Hieken, TJ

Abstract Background: Male breast cancer (MBC) is rare, and usually managed by extrapolation from female breast cancer. We report on the characteristics and survival outcomes of MBC patients from Mayo Clinic Rochester (MCR). Methods: Medical records of MBC patients treated at MCR during a 25-year period (1990-2015) were reviewed. Demographic variables, tumor characteristics, recurrences, and overall survival (OS) were collected. Progression free survival (PFS) and OS were estimated by the Kaplan-Meier method. Multivariate Cox-proportional hazard regression was used to identify predictors of OS. Results: One hundred sixty-seven patients were included in the final analysis, with a median follow-up of 58 months after diagnosis. Baseline characteristics are presented in Table 1. Eighty percent of patients with ER-positive tumors received endocrine therapy. Among men with stage I-III disease, approximately 90% underwent mastectomy, and 44% received adjuvant chemotherapy. The 5-year locoregional and distant recurrence rates for patients with stage I-III disease were 4.4% and 21.5%, respectively. The 5-year PFS and OS for patients with stage I-III disease were 65.5% and 80.1%, respectively. In a multivariate analysis assessing predictors of OS in patients with stage I-III disease, older age (HR 1.05; 95% CI: 1.02 – 1.09), stage II (HR 11.06; 95% CI: 3.84 – 31.85) or stage III disease (HR 14.74; 95% CI (3.99 – 54.45), and omission of surgery (HR 45.33; 95% CI: 3.97 – 517.32) were associated with poorer OS, while endocrine therapy (HR 0.21, 95% CI: 0.09 – 0.51) was associated with better OS. ER, PR, HER2 and grade were not independently prognostic. The median OS for stage IV patients was 10 months, though this 11-man cohort was too small to allow assessment of prognostic factors in advanced male breast cancer. Conclusions: MBC remains an understudied condition. Prognostic factors in this stage I-III disease are consistent with those identified in other MBC retrospective cohorts. Prospective studies are needed to better understand the unique clinical features of MBC, and to improve outcomes, particularly for advanced disease. Table 1:Baseline characteristics N=167 Median age at diagnosis (Years)64.4 Ethnicity/Race: Caucasian131 (78.4%)African American4 (2.4%)Other or unknown32 (19.2%) Overall AJCC 7th edition stage: Stage I39 (23.4%)Stage II80 (47.9%)Stage III32 (19.2%)Stage IV11 (6.6%)Unknown5 (3.0%) Grade: 18 (4.8%)247 (28.1%)3101 (60.5%)Unknown12 (7.1%) ER status: Negative8 (4.8%)Positive153 (91.6%)Unknown6 (3.6%) PR status: Negative17 (10.2%)Positive141 (84.4%)Unknown9 (5.4%) HER-2 status: Negative70 (41.9%)Positive12 (7.2%)Unknown85 (50.9%) Citation Format: Yadav S, Leon-Ferre RA, Jimenez RE, Hawse JR, Hieken TJ, Couch FJ, Boughey JC, Ruddy KJ. Clinical characteristics and survival of patients with male breast cancer: The Mayo Clinic experience [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 P6-19-05.

Abstract Background Metaplastic breast cancer (MBC), characterized by a mixture of epithelial, squamous or mesenchymal elements and a usually triple-negative (TN) phenotype, accounts for <1% of breast cancer diagnoses. MBC has a poor prognosis with frequent distant spread, but, paradoxically, a lower than expected rate of nodal positivity (6 to 40%). Due to its rarity there is little data on how best to evaluate and manage the axilla in women with these tumors. Thus we undertook this study to evaluate axillary management and oncologic outcomes. Methods With IRB approval, we identified adult patients diagnosed with MBC at our institution from 2001 to 2011 from our prospective surgical pathology database. Patient, pathology, imaging, treatment and outcome data were obtained from electronic medical record, tumor registry, pathology slide and imaging review. Median follow-up for surviving patients was 66 months. Statistical analyses were performed using JMP 10.0 software. Results We identified 41 MBC patients, median age 60 years (range 33-89 years), with a median tumor size of 2.7 cm; 33 (80%) were TN. 23 patients (56%) had a preoperative axillary ultrasound (AUS): 9 (39%) showed at least one suspicious axillary lymph node (LN) of whom 6 had a preoperative fine needle LN biopsy (FNA) of which 3 were positive for metastasis. 6 patients, including the 3 LN+ on FNA, had neoadjuvant chemotherapy (NAC). Operation included axillary dissection (ALND) in 14, sentinel LN biopsy (SLNB) in 23, and SLNB followed by ALND in 1, while 3 patients had no axillary surgery. 10 patients were LN+ at operation. Among 22 patients who had both an AUS and axillary surgery, AUS had a sensitivity of 100% and specificity of 78%. Patient and tumor variables in association with pathologic LN status are summarized in the table. LN positivity correlated with increasing tumor size, T stage, grade and angiolymphatic invasion. 16 patients recurred, most with distant disease (10/16, 63%), although there was a solitary axillary recurrence 8 months after a negative SLNB in one patient who did not have a preoperative AUS. Thus the accuracy of SLNB was 96% (23/24) overall, but among those without preoperative AUS, 1/7 (14%) SLNBs were falsely negative. 5-year disease-free and breast cancer-specific survival estimates were 49% and 63%. LN- N=28 (74%)LN+ N=10 (26%)p-valueSize, median (IQR), cm2.7 (1.6-4.6)6.6 (2.5-16.5)0.001T stage 0.03T19 (100%)0 (0%) T214 (78%)4 (22%) T33 (60%)2 (40%) T42 (33%)4 (67%) Grade 0.04Low6 (16%)0 (0%) Intermediate/High22 (58%)10 (26%) Estrogen Receptor 0.61Positive (>1%)5 (71%)2 (29%) Negative (<1%)23 (74%)8 (26%) Angiolymphatic Invasion 0.002No26 (87%)4 (13%) Yes2 (25%)6 (75%) Dominant Histology 0.65Adenosquamous2 (100%)0 (0%) Matrix producing4 (80%)1 (20%) Spindle cell14 (74%)5 (26%) Squamous*8 (67%)4 (33%) *any squamous component Conclusion Our study is the first to specifically address AUS and SLNB for patients with metaplastic breast cancer. AUS had 100% sensitivity and 78% specificity, while one patient without a preoperative AUS had a falsely negative SLNB. Further, AUS with FNA of suspicious LNs was useful for staging at the time of diagnosis and informing treatment. We recommend this approach for patients with MBC. Citation Format: Murphy BL, Fazzio RT, Hoskin TL, Glazebrook KN, Keeney MG, Habermann EB, Hieken TJ. Management of the axilla in metaplastic breast carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-01.

Abstract Background: Post-mastectomy radiotherapy improves survival in women with node-positive breast cancer. Pencil beam scanning proton therapy is attractive due to potential to reduce the dose to the heart and lungs compared with traditional photon techniques while improving conformality and limiting skin dose compared with passively scanned proton therapy. The optimal dose and fractionation for pencil-beam scanning proton therapy remains unknown. Trial Design: This is a multi-center open label phase II randomized controlled trial to determine the safety of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation. Eligibility Criteria: Patients ≥ 18 years with primary, non-inflammatory invasive breast cancer who have undergone mastectomy with or without immediate reconstruction and chest wall and regional nodal irradiation planned. Aims: To determine whether the 24 month complication rate (defined as grade 3 or greater late adverse events, and unplanned surgical intervention in patients who undergo mastectomy with reconstruction) of 15 fraction chest wall and regional node pencil beam scanning proton radiotherapy is acceptable relative to 25 fraction chest wall and regional nodal pencil beam scanning proton radiotherapy and worthy of further investigation. Statistical methods: The study is designed as a non-inferiority/superiority “hybrid” design using the approach of Freidlin et al. It is Using a one-sided type I error rate of 0.05 (corresponding equivalently to constructing a 1-sided 95% confidence limit), 72 evaluable patients will have 80% power to reject the null hypothesis that the 24-month complication rate in the experimental arm is higher than that of the control arm by more than 10% (i.e. rule out inferiority) under the alternative hypothesis that the complication rate in the experimental arm is 5% less than that of the control arm (i.e. superiority). However, the design will have only 41% power when the two treatment arms are equivalent (i.e. the complication rate is 10% for both arms). Accrual: The study opened in June 2016. Five of a planned eighty-two patients have been accrued to date. Citation Format: Mutter RW, Park SS, Hieken TJ, Vargas CE, Mei-Yin PC, Kathryn RJ, Hector VR, Kimberly CS, Elizabeth YS, Daniel VW. A randomized trial of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-03-03.

Abstract Background:Neoadjuvant chemotherapy (NCT) is used frequently to downstage locally advanced tumors and facilitate breast conservation. However, we have previously reported that achievement of radiographic complete response (rCR) or pathologic complete response (pCR) does not impact choice of surgery for many patients. This secondary analysis reports treatment outcomes across 9 NCI comprehensive cancer centers in women receiving both NCT and breast MR imaging to assess whether treatment outcomes among women receiving NCT differs according to choice of locoregional treatment. Methods:1077 women from 9 institutions were retrospectively identified as having undergone NCT with MR imaging obtained both before and after systemic treatment. Systemic treatment regimen was not prespecified, but receipt of at least 80% of all planned cycles was required prior to final MR imaging. We performed a univariate analysis as well as a multivariable Cox proportional hazard regression to identify covariates associated with overall survival (OS), disease-free survival (DFS) and time to recurrence (TTR). rCR was defined as no residual enhancement on post-treatment breast MRI. Results:1077 patients diagnosed and treated with NCT for stage I-III invasive breast cancer from January 1, 2002 to June 16, 2014 were analyzed for all endpoints. Median follow-up was 4.2 years, (range 0.1 to 13 years). Median age of the cohort was 50 years, (range 19-87 years). 473 (43.9%) had ER(+) and/or PR(+)/HER2(-) disease, 348 (32.3%) had HER2(+) disease, and 256 (23.8%) had ER(-)/PR(-)/HER2(-) (triple negative) disease. Mastectomy or breast conserving therapy (BCT) was recorded as the definitive surgery in 675 (62.7%) and 402 (37.3%) of patients, respectively. Radiation receipt was confirmed in 84.1% of BCT and 68.3% of mastectomy patients. Overall there were 134 recurrences, 168 disease events and 89 deaths. Among patients with pCR, there were 7/161 (7.2%) recurrences in those undergoing mastectomy and 6/143 (5.1%) in those undergoing lumpectomy (p=0.81). Among patients who achieved an rCR, there were recurrences in 5% of those undergoing mastectomy and 2.9% in those undergoing lumpectomy (p=0.53). In multivariable analysis of the entire cohort, only clinical stage, ER status and pCR remained independently associated with DFS. Notably, subset analysis showed that lumpectomy was independently associated with improved TTR (HR 0.40; 95% CI 0.17-0.97) in the triple negative group only, but this did not translate into improved DFS with lumpectomy in this group. Radiographic CR as determined by breast MRI accurately predicted presence or absence of pCR in 74% of cases, but was not independently associated with DFS, OS or TTP. Conclusions:Among a contemporary cohort of women receiving neoadjuvant systemic therapy and breast MR imaging at 9 NCI designated cancer centers, type of surgery did not impact DFS, OS or TTP. The only exception was found in the triple negative group in which the lumpectomy group had a more favorable TTP compared to the mastectomy group. These findings provide additional evidence that in women who are appropriate candidates for lumpectomy after NCT, BCT does not compromise long-term cancer outcomes. Citation Format: De Los Santos J, Hyslop T, Alvarado M, Forero A, Golshan M, Hieken T, Horton J, Hudis C, McGuire K, Meric-Bernstam F, Nanda R, Zagar T, Hwang S. Treatment outcomes in patients with invasive breast cancer treated with neoadjuvant systemic therapy and breast MR imaging: Results of a secondary analysis of TBCRC 017. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S3-06.

Abstract Background Women with benign breast disease (BBD) have an increased risk for breast cancer (BC). Almost 30% of all BCs develop in women with prior BBD. Information about the features of the expected BCs after BBD would enable individualized surveillance and prevention strategies for these women. We sought to characterize BCs developing in a large cohort of women with BBD. Methods Our cohort includes 13,485 women who underwent breast biopsy for mammographic or palpable concern between 1967-2001. Biopsy slides were reviewed and classified as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). BCs were identified by follow-up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed. Results With a median follow-up of 15.8 years, 1273 women developed BC. Most BCs were invasive (81%), among which 61% were ductal, 13% mixed ductal/lobular, and 14% lobular. Two thirds were intermediate or high-grade, and 29% were node positive. Cancer characteristics were similar across the three histologic categories of BBD, with similar frequency of DCIS and invasive disease, tumor size, time to invasive BC, histologic type of BC, nodal positivity and HER2 positivity. Women with AH had a higher frequency of ER+ BC (91%) vs women with PD (80%) or NP (85%), p=0.02. Conclusion A substantial proportion of all BCs develop in women with prior BBD. We show that the majority of BCs after BBD are invasive tumors of ductal type, with a substantial proportion node positive. 84% of cancers were ER-positive. Chemoprevention should be strongly encouraged in higher-risk women with BBD. Citation Format: Visscher DW, Frost MH, Hartmanan LC, Frank RD, Vierkant RA, McCullough AE, Winham SJ, Vachon C, Ghosh K, Brandt KR, Farrell AM, Tarabishy Y, Hieken TJ, Haddad TC, Kraft RA, Radisky DC, Degnim AC. Clinicopathologic features of breast cancers that develop in women with previous benign breast disease. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-19.

Abstract Background Activating mutations in PIK3CA occur in approximately 40% ER+BC. MK-2206 (M), a pan-AKT inhibitor, induced apoptosis of ER+ BC under estrogen deprivation in preclinical studies. We conducted this neoadjuvant trial to determine the pathologic complete response (pCR) rate of M plus anastrozole (A) for PIK3CA mutant (Mut) ER+ BC. Methods This single arm open label study of M+A used a 2-stage Simon phase II design (stage 1, n=16; stage 2, n=13, alpha=0.10, power=0.90) to test whether pCR rate <1% (based on historical data with A alone), against the alternative that pCR rate ≥15% in PIK3CA Mut ER+ BC. At least 1 pCR in stage 1 was required to proceed to stage 2. Eligible patients (pts) with clinical stage II or III ER+HER2- BC were pre-registered and proceeded to a research tumor biopsy for PIK3CA sequencing, followed by treatment with daily A monotherapy for 28 days (cycle 0). Pts with PIK3CA Mut BC were subsequently registered, underwent a second biopsy, and started M (150mg PO weekly) with daily A on cycle 1 day 1 (C1D1) for a maximum of four 28-day cycles followed by surgery. Goserelin was added for premenopausal pts. A tumor biopsy on C1D17, 17 days post the start of M, was performed. Those with C1D17 Ki67 >10% discontinued study treatment. pCR was defined as no invasive cancer in the breast and the lymph nodes. Tumor specimens collected at all timepoints are being analyzed for markers of proliferation, apoptosis, and PI3K pathway activity, gene expression microarray, intrinsic subtypes, and next generation sequencing of 83 genes. Results Of the 51 pts pre-registered, 35 pts did not register due to no PIK3CA mutation (n=22), inadequate specimen for testing (n=6), physician/pt decision (n=7). The remaining 16 pts (median age: 58, range: 40-77 years) received combination therapy. Three pts did not complete 4 cycles due to C1D17 Ki67 >10% (n=2) and intolerability (grade (Gr) 4 transaminase elevation in C1, n=1). Other severe toxicities possibly related to M included Gr 3 rash (25%) and pruritus (12.5%). Of the 13 pts completed study therapy and underwent surgery, all had residual disease in the breast and 7 also had positive nodes. Table 1 summarized changes in Ki67 during treatment. ComparisonsnAbsolute changes in Ki67 median (range)Wilcoxon signed rank p-valueC1D1 relative to pre-registration11-17.0% (-49.8 to 4.1%)0.0020C1D17 relative to pre-registration14-16.4% (-51.4 to 4.1%)0.0004C1D17 relative to C1D112-1.5% (-18.6 to 15.8%)0.9697C1D1, biopsy post 28 days of A alone; C1D17 biopsy post 17 days on combination therapy Although Ki67 levels post A monotherapy (C1D1) or M+A (C1D17) were significantly lower than that of pre-registration samples, Ki67 did not differ between C1D17 and C1D1 samples. Other correlative studies are ongoing and results will be presented. Conclusion Despite the small sample size, biomarker analysis on serial biopsy specimens demonstrated that M+A is unlikely to be more effective than A alone in PIK3CA Mut ER+ BC. This trial demonstrated the feasibility of genomic sequencing for pt selection and the value of a small, well-designed proof-of-principle neoadjuvant trial for the evaluation of targeted agents. Citation Format: Ma CX, Suman VJ, Goetz M, Northfelt D, Burkard M, Ademuyiwa F, Naughton M, Margenthaler J, Aft R, Gray R, Tavaarwerk A, Wilke L, Haddad T, Moynihan T, Loprinzi C, Hieken T, Hoog J, Guo Z, Han J, Vij K, Mardis E, Sanati S, Al-Kateb H, Doyle L, Erlichman C, Ellis MJ. A phase II neoadjuvant trial of MK-2206, an AKT inhibitor, in combination with anastrozole for clinical stage 2 or 3 PIK3CA mutant estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-13-04.

Abstract Background: Metaplastic breast carcinoma (MBC) accounts for <5% of all breast malignancies. This entity represents a heterogenous group of tumors in which the adenocarcinomatous element is admixed with one or more neoplastic mesenchymal (spindle, squamous, chondroid, or osseous) elements. Patients typically present with large triple negative tumors and have a poor prognosis. The likelihood of lymph node (LN) involvement has been reported to be low in MBC patients. Due to the paucity of data, we undertook this study to explore the role of axillary ultrasound (US) and sentinel LN biopsy (SLNB) in the management of MBC. Methods: With IRB approval, we retrospectively identified patients diagnosed with MBC from 2001–2011 from the surgical pathology database. Histopathology and imaging were reviewed. Demographic, treatment and outcome data were obtained by clinical chart review. Data were analyzed using JMP 9.0 software. Results: We identified 41 women with MBC. Median age was 60 years (range 33–90). Histologic subtypes were spindle cell (46%), mixed adenocarcinoma and mesenchymal elements (20%), squamous cell (17%) chondroid/osseous (10%) and adenosquamous (7%). Tumor stage was T1 (24%), T2 (44%), T3 (12%) and T4 (20%). 26 patients (63%) were treated by mastectomy and 15 (37%) by wide excision. Of the 38 patients who underwent LN surgery (6 low-grade MBC, 32 intermediate/high-grade MBC), 10 (26%) were LN positive. All low-grade MBC patients were LN negative while 10 of 32 intermediate/high-grade MBC patients (31%) had LN metastasis. 22 patients had a preoperative axillary US. 14 patients had a negative axillary US and none had LN metastasis. 4 of 8 patients with suspicious axillary US findings had a preoperative axillary LN fine needle aspiration biopsy (FNAB) and 3 were positive for cancer. These patients proceeded directly to axillary LN dissection (ALND). 24 patients had a SLNB of whom one was SLN positive and underwent completion ALND. LN metastasis was associated with larger tumor size (p = 0.003), higher tumor grade (p = 0.04), angioinvasion (p = 0.07) and abnormal axillary US (p = 0.003). Surviving patients were followed for a mean (median) of 41 (30) months during which 13 (32%) recurred at a median of 6 months (IQR 3–17 months) and 11 (27%) subsequently died of disease. One SLN negative patient developed an axillary recurrence at 8 months, was successfully treated by ALND and is disease-free at 38 months. There were no axillary LN relapses after ALND. Conclusions: For clinically node-negative MBC patients, our contemporary data series suggests the incidence of occult LN metastasis is sufficiently high to warrant LN staging especially for patients with intermediate and high-grade tumors. This can be accomplished in a minimally invasive fashion with reasonable accuracy (∼97%) with axillary US, FNAB of sonographically suspicious LNs, and SLNB for patients with negative axillary US or FNAB. Axillary LND should be performed for patients with clinically and/or FNAB-positive LN for enhanced disease control. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-22.