Prophylactic mastectomy and occult malignancy: Surgical and imaging considerations.

BACKGROUND: Sentinel node biopsy (SLNB) is not routinely recommended for patients undergoing prophylactic mastectomy (PM), yet omission remains a subject of debate among surgeons. A modern patient cohort was examined to determine occult malignancy (OM) incidence within PM specimens to reinforce current recommendations. METHODS: All PM performed over a 5-year period were retrospectively identified, including women with unilateral breast cancer who underwent synchronous or delayed contralateral PM or women with elevated cancer risk who underwent bilateral PM. RESULTS: The study population included 772 patients (598 CPM, 174 BPM) with a total of 39 OM identified: 17 invasive cancers (14 CPM, 3 BPM) and 22 DCIS (19 CPM, 3 BPM). Of the 86 patients for whom SLNB was selectively performed, 1 micrometastasis was identified. In the CPM cohort, risk of OM increased with age, presence of LCIS of either breast, or presence of a non-BRCA high-penetrance gene mutation, while preoperative magnetic resonance imaging was associated with lower likelihood of OM. CONCLUSIONS: Given the low incidence of invasive OM in this updated series, routine SLNB is of low value for patients undergoing PM. For patients with indeterminate radiographic findings, discordant preoperative biopsies, LCIS, or non-BRCA high-penetrance gene mutations, selective SLNB implementation could be considered.

Management of early stage HER2 positive breast cancer and increased implementation of axillary imaging to improve identification of nodal metastasis.

BACKGROUND AND OBJECTIVES: Given the significant benefit of targeted therapies for HER2+ breast cancer patients in both the neoadjuvant and adjuvant settings, it is critical to identify all eligible patients for these treatments. We sought to investigate cT1cN0 HER2+ patients to determine the rate of postsurgical nodal positivity, and to identify presurgical factors associated with nodal positivity. We hypothesize there is a subset of underdiagnosed HER2+ patients who would benefit from preoperative axillary imaging and inclusion in neoadjuvant chemotherapy regimens. METHODS: We performed a 10-year retrospective analysis of T1 HER2+ breast cancer patients. Clinicopathologic characteristics were evaluated based on surgical nodal data. RESULTS: We identified 38 patients with cT1cN0 HER2+ cancer. Of this cohort, 24% had positive lymph nodes on final pathology. High tumor grade (p = 0.035) on core needle biopsy and the presence of lymphovascular invasion (p = 0.0036) were associated with an increased likelihood of lymph node positivity. The majority (66%) of lymph node positive patients were clinically T1c. CONCLUSIONS: We identified a 24% nodal positivity rate in clinically node negative T1 HER2+ breast cancer patients. In particular, HER2+ patients with high-grade T1c cancers should undergo preoperative diagnostic axillary imaging to expand potential benefit from targeted therapies.

Factors associated with disease-free and abdominal recurrence-free survival in abdominopelvic and retroperitoneal sarcomas.

BACKGROUND AND OBJECTIVES: Retroperitoneal and abdominopelvic sarcomas are rare heterogeneous malignancies. The only therapy proven to improve disease-free survival (DFS) is R0/R1 surgical resection. We sought to analyze whether additional factors such as radiation and systemic therapy were associated with DFS and abdominal recurrence-free survival (RFS). METHODS: Retrospective review of adults (≥18) with resectable abdominopelvic and retroperitoneal sarcomas who underwent intent-to-cure surgery at a high-volume tertiary referral center between 1998 and 2015. The main outcome measures were DFS and abdominal RFS. RESULTS: Overall, 159 patients met the criteria for inclusion. Median follow-up was 4.8 years (range 0.1-18.9 years). The most common histology was liposarcoma (49%). Systemic therapy was administered to 48% of patients and was not associated with improved outcomes. The neoadjuvant radiotherapy group (11%) had improved adjusted DFS (5.46 years, 95% CI [3.68, 7.24] vs. 3.1 years, 95% CI [2.48, 3.73]) and abdominal RFS (6.14 years, 95% CI [4.38, 7.89] vs. 3.22 years, 95% CI [2.61, 3.84]). The adjuvant radiotherapy group (19%) had no improvement. CONCLUSIONS: In a cohort of patients undergoing resection for retroperitoneal or abdominopelvic sarcoma, neoadjuvant radiation improved DFS and abdominal RFS. A follow-up of over three years was needed to appreciate a difference in outcomes.

Impact of Breast Cancer Pretreatment Nodal Burden and Disease Subtype on Axillary Surgical Management.

BACKGROUND: The management of clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC) has progressed with the potential to avoid the morbidity of axillary lymph node dissection in patients with complete response to therapy. This study addresses the impact of pretreatment nodal burden and tumor subtype on axillary pathologic complete response (AXpCR) in patients treated with NAC to better inform axillary surgical management. METHODS: A prospective database was reviewed to identify clinically node-positive patients who underwent NAC followed by axillary lymph node dissection. Patients were stratified in accordance with abnormal nodal burden on pretreatment axillary imaging defined as low (1-2 nodes) or high (≥3 nodes), and biologic subtype defined by hormone receptor (HR+, HR-) and HER2 (human epidermal growth factor receptor 2) status. The primary outcome was AXpCR. RESULTS: AXpCR was 43% in the study population. There was no difference in AXpCR between low and high nodal burden groups (44% versus 42%, P = 0.87). Subtype correlated to AXpCR (P < 0.001) with the highest rate (78%) in the HR-/HER2+ group. Overall, HER2+ patients had a significantly higher AXpCR than HER2- subtypes (66% versus 28% P < 0.001). HR and HER2 status were also predictive of AXpCR when comparing patient, tumor, and treatment variables. CONCLUSIONS: Biologic subtype better correlated with rates of AXpCR than nodal burden alone with the highest rates of AXpCR in HER2+ patients. Consideration of tumor biology is more informative than nodal burden when evaluating options for axillary management after NAC.

Immunotherapy for Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive form of skin cancer which, while chemosensitive, has high rates of relapse and chemoresistance, limiting the impact of chemotherapy. An immunogenic tumor, the management of advanced MCC has changed dramatically with the introduction of checkpoint inhibitors. This review will focus on the impact of immunotherapy in unresectable and metastatic MCC, ongoing research in the adjuvant and neoadjuvant settings, and future directions of immune-based strategies for this challenging cancer.

Opioid prescribing exceeds consumption following common surgical oncology procedures.

BACKGROUND AND OBJECTIVES: Surgical oncology patients are vulnerable to persistent opioid use. As such, we aim to compare opioid prescribing to opioid consumption for common surgical oncology procedures. METHODS: We prospectively identified patients undergoing common surgical oncology procedures at a single academic institution (August 2017-March 2018). Patients were contacted by telephone within 6 months of surgery and asked to report their opioid consumption and describe their discharge instructions and opioid handling practices. RESULTS: Of the 439 patients who were approached via telephone, 270 completed at least one survey portion. The median quantity of opioid prescribed was significantly larger than consumed following breast biopsy (5 vs. 2 tablets of 5 mg oxycodone, p < .001), lumpectomy (10 vs. 2 tablets of 5 mg oxycodone, p < .001), and mastectomy or wide local excision (20 tablets vs. 2 tablets of 5 mg oxycodone, p < .001). The majority of patients reported receiving education on taking opioids, but only 27% received instructions on proper disposal; 82% of prescriptions filled resulted in unused opioids, and only 11% of these patients safely disposed of them. CONCLUSIONS: This study demonstrates that opioid prescribing exceeds consumption following common surgical oncology procedures, indicating the potential for reductions in prescribing.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

Axillary Pathologic Complete Response in Inflammatory Breast Cancer Patients: Implications for SLNB?

BACKGROUND: Sentinel lymph node biopsy (SLNB) is increasingly utilized after neoadjuvant chemotherapy (NAC) in responsive adenopathy, particularly with placement of a marking clip in the involved node(s). This may allow a subset of patients to avoid axillary lymph node dissection. SLNB is still discouraged in inflammatory breast cancer (IBC). The purpose of this study is to examine the axillary pathologic complete response (AXpCR) in IBC patients with clinical adenopathy. There may be an implication to approach a subset of IBC patients for SLNB after NAC. METHODS: A single-institution institutional review board-approved database was reviewed. Inclusion criteria were clinicopathologic diagnosis of IBC and age ≥ 18 years. Stage IV disease was excluded. We collected data on demographics, tumor characteristics including histology and subtype, axillary status, and treatment effect details. RESULTS: Sixty-six patients fulfilled criteria. Mean follow-up was 4.1 years. The AXpCR was 6% for luminal A and luminal B [human epidermal growth factor receptor (HER)2 -] subtypes, and 24% for basal subtype. The AXpCR rate was 64% for HER2-enriched and luminal B (HER2 +) patients. Achievement of AXpCR among these HER2-positive patients was statistically significant (p = 0.0001). There was minimal difference in achieving AXpCR in HER2-overexpressing patients regardless of hormone receptor status (p = 1.000). CONCLUSIONS: Understanding the best patients to select for use of SLNB or targeted lymph node dissection after treatment is evolving. This unique series identified and described the axillary pathologic characteristics of IBC patients following NAC. Further research is needed to confirm that the approach, axillary node clip placement prior to treatment, is feasible and accurate in IBC.

The Impact of Education and Prescribing Guidelines on Opioid Prescribing for Breast and Melanoma Procedures.

BACKGROUND: Excessive opioid prescribing is common in surgical oncology, with 72% of prescribed opioids going unused after curative-intent surgery. In this study, we sought to reduce opioid prescribing after breast and melanoma procedures by designing and implementing an intervention focused on education and prescribing guidelines, and then evaluating the impact of this intervention. METHODS: In this single-institution study, we designed and implemented an intervention targeting key factors identified in qualitative interviews. This included mandatory education for prescribers, evidence-based prescribing guidelines, and standardized patient instructions. After the intervention, interrupted time-series analysis was used to compare the mean quantity of opioid prescribed before and after the intervention (July 2016-September 2017). We also evaluated the frequency of opioid prescription refills. RESULTS: During the study, 847 patients underwent breast or melanoma procedures and received an opioid prescription. For mastectomy or wide local excision for melanoma, the mean quantity of opioid prescribed immediately decreased by 37% after the intervention (p = 0.03), equivalent to 13 tablets of oxycodone 5 mg. For lumpectomy or breast biopsy, the mean quantity of opioid prescribed decreased by 42%, or 12 tablets of oxycodone 5 mg (p = 0.07). Furthermore, opioid prescription refills did not significantly change for mastectomy/wide local excision (13% vs. 14%, p = 0.8), or lumpectomy/breast biopsy (4% vs. 5%, p = 0.7). CONCLUSION: Education and prescribing guidelines reduced opioid prescribing for breast and melanoma procedures without increasing the need for refills. This suggests further reductions in opioid prescribing may be possible, and provides rationale for implementing similar interventions for other procedures and practice settings.

Pleomorphic Lobular Carcinoma In Situ: Imaging Features, Upgrade Rate, and Clinical Outcomes.

OBJECTIVE: Pleomorphic lobular carcinoma in situ (PLCIS) is an aggressive subtype of lobular carcinoma in situ treated similarly to ductal carcinoma in situ. The purpose of this study was to determine the imaging findings, upgrade rate of PLCIS at core needle biopsy (CNB), and the treatment and outcomes of these patients. MATERIALS AND METHODS: This retrospective single-institution study included women with PLCIS at CNB or excisional biopsy without concomitant DCIS or invasive carcinoma between January 1, 1999, and July 20, 2016. Imaging findings, detection mode, treatment, and outcomes were reviewed. Retrospective review of the images was performed. Upgrade rate to ductal carcinoma in situ or invasive carcinoma at lumpectomy was calculated. RESULTS: Twenty-one patients had a finding of PLCIS at CNB (n = 16) or excisional biopsy (n = 5). Four of 15 (27%; 95% CI, 4-49%) cases of PLCIS at CNB were upgraded to DCIS (two cases) or invasive lobular cancer (two cases) at lumpectomy (one patient declined excision). No unique mammographic features were predictive of need to upgrade or extent of disease. Among the patients with pure PLCIS (not upgraded), 13 of 16 (81%) presented with fine pleomorphic calcifications on screening mammograms, 1 of 16 (6%) with distortion and calcifications, 1 of 16 (6%) with a mass, and 1 of 16 (6%) with nonmass enhancement at MRI. The median imaging size was 11 mm (mean, 14 mm; range, 3-47 mm). Twelve of 16 (75%) patients were treated with lumpectomy and 4 of 16 (25%) with mastectomy. Eight of 16 (50%) patients received adjuvant hormonal therapy, and 2 of 16 (17%) received radiation. There were no local recurrences. CONCLUSION: PLCIS most commonly presented as fine pleomorphic calcifications on mammograms and had a high upgrade rate after CNB. CNB diagnosis of PLCIS requires surgical excision.

Surgeon and Radiation Oncologist Views on Omission of Adjuvant Radiotherapy for Older Women with Early-Stage Breast Cancer.

PURPOSE: Although clinical trials have shown no survival advantage and only a modest improvement in local control from adjuvant radiotherapy after lumpectomy in older women with stage I, estrogen receptor-positive (ER+) breast cancer, radiotherapy is commonly administered, raising concerns about overtreatment. Therefore, we sought to evaluate physician views on omission of radiotherapy in older women with favorable prognosis breast cancer. METHODS: We surveyed a national sample of 713 radiation oncologists and 879 surgeons. Of these, 1504 were eligible and 825 responded (55%). We assessed responses to clinical scenarios, knowledge of pertinent risk information, and correlates of views on radiotherapy omission. RESULTS: Omission of radiotherapy in patients age ≥70 years with stage I, ER+ breast cancer, treated with lumpectomy and endocrine therapy, was felt to be unreasonable by 40% of surgeons and 20% of radiation oncologists. Many surgeons (29%) and radiation oncologists (10%) erroneously associated radiotherapy in older women with improvement in survival. Similarly, 32% of surgeons and 19% of radiation oncologists tended to substantially overestimate the risk of locoregional recurrence in older women with omission of RT. In a scenario with an 81-year-old with multiple comorbidities, 31% of surgeons and 35% of radiation oncologists would still recommend radiotherapy. CONCLUSIONS: Many radiation oncologists and surgeons continue to consider omission of radiotherapy as substandard therapy and overestimate the benefits of radiotherapy. Surgeons, in addition to radiation oncologists, may have an opportunity to play a pivotal role in reducing overuse of aggressive care in this setting.

Impact of neoadjuvant chemotherapy on surgical outcomes among patients with hormone receptor positive breast cancer.

BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is a surrogate for outcome, but not necessarily conversion to BCT eligibility. We sought to examine the impact of NACT on surgical decision making among HR+ patients. METHODS: Our IRB-approved breast cancer database was queried for patients who underwent NACT, including the clinicopathologic data and surgeon's pre- and post-NACT assessment. Surgical conversion rate (SCR) was defined as patients ineligible for BCT prior to NACT, who were given the choice following NACT. RESULTS: Among 289 patients, pCR rates were highest among patients with HER2-enriched subtype (60%) and lowest in patients with luminal A disease (4%). Overall, the BCT rate was 41%, while 28% opted for bilateral mastectomy across subtypes. Despite a low pCR, the SCR was still high (54%) among patients with the luminal A subtype. CONCLUSION: Despite poor pCR rates, NACT still has potential to improve surgical outcomes among hormone receptor positive patients. The surgical conversion rate is a superior measure of the impact of NACT on surgical decision making than examining BCT rates.

The natural history of thin melanoma and the utility of sentinel lymph node biopsy.

BACKGROUND AND OBJECTIVES: Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. METHODS: Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. RESULTS: Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2 , and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age ≤45 and ulceration. CONCLUSIONS: SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2 , and/or with ulceration. Thin melanoma <0.85 mm without high-risk features may be treated with WLE alone.

EZH2 expands breast stem cells through activation of NOTCH1 signaling.

Breast cancer is the second-leading cause of cancer-related deaths in women, but the details of how it begins remain elusive. Increasing evidence supports the association of aggressive triple-negative (TN) breast cancer with heightened expression of the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) and increased tumor-initiating cells (TICs). However, mechanistic links between EZH2 and TICs are unclear, and direct demonstration of a tumorigenic function of EZH2 in vivo is lacking. Here, we identify an unrecognized EZH2/NOTCH1 axis that controls breast TICs in TN breast carcinomas. EZH2 overexpression increases NOTCH1 expression and signaling, and inhibition of NOTCH1 activity prevents EZH2-mediated stem cell expansion in nontumorigenic breast cells. We uncover a unique role of EZH2 in activating, rather than repressing, NOTCH1 signaling through binding to the NOTCH1 promoter in TN breast cancer cells. EZH2 binding is independent of its catalytic histone H3 lysine 27 methyltransferase activity and of the Polycomb Repressive Complex 2 but corresponds instead to transcriptional activation marks. In vivo, EZH2 knockdown decreases the onset and volume of xenografts derived from TN breast TICs. Conversely, transgenic EZH2 overexpression accelerates mammary tumor initiation and increases NOTCH1 activation in mouse mammary tumor virus-neu mice. Consonant with these findings, in clinical samples, high levels of EZH2 are significantly associated with activated NOTCH1 protein and increased TICs in TN invasive carcinomas. These data reveal a functional and mechanistic link between EZH2 levels, NOTCH1 signaling activation, and TICs, and provide previously unidentified evidence that EZH2 enhances breast cancer initiation.

Trends in Media Reports of Celebrities' Breast Cancer Treatment Decisions.

BACKGROUND: Although the increasing use of bilateral mastectomies is multifaceted, one source of influence may be the media, including coverage of celebrity breast cancer treatment. We examined trends in media reporting that might impact decision making among women with breast cancer. METHODS: We performed searches of two comprehensive online databases for articles from major U.S. print publications mentioning celebrities and terms related to the word "breast" and terms related to cancer treatment. Automated analysis using custom-created dictionaries was used to determine word frequencies over time. An analysis of net media tone was conducted using Lexicoder Sentiment Dictionaries. RESULTS: Celebrity breast cancer media reports significantly increased since 2004 (p < .05). Dramatic increases in bilateral mastectomy articles occurred in 2008-2009, with an increase in net positive tone. The surgical treatment was significantly more likely to be mentioned when a celebrity had bilateral mastectomies than unilateral mastectomy or breast conservation (44.8 vs 26.1 %, p < .001). The majority (60 %) of articles on celebrities undergoing bilateral mastectomy for cancer had no mention of genetics, family history, or risk. CONCLUSIONS: Media reports of celebrity breast cancer present a bias toward bilateral mastectomies in both frequency and tone. This may sway public opinion, particularly when factors such as risk and genetics are excluded. Surgeons need to work with the media to improve cancer reporting and identify methods to better educate patients prior to surgical consultations.