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.

Therapeutic Value of Sentinel Lymph Node Biopsy in Patients With Melanoma: A Randomized Clinical Trial.

Importance: Sentinel lymph node (SLN) biopsy is a standard staging procedure for cutaneous melanoma. Regional disease control is a clinically important therapeutic goal of surgical intervention, including nodal surgery. Objective: To determine how frequently SLN biopsy without completion lymph node dissection (CLND) results in long-term regional nodal disease control in patients with SLN metastases. Design, Setting, and Participants: The second Multicenter Selective Lymphadenectomy Trial (MSLT-II), a prospective multicenter randomized clinical trial, randomized participants with SLN metastases to either CLND or nodal observation. The current analysis examines observation patients with regard to regional nodal recurrence. Trial patients were aged 18 to 75 years with melanoma metastatic to SLN(s). Data were collected from December 2004 to April 2019, and data were analyzed from July 2020 to January 2022. Interventions: Nodal observation with ultrasonography rather than CLND. Main Outcomes and Measures: In-basin nodal recurrence. Results: Of 823 included patients, 479 (58.2%) were male, and the mean (SD) age was 52.8 (13.8) years. Among 855 observed basins, at 10 years, 80.2% (actuarial; 95% CI, 77-83) of basins were free of nodal recurrence. By univariable analysis, freedom from regional nodal recurrence was associated with age younger than 50 years (hazard ratio [HR], 0.49; 95% CI, 0.34-0.70; P < .001), nonulcerated melanoma (HR, 0.36; 95% CI, 0.36-0.49; P < .001), thinner primary melanoma (less than 1.5 mm; HR, 0.46; 95% CI, 0.27-0.78; P = .004), axillary basin (HR, 0.61; 95% CI, 0.44-0.86; P = .005), fewer positive SLNs (1 vs 3 or more; HR, 0.32; 95% CI, 0.14-0.75; P = .008), and SLN tumor burden (measured by diameter less than 1 mm [HR, 0.39; 95% CI, 0.26-0.60; P = .001] or less than 5% area [HR, 0.36; 95% CI, 0.24-0.54; P < .001]). By multivariable analysis, younger age (HR, 0.57; 95% CI, 0.39-0.84; P = .004), thinner primary melanoma (HR, 0.40; 95% CI, 0.22-0.70; P = .002), axillary basin (HR, 0.55; 95% CI, 0.31-0.96; P = .03), SLN metastasis diameter less than 1 mm (HR, 0.52; 95% CI, 0.33-0.81; P = .007), and area less than 5% (HR, 0.58; 95% CI, 0.38-0.88; P = .01) were associated with basin control. When looking at the identified risk factors of age (50 years or older), ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5% or greater and excluding missing value cases, basin disease-free rates at 5 years were 96% (95% CI, 88-100) for patients with 0 risk factors, 89% (95% CI, 82-96) for 1 risk factor, 86% (95% CI, 80-93) for 2 risk factors, 80% (95% CI, 71-89) for 3 risk factors, 61% (95% CI, 48-74) for 4 risk factors, and 54% (95% CI, 36-72) for 5 or 6 risk factors. Conclusions and Relevance: This randomized clinical trial was the largest prospective evaluation of long-term regional basin control in patients with melanoma who had nodal observation after removal of a positive SLN. SLN biopsy without CLND cleared disease in the affected nodal basin in most patients, even those with multiple risk factors for in-basin recurrence. In addition to its well-validated value in staging, SLN biopsy may also be regarded as therapeutic in some patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00297895.

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.

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.

Speaker Introductions at Grand Rounds: Differences in Formality of Address by Gender and Specialty.

Background: Despite increasing representation of women in medicine, gender bias remains pervasive. The authors sought to evaluate speaker introductions by gender in the grand rounds of multiple specialties at a large academic institution to understand the cultural context of this behavior and identify predictors of formality. Materials and Methods: The authors reviewed grand rounds recordings of speakers with doctorates presenting to the departments of family medicine, general surgery, internal medicine, obstetrics and gynecology, and pediatrics at one institution from 2014 to 2019. The primary outcome was whether a speaker's professional title was used as the first form of address. The authors assessed factors correlated with professional introduction using multivariable logistic regression. Results: Speakers were introduced professionally in 346/615 recordings (56.3%). Female introducers were more likely to introduce speakers professionally (odds ratio [OR]: 2.52). A significant interaction existed between speaker gender and home institution: female speakers visiting from an external institution were less likely than male external speakers to be introduced professionally (OR: 0.49), whereas female speakers internal to the institution were more likely to be introduced professionally than male internal speakers (OR: 1.75). Use of professional titles varied by specialty and was higher than average for family medicine (83.2%), surgery (75.8%), and pediatrics (64.0%) and lower for internal medicine (37.5%) and obstetrics and gynecology (50.7%). Conclusions: These findings suggest a complex relationship between gender and formality of introduction that merits further investigation. Understanding differences in culture across specialties is important to inform efforts to promote equity.

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.

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.

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.

CX3CR1-CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironment.

Although blockade of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint has revolutionized cancer treatment, how it works on tumor-infiltrating CD8+ T cells recognizing the same antigen at various differentiation stages remains elusive. Here, we found that the chemokine receptor CX3CR1 identified 3 distinct differentiation states of intratumor CD8+ T cell subsets. Adoptively transferred antigen-specific CX3CR1-CD8+ T cells generated phenotypically and functionally distinct CX3CR1int and CX3CR1hi subsets in the periphery. Notably, expression of coinhibitory receptors and T cell factor 1 (Tcf1) inversely correlated with the degree of T cell differentiation defined by CX3CR1. Despite lower expression of coinhibitory receptors and potent cytolytic activity, in vivo depletion of the CX3CR1hi subset did not alter the antitumor efficacy of adoptively transferred CD8+ T cells. Furthermore, differentiated CX3CR1int and CX3CR1hi subsets were impaired in their ability to undergo proliferation upon restimulation and had no impact on established tumors upon second adoptive transfer compared with the CX3CR1- subset that remained effective. Accordingly, anti-PD-L1 therapy preferentially rescued proliferation and cytokine production of the CX3CR1- subset and enhanced antitumor efficacy of adoptively transferred CD8+ T cells. These findings provide a better understanding of the phenotypic and functional heterogeneity of tumor-infiltrating CD8+ T cells and can be exploited to develop more effective immunotherapy.

Clinical Cancer Advances 2020: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

A MESSAGE FROM ASCO'S PRESIDENT: Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn't been sure she wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies.Clinical research is about saving and improving the lives of individuals with cancer. It's a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO's Clinical Cancer Advances report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology.ASCO's 2020 Advance of the Year-Refinement of Surgical Treatment of Cancer-highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery.Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer.While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can't rest on our laurels. With ASCO's Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we've identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress.Of course, the effectiveness or number of new treatments is meaningless if patients don't have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge.Sincerely,Howard A. "Skip" Burris III, MD, FACP, FASCOASCO President, 2019-2020.

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.

Association of B7-H4, PD-L1, and tumor infiltrating lymphocytes with outcomes in breast cancer.

B7-H4 (VTCN1) is a member of the CD28/B7 family of immune co-inhibitory molecules. The relationship of tumor and stromal B7-H4 protein expression with PD-L1, tumor infiltrating lymphocytes (TILs) and its association with clinico-pathological variables are not well defined. Herein, we explore the expression level of B7-H4 protein in breast cancer and evaluate its association with TILs, levels of PD-L1 expression, and clinico-pathological characteristics in two independent populations. In this study, we used multiplexed automated quantitative immunofluorescence (QIF) to measure the levels of B7-H4 and PD-L1 protein and determined TILs through pathologist assessment of H&E-stained preparations in over a thousand breast cancer cases from two institutions represented in tissue microarray format. Associations between the marker levels, major clinico-pathological variables, and survival were analyzed. We detected B7-H4 protein was highly expressed in both breast cancer and stromal cells. Its expression was independent of breast cancer intrinsic subtypes. PD-L1 expression was higher in triple negative breast cancers. Neither B7-H4 nor PD-L1 were associated with survival in breast cancer. Our study shows there is a mutually exclusive pattern of B7-H4 with both tumor PD-L1 expression and TILs in all breast cancers, independent of breast cancer intrinsic subtype. This exclusive pattern suggests that some breast tumors may preferentially use one B7-related immune evasion mechanism/pathway. This could explain the clinical benefit that is seen only in a fraction of patients with immune checkpoint inhibitors directed exclusively towards PD-L1 in breast cancer.