. Further studies are needed to elucidate the appropriate treatment for these patients.

Background: Patients achieving a pathologic complete response (pCR) following neoadjuvant therapy have significantly improved event-free survival relative to those who do not; and pCR is an FDA-accepted endpoint to support accelerated approval of novel agents/combinations in the neoadjuvant treatment of high risk early stage breast cancer. Previous studies have shown that recurrence risk increased with increasing burden of residual disease (as assessed by the RCB index). As well, these studies suggest that patients with minimum residual disease (RCB-I class) also have favorable outcomes (comparable to those achieving a pCR) within high risk tumor subtypes. In this study, we assess whether integrating RCB with MRI functional tumor volume (FTV), which in itself is prognostic, can improve prediction of distant recurrence free survival (DRFS); and identify a subset of patients with minimal residual disease with comparable DRFS as those who achieved a pCR. Imaging tools can then be used to identify the subset that will do well early and guide the timing of surgical therapy. Method: We performed a pooled analysis of 596 patients from the I-SPY2 TRIAL with RCB, pre-surgical MRI FTV data and known follow-up (median 2.5 years). We first assessed whether FTV predicts residual disease (pCR or pCR/RCB-I) using ROC analysis. We applied a power transformation to normalize the pre-surgical FTV distribution; and assessed its association with DRFS using a bi-variate Cox proportional hazard model adjusting for HR/HER2 subtype. We also fitted a bivariate Cox model of RCB index adjusting for subtype; and assessed whether adding pre-surgical FTV to this model further improves association with DRFS using a likelihood ratio (LR) test. For the Cox modeling, penalized splines approximation of the transformed FTV and RCB index with 2 degrees of freedom was used to allow for non-linear effects of FTV and RCB on DRFS. Result: Pre-surgical MRI FTV is significantly associated with DRFS (Wald p Conclusion: Pre-surgical MRI FTV is effective at predicting minimal residual disease (RCB0/I) in the I-SPY 2 TRIAL. Despite the association between FTV and RCB, FTV appears to provide independent added prognostic value (to RCB and subtype), suggesting that integrating MRI volume measures and RCB into a composite predictor may improve DRFS prediction. Citation Format: Hylton NM, Symmans WF, Yau C, Li W, Hatzis C, Isaacs C, Albain KS, Chen Y-Y, Krings G, Wei S, Harada S, Datnow B, Fadare O, Klein M, Pambuccian S, Chen B, Adamson K, Sams S, Mhawech-Fauceglia P, Magliocco A, Feldman M, Rendi M, Sattar H, Zeck J, Ocal I, Tawfik O, Grasso LeBeau L, Sahoo S, Vinh T, Yang S, Adams A, Chien AJ, Ferero-Torres A, Stringer-Reasor E, Wallace A, Boughey JC, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, Haugen PK, van't Veer LJ, Perlmutter J, Melisko ME, Wilson A, Peterson G, Asare AL, Buxton MB, Paoloni M, Clennell JL, Hirst GL, Singhrao R, Steeg K, Matthews JB, Sanil A, Berry SM, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, I-SPY 2 TRIAL Consortium, Yee D, Pusztai L, DeMichele A, Asare SM, Berry DA, Esserman LJ. Refining neoadjuvant predictors of three year distant metastasis free survival: Integrating volume change as measured by MRI with residual cancer burden [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-03.

This abstract was withdrawn by the authors. Citation Format: Schwab R, Clark A, Yau C, Wolf D, Chien AJ, Majure M, Ewing C, Wallace A, Roesch E, Helsten T, Forero A, Stringer-Reasor E, Vaklavas C, Nanda R, Jaskowiak N, Boughey J, Haddad T, Han H, Lee C, Albain K, Isaacs C, Elias A, Ellis E, Shah P, Lang J, Lu J, Tripathy D, Kemmer K, Yee D, Haley B, Korde L, Edmiston K, Northfelt D, Viscusi R, Khan Q, I-SPY 2 Consortium, Symmans WF, Perlmutter J, Hylton N, Rugo H, Melisko M, Wilson A, Singhrao R, Asare S, van't Veer L, DeMichele A, Berry D, Esserman L. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-02.

Background: Smoking is a known risk factor for various types of cancer, and breast cancer patients who smoke are known to have higher breast cancer mortality. However, few studies have found an association between smoking and breast cancer incidence or tumor biology. The Athena Breast Health Network distributes an intake questionnaire at the UCSF and UCSD breast care centers which can be used to investigate links between tobacco exposure and the characteristics of incident breast cancer. Methods: Intake questionnaires were distributed to all new patients at the UCSF and UCSD breast care centers from December 2012 to May 2018. Patients who completed the questionnaire with a known diagnosis of breast cancer were compared to those without in a case-control study. Breast cancer diagnoses were determined by ICD9 diagnosis codes from the patients' medical records. The association of smoking and breast cancer prevalence and biology was analyzed using generalized linear models and Fisher tests in R. Results: Of the 7727 patients who completed the Athena intake questionnaire at UCSF and UCSD, 5499 consented to have their data used for research. A first analysis was conducted on 4175 UCSF patients alone: 2186 of the UCSF patients who had completed the questionnaire had a documented breast cancer diagnosis, vs 1989 with no known diagnosis at the time of this analysis. 1096 of the 4175 UCSF patients reported having ever smoked, including 73 who had accrued 30 or more pack years. Complete pathology data was available for 1120 cancer patients. Controlling for age, more patients with invasive breast cancer reported having ever smoked, with an odd's ratio (OR) of 2.32 (p = .0043). By including DCIS, the OR drops slightly to 2.26 (p = .0058). Taking alcohol consumption into account as a confounder lowered the OR to 2.19 (p = .0454). Overall, the risk of breast cancer increases with each additional pack year (OR = 1.08, p = .0211), independent of age. There are no significant differences in tumor biology for any smoking group. Conclusions: A history of smoking is associated with an increased risk of developing breast cancer and is directly related to cumulative pack years exposure. This association should be further validated in cohort studies. Citation Format: Dreher N, Layton TM, Parker BA, Shibley WP, Acerbi I, Wallace AM, Blair S, Pierce JP, Glantz S, Guydish J, Hiatt R, van 't Veer L, Esserman L, Athena Breast Health Network Investigators and Advocate Partners. Tobacco exposure and breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-03.

Background: In women with breast cancer receiving neoadjuvant chemotherapy, residual cancer burden (RCB) predicts distant recurrence and survival. In those with high risk tumors, locoregional recurrence (LRR) remains a concern, and has been associated with type of local therapy received. We evaluated the impact of local therapy on LRR in the ISPY-2 TRIAL. Methods: Data were analyzed in Stata 14.2, using Chi2 test, log rank test, and a Cox proportional hazards model. RCB was considered a categorical variable (0/1 versus 2/3), as described in prior publications. Breast surgery categories were lumpectomy +/- radiotherapy, or mastectomy +/- radiotherapy. Axillary surgery was defined as sentinel lymph node (SLN) surgery (≤6 nodes removed) or axillary dissection (>6 nodes). Results: Follow up data from the I-SPY2 TRIAL were available for 630 patients (median follow up 2.76 yrs, range 0.4-7.2). Type of local therapy was significantly associated with clinical stage at presentation, with stage III patients most frequently undergoing mastectomy + radiation (p In a Cox model adjusting for clinical stage, tumor subtype, surgical therapy, RCB status, nodal radiation, and age, significant predictors for LRR were tumor subtype and RCB status. Hazard ratio (HR) for LRR in those with RCB 0/1 was 0.39 compared to those with RCB 2/3 (95% CI 0.17-0.87, p=0.021). There was no difference in LRR between breast conservation and mastectomy; within the breast conservation group, those who had lumpectomy alone had higher hazard of LRR compared to those having lumpectomy + radiation (HR 3.1, 95% CI 1.1-9.2, p=0.043). Conclusions: Extent of surgical therapy was not associated with local tumor control, regardless of advanced tumor stage at presentation. Rather, tumor biology and response to therapy were the best predictors of LRR. These data highlight the opportunity to minimize the morbidity of extensive surgical therapy for patients with excellent response to systemic therapy. LRR rates by clinical features and treatment status FrequencyLRR RateP valueClinical Stage 0.5I240 (47.5%)5.8% II185 (36.6%)8.7% III80 (15.8%)6.3% Tumor Subtype 0.014ER+PR+Her2-161 (26.4%)3.1% ER+PR-Her2-56 (9.2%)3.6% Her2+176 (28.9%)6.3% Triple negative216 (35.5%)11.1% Local therapy 0.169Lumpectomy85 (13.5%)11.8% Lumpectomy with radiation198 (31.4%)5.6% Mastectomy173 (27.5%)5.2% Mastectomy with radiation174 (27.6%)8.6% Axillary surgery 0.23None5 (0.8%)20% SLN329 (52.2%)5.8% ALND296 (47%)8.5% Axillary radiation 0.535Yes42 (6.7%)9.5% No588 (93.3%)7.0% Axillary management 0.2No surgery or radiation5 (0.8%)20.0% SLN312 (50%)5.3% SLN+Axillary radiation17 (2.7%)8.3% ALND271 (43%)10.3% ALND+Axillary radiation25 (4%)5.4% RCB 0.0020/1293 (50.1%)3.8% 2/3292 (49.9%)10.3% Citation Format: Silverstein J, Suleiman L, Yau C, Price ER, Singhrao R, Yee D, DeMichele A, Isaacs C, Albain KS, Chien AJ, Forero-Torres A, Wallace AM, Pusztai L, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Leyland-Jones B, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, I-SPY 2 TRIAL Consortium, Berry DA, Asare SM, Esserman LJ, Boughey JC, Mukhtar RA. The impact of local therapy on locoregional recurrence in women with high risk breast cancer in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-01.

Diffusion-weighted (DW) echo-planar imaging (EPI) is prone to geometric distortions due to BThe purpose of this work was to evaluate the performance of reduced-field-of-view (FOV) acquisition and retrospective distortion correction methods in decreasing distortion artifacts for breast imaging. Coverage of the axilla in reduced-FOV DW magnetic resonance imaging (MRI) and residual distortion were also assessed.Retrospective.Breast phantom and 169 women (52.4 ± 13.4 years old) undergoing clinical breast MRI.A 3.0 T/ full- and reduced-FOV DW gradient-echo EPI sequence.Performance of reversed polarity gradient (RPG) and FSL topup in correcting breast full- and reduced-FOV EPI data was evaluated using the mutual information (MI) metric between EPI and anatomical images. Two independent breast radiologists determined if coverage on both EPI data sets was adequate to evaluate axillary nodes and identified residual nipple distortion artifacts.Two-way repeated-measures analyses of variance and post hoc tests were used to identify differences between EPI modality and distortion correction method. Generalized linear mixed effects models were used to evaluate differences in axillary coverage and residual nipple distortion.In a breast phantom, residual distortions were 0.16 ± 0.07 cm and 0.22 ± 0.13 cm in reduced- and full-FOV EPI with both methods, respectively. In patients, MI significantly increased after distortion correction of full-FOV (11 ± 5% and 18 ± 9%, RPG and topup) and reduced-FOV (8 ± 4% both) EPI data. Axillary nodes were observed in 99% and 69% of the cases in full- and reduced-FOV EPI images. Residual distortion was observed in 93% and 0% of the cases in full- and reduced-FOV images.Minimal distortion was achieved with RPG applied to reduced-FOV EPI data. RPG improved distortions for full-FOV images but with more modest improvements and limited correction near the nipple.3 TECHNICAL EFFICACY: Stage 1.

The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.

PURPOSEThe current trend in ductal carcinoma in situ (DCIS) research is towards treatment de-escalation. Problematically, prognostic indicators for patients at high risk of breast cancer mortality (BCM), rather than recurrence, have not been identified. We aim to identify prognostic factors for the development of metastatic disease and mortality.EXPERIMENTAL DESIGNPatients diagnosed with DCIS in a local cancer registry as well as in the National Cancer Database (NCDB) and the Surveillance, Epidemiology and End Results (SEER) program were assessed for factors prognostic of metastatic disease, overall, and breast-cancer specific survival. Cox and competing risks regressions were developed.RESULTSAmong 5 patients who developed distant metastatic disease in the cancer registry, 3 had identifiable growth distribution; all 3 were diffuse type. None had in-breast invasive or DCIS recurrences before metastasis. In NCDB and SEER, cumulative incidence of any cause mortality (ACM) and BCM at 10 years was 12%/5.0% for diffuse lesions; 8%/3.6% for patients with microinvasive disease, 7.4%/2.3% for lesions >5 cm, 5.6%/1.4% for lesions 2-5 cm and 5.5%/1.5% for lesions CONCLUSIONDiffuse DCIS represents an uncommon but deadly subtype for whom treatment escalation, rather than de-escalation, is likely necessary. Further studies elucidating the mechanism of metastasis and best treatment course are needed.

PurposeDiffusion-weighted magnetic resonance imaging (DW-MRI) is a contrast-free modality that has demonstrated ability to discriminate between pre-defined benign and malignant breast lesions. However, the ability of DW-MRI to discriminate cancer tissue from all other breast tissues in a clinical setting is unknown. Here we explore the ability to distinguish breast cancer from healthy breast tissues using signal contributions from the newly developed three-component multi-b-value DW-MRI model.Experimental designPathology-proven breast cancer patients from two datasets (n=81 and n=25) underwent multi-b-value DW-MRI. The three-component signal contributions C1 and C2 and their product, C1C2, were compared to the image defined on maximum b-value (DWImax), conventional apparent diffusion coefficient (ADC), and apparent diffusion kurtosis (Kapp). Ability to discriminate between cancer and healthy breast tissues was assessed by the false positive rate given sensitivity of 80% (FPR80) and receiver operating characteristic (ROC) area under the curve (AUC).ResultsMean FPR80 for both datasets was 0.016 (95%CI=0.008–0.024) for C1C2, 0.136 (95%CI=0.092–0.180) for C1, 0.068 (95%CI=0.049–0.087) for C2, 0.159 (95%CI=0.114–0.204) for DWImax, 0.731 (95%CI=0.692–0.770) for ADC and 0.684 (95%CI=0.660–0.709) for Kapp. Mean ROC AUC for C1C2 was 0.984 (95%CI=0.977–0.991).ConclusionsThe three-component model yields a clinically useful discrimination between cancer and healthy breast tissues, superior to other DW-MRI methods and obliviating pre-defining lesions by radiologists. This novel DW-MRI method may serve as non-contrast alternative to standard-of-care dynamic contrast-enhanced MRI (DCE-MRI); removing the need to administer Gadolinium contrast decreases scan time and any accumulation of Gadolinium in the brain.

PurposeDiffusion weighted (DW) echo-planar imaging (EPI) is prone to geometric and intensity distortions due to B0 inhomogeneities. Pulse sequences that excite spins within a reduced field-of-view (FOV) in the phase encoding (PE) direction have been developed to decrease such distortions. In addition, use of the reverse polarity gradient (RPG) method, a retrospective approach to correct distortion artifacts, has been shown to improve the localization of tumor lesions. The purpose of this work was to evaluate the performance of reduced-FOV acquisition and RPG in decreasing distortion artifacts for breast imaging.MethodsEPI data were acquired with full and reduced-FOV in a breast phantom and in a group of 170 women at 3T. The performance of RPG in correcting distortion artifacts in EPI data was evaluated using the mutual information (MI) metric between EPI and anatomical low-distortion images before and after distortion correction.ResultsRPG corrected distortions by 61% in full-FOV EPI and 48% in reduced-FOV EPI in a breast phantom. In patients, MI increased on average 13±8% and 8±6% for both full and reduced-FOV EPI data after distortion correction, respectively. The 95th percentile and maximum displacement between uncorrected and corrected full-FOV EPI datasets were 0.8±0.3cm and 1.9±0.3cm, and for reduced-FOV were 0.4±0.2cm and 1.3±0.3cm.ConclusionMinimal distortion was achieved with RPG applied to reduced-FOV EPI data. RPG improved distortions for full-FOV, but with more modest improvements and limited correction near the nipple.

Author(s): Gabriel, Rodney A; Finneran, John J; Swisher, Matthew W; Said, Engy T; Sztain, Jacklynn F; Khatibi, Bahareh; Wallace, Anne M; Hosseini, Ava; Trescot, Andrea M; Ilfeld, Brian M | Abstract: BackgroundAcute post-mastectomy pain is frequently challenging to adequately treat with local anesthetic-based regional anesthesia techniques due to its relatively long duration measured in multiple weeks.CaseWe report three cases in which preoperative ultrasound-guided percutaneous intercostal nerve cryoneurolysis was performed to treat pain following mastectomy. Across all postoperative days and all three patients, the mean pain score on the numeric rating scale was 0 for each day. Similarly, no patient required any supplemental opioid analgesics during the entire postoperative period; and, no patient reported insomnia or awakenings due to pain at any time point. This was a significant improvement over historic cohorts.ConclusionsUltrasound-guided percutaneous cryoanalgesia is a potential novel analgesic modality for acute pain management which has a duration that better-matches mastectomy than other currently-described techniques. Appropriately powered randomized, controlled clinical trials are required to demonstrate and quantify both potential benefits and risks.

The impact of HER2 status in ductal carcinoma in situ (DCIS) on the risk of progression to invasive ductal carcinoma (IDC) has been debated. We aim to use a national database to identify patients with known HER2 status to elucidate the effect of HER2 overexpression on ipsilateral IDC (iIDC) development. We performed survival analysis on patient-level data using the US National Cancer Institute’s Surveillance, Epidemiology, and End Results program. We identified patients diagnosed with DCIS who underwent lumpectomy and had known HER2 status. Competing risks analysis was performed. 1,540 patients had known HER2 status and met inclusion criteria. Median age at diagnosis was 60, median follow-up time was 44.5 months. 417 (27.1%) patients were HER2 positive and 1,035 (67.2%) were HER2 negative. 22 (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% for HER2 negative and borderline patients, and 3.9% for HER2 positive patients. On multivariate competing risks regression, two factors were significant for iIDC: radiation (protective) therapy within 24 months (HR=0.05, p=0.00006) and HER2 overexpression (increased likelihood) (HR=2.72, p=0.044). Patients with HER2 positive DCIS were more likely to have recurrences with receptor discordance. HER2 may serve as a prognostic factor for invasive recurrence and was the only lesion-related factor to significantly relate to iIDC development. It may also be associated with receptor discordance of recurrences. Further large studies will be needed to confirm these results.

The combination of PD-L1-inhibitor durvalumab and PARP-inhibitor olaparib (DOP) in addition to standard neoadjuvant chemotherapy was investigated in the phase II I-SPY2 platform trial of stage II/III HER2-negative breast cancer. Seventy-three HER2-negative participants were randomized to DOP and 299 to standard of care control. DOP graduated in all subtypes, increasing pCR rates in all HER2-negative (22 to 37%), HR-positive/HER2-negative (14% to 28%), TNBC (27% to 47%). In HR-positive/HER2-negative cancers, pCR rate in MammaPrint ultra high (MP2) cases was considerably higher than MP1, 64% vs 22%. Overall,12.3% of patients in the experimental arm experienced immune-related grade 3 adverse events vs. 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has potential benefits over standard neoadjuvant therapy in HER2-negative early breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.

INTRODUCTION: No prior studies have compared Tc-99m tilmanocept (TcTM) one-day and two-day injection protocols for sentinel lymph node (SLN) biopsy in breast cancer (BC). METHODS: We retrospectively identified clinically node-negative BC patients undergoing SLN biopsy at our institution. Patients received a single, intradermal peritumoral injection of TcTM on day-of surgery or day-prior to surgery in addition to an intraoperative injection of isosulfan blue dye. Univariable and multivariable Poisson regression count models were constructed to assess the effects of injection timing, radiologist, patient, and surgeon characteristics on the number of removed SLNs. RESULTS: 617 patients underwent SLN biopsy with TcTM and blue dye. Sixty-seven (10.9%) patients were injected with the two-day protocol. Patients in the one-day protocol had a mean of 3.0 (standard deviation (SD) 1.9) SLNs removed compared to 2.7 (SD 1.4) SLNs in the two-day protocol, p-value = 0.13. On multivariable analysis, patient age and operating surgeon significantly affected the number of removed SLNs; however, the injection timing and the nuclear radiologist did not influence the number of removed SLNs. CONCLUSIONS: The performance of Tc-99m tilmanocept did not differ significantly between one-day and two-day injection protocols. These results are similar to other radiotracers used for SLN biopsy in BC.