Delayed adjuvant endocrine therapy is associated with decreased recurrence-free survival following neoadjuvant chemotherapy for breast cancer.

BACKGROUND: In hormone receptor-positive breast cancer (HRPBC), endocrine therapy is often initiated after adjuvant radiotherapy given concerns of radiation fibrosis. No studies have investigated how this may impact outcomes in high-risk patients undergoing neoadjuvant chemotherapy (NAC). METHODS: Females with nonmetastatic HRPBC receiving NAC from 2011 to 2017 were identified from our multi-institutional database. Interval from surgery to endocrine therapy (ISET) was calculated in weeks. Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: Of 280 patients, 179 (64%) received adjuvant radiotherapy; all deaths (n = 25) and 90% (n = 27) of recurrences occurred in this group, which was the focus of subsequent analysis. Median follow-up was 49 months. Recurrences were predominantly distant metastases (n = 21, 81%). Median ISET was 12 weeks (range 0-55 weeks). On multivariable analysis, ISET >14 weeks was independently associated with worse RFS (HR 3.20, 95% C.I. 1.22-8.40, P = 0.02) but not OS (HR 2.15, 95% C.I. 0.75-6.15, P = 0.15). CONCLUSION: In patients with HRPBC treated with NAC and adjuvant radiation, increasing ISET is associated with adverse oncologic outcomes.

Variation in adoption of skin and nipple sparing mastectomy: An opportunity to enhance patient outcomes.

BACKGROUND: Nipple-sparing mastectomies (NSM) for breast cancer are under-utilized. We sought to investigate NSM utilization. METHODS: Females with nonmetastatic breast cancer undergoing mastectomy in the Legacy Health System from 2007 to 2020 were identified. Multivariable logistic regression was utilized to evaluate odds of receiving NSM. RESULTS: Three-thousand-four-hundred-seventeen mastectomies were performed with 772 undergoing NSM. On multivariable analysis, later year (OR 1.22/year, P < 0.001), neoadjuvant chemotherapy (OR 1.33, P = 0.04), HR+ (OR 1.61, P = 0.001) and surgeon volume (OR 1.16/10 yearly mastectomies, P < 0.001) were independently associated with increased odds of receiving a NSM while age (OR 0.94/year, P < 0.001), IDC (OR 0.58, P = 0.01), T3/T4 stage (OR 0.36, P = 0.009), and clinical node positivity (OR 0.63, P = 0.003) were independently associated with decreased odds. Surgeon volume was not associated with odds of receiving a non-NSM with reconstruction (OR 1.01 P = 0.48). CONCLUSION: NSM is under-utilized by low-volume breast surgeons. Understanding barriers to adoption is an is an opportunity to enhance patient-centered outcomes.

Loss of HER2-positivity following neoadjuvant targeted therapy for breast cancer is not associated with inferior oncologic outcomes.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are treated with trastuzumab-based neoadjuvant therapy (NAT); some patients with residual disease post-NAT show loss of HER2 amplification and has been inconsistently associated with oncologic outcomes. METHODS: We queried our multi-institutional cancer registry for women with HER2-positive breast cancer undergoing NAT from 2011 to 2018. Clinicopathologic, treatment-related, and outcomes data were collected. Kaplan-Meier and Cox proportional hazards analysis were used to evaluate oncologic outcomes. RESULTS: A total of 348 patients were identified; 166 (48%) had a pathologic complete response. Of the 182 patients with residual disease, 87 (48%) were HER2-positive, 34 (19%) were HER2-negative, and 61 (33%) were HER2-unknown, with a median follow-up of 44 months. There were no factors associated with HER2 loss apart from age. On Kaplan-Meier analysis, estimated 5-year recurrence-free survival (RFS) and overall survival (OS) for patients with HER2-positive residual disease was 81% and 92%, respectively, and 74% (log rank p = 0.75) and 81% (p = 0.35) in patients with HER2-negative residual disease. CONCLUSION: The loss of HER2-positivity following NAT is not associated with worse 5-year RFS or OS. We do not recommend retesting HER2 status following NAT for the purpose of clinical management; these patients should complete targeted adjuvant therapy.

Time to surgery following neoadjuvant chemotherapy for breast cancer impacts residual cancer burden, recurrence, and survival.

BACKGROUND: The impact of length of time to surgery (TTS) on oncologic outcomes following neoadjuvant chemotherapy (NAC) in breast cancer patients is unclear. We investigated the relationship between TTS on residual cancer burden (RCB) score and oncologic outcomes. METHODS: Patients with breast cancer receiving NAC from 2011 to 2017 were identified. The association of TTS with recurrence-free survival (RFS), overall and disease-specific survival (OS, DSS), and RCB score was examined with Kaplan-Meier and Cox proportional hazards analysis, adjusting for relevant clinicopathologic factors. RESULTS: We identified 463 patients. Median TTS was 29 days (range 11-153). Median follow-up was 57 months (range, 2-93 months). Five-year local recurrence-free survival, locoregional RFS, OS, and DSS was 86%, 96%, 89%, and 91%, respectively. On multivariate analysis, TTS >6 weeks was independently associated with worse RFS (HR [hazard ratio] 3.45; p < .001) and DSS (HR 2.82; p < .05), while TTS >6 weeks was independently associated with a positive size of the effect on RCB score of 0.59 (p < .0001). CONCLUSION: Prolonged TTS is a modifiable risk factor for adverse oncologic outcomes following NAC for breast cancer, possibly mediated by increasing RCB score overtime after NAC. In the absence of contraindications, surgery should be performed within 6 weeks following NAC for optimal oncologic outcomes.

Adequate sentinel node harvest is associated with low false negative rate in breast cancer managed with neoadjuvant chemotherapy and targeted axillary dissection.

INTRODUCTION: After neoadjuvant chemotherapy (NAC) for clinically node-positive breast cancer (NPBC), targeted axillary dissection (TAD) reduces the false negative rate (FNR) of axillary node sampling. Axillary lymph node dissection (ALND) is indicated if the clipped node cannot be identified. Prior studies have indicated that a sentinel lymph node harvest (SLNH) of ≥3 also leads to low FNR. We investigated the performance of SLNH thresholds at inferring the status of the axilla during TAD. METHODS: Retrospective review of the Legacy Health System Tumor Registry was performed. We identified NPBC patients between 2011 and 2016 managed with NAC and TAD. RESULTS: In 29 patients, the FNR of the SLNB component of TAD was 11% with SLNH of ≥3; with SLNH of ≤2 nodes the FNR was 20%. CONCLUSIONS: In patients with NPBC receiving NAC, adequate SLNH is associated with acceptably low FNR. The decision to pursue ALND for clip identification should be made on a case-by-case basis.

Surgical timing following neoadjuvant chemotherapy for breast cancer affects postoperative complication rates.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is increasingly used in the treatment of breast cancer. The time interval from last dose of cytotoxic chemotherapy to surgery (TTS) can vary widely. We aimed to evaluate the effect of TTS on postoperative complications. METHODS: A retrospective review for women treated with NAC at our institution between January 2011 through December 2016 was performed. Charts were reviewed for postoperative wound complications, and multivariate analysis was performed. RESULTS: 455 patients were identified. Median TTS was 30 days (range 11-228). On multivariate analysis, TTS of less than 28 days was associated with 70% higher odds of any wound complication (p < 0.05). Increasing age had the strongest association with the presence of any wound complication (p < 0.0001). The majority of complications were treated in the outpatient setting (n = 80, 83%). CONCLUSION: Following NAC for breast cancer, TTS less than 28 days is a risk factor for postoperative wound complications; however, the majority of complications are minor and treated in the outpatient setting. Additional data are needed to determine optimal TTS for oncologic outcomes.

Atypical ductal hyperplasia: Clinicopathologic factors are not predictive of upgrade after excisional biopsy.

INTRODUCTION: National Comprehensive Cancer Network (NCCN) guidelines currently recommend excisional biopsy for atypical ductal hyperplasia (ADH) diagnosed on core needle biopsy (CNB) due to the possibility of pathologic upgrade to breast cancer upon excisional biopsy. We aimed to quantify the current rate of upgrade and identify risk factors. METHODS: A retrospective review of women in the Legacy Health Care System with a diagnosis of ADH was performed for 2014 through 2015. Initial pathology and patient factors were reviewed for potential predictors of upgrade. RESULTS: 91 women with ADH were identified. 84 (92%) underwent excisional biopsy; 16 (19%) were upgraded to breast cancer. Those upgraded were significantly older than non-upgraded patients (64.6 versus 56.7 years, p < 0.01), and 15 (94%) had greater than one duct involved by ADH. CONCLUSION: The principal clinicopathologic factor associated with upgrade is increasing patient age, however this is not sufficiently predictive. Excisional biopsy in patients diagnosed with ADH on CNB should continue. Further study may provide an avenue for selective excisional biopsy in patients with ADH.

Breast cancer in women under 50: Most are not high risk.

BACKGROUND: In 2009, the United States Preventive Services Task Force changed the recommended starting age for annual screening mammography from 40 to 50 for non-"high risk" women. In 2015, the American Cancer Society issued similar guidelines, with a starting age of 45. Our hypothesis is that most women diagnosed with breast cancer in this age group do not fall into a "high risk" category. METHODS: A retrospective review of women less than 50 years of age diagnosed with breast cancer in the Legacy Health Care System was performed for January 2013 through December 2015. Validated risk assessment models were used to quantify risk. High risk was defined as lifetime risk of breast cancer greater than 20%. RESULTS: 249 women were identified. Of these, 79 (32%) of women were high risk. 170 (68%) did not fall into the high risk category. CONCLUSION: In our population, approximately two thirds of women with breast cancer under 50 are non-"high risk". We argue that women should receive annual mammograms starting at age 40, because low risk is not protective.

Side effects of aromatase inhibitors versus tamoxifen: the patients' perspective.

BACKGROUND: Hormonal therapy is a mainstay in the management of estrogen receptor-positive (ER+) breast cancer. Tamoxifen (TAM) has been the drug widely used until the recent emergence of the aromatase inhibitors (AIs). Although AIs appear to be better tolerated than tamoxifen, they do have a different safety profile and these side effects have not been well characterized in community practice. We surveyed patients with ER+ breast cancers who received adjuvant hormonal therapy to determine how these medications impacted their quality of life and whether side effects or cost influenced decisions to continue therapy. METHODS: A mailed questionnaire and community cancer registry were used. RESULTS: Four hundred fifty-two of 902 surveys were returned for a 50% response rate. Eighty-two percent of respondents were placed on (adjuvant hormonal therapy) some form of estrogen-blocking therapy. Fifty-four percent of these were placed on tamoxifen and 46% on an AI. The most troublesome symptoms for tamoxifen and AI users, respectively, included hot flashes (35%/30%), weight gain (14%/15%), insomnia (17%/17%), and joint aches (12%/23%, P = .002). Thirty-nine percent of TAM users and 46% of AI users were taking medications to control their symptoms. Fifty percent of TAM users and 39% of AI users took vitamin E to help control hot flashes. Forty-two percent of TAM users versus 32% of AI users took Advil (Wyeth, Richmond, VA) for muscle/joint aches; 47.5% of AI users switched medication to improve symptoms as compared with only 37% of tamoxifen users (P = .015). The average cost of medications to control side effects for both tamoxifen and AI users was $67.36 per month. CONCLUSIONS: In our survey, both tamoxifen and AI users reported significant and different side effects. AI users suffered more frequently from musculoskeletal complaints, and more AI users switched therapy. Both AI and tamoxifen users used adjunctive medications for symptom control. In both groups, a large number used vitamin E to help hot flashes despite weak evidence to support its effectiveness in this setting. Cost of therapy and symptom control was not a major barrier to care.

Transgenic introduction of androgen receptor into estrogen-receptor-, progesterone-receptor-, and androgen-receptor-negative breast cancer cells renders them responsive to hormonal manipulation.

BACKGROUND: Estrogen-receptor (ER)-, progesterone-receptor (PR)-, and androgen-receptor (AR)-negative breast cancer cells are unaffected by treatment with dehydroepiandrosterone-sulfate (DHEAS) and an aromatase inhibitor (AI). We hypothesized that cell growth would be inhibited with DHEAS/AI treatment after successful transfection of an AR expression vector. METHODS: ER/PR/AR-negative breast cancer cells were transfected with an AR expression vector and treated with DHEAS/AI for 2 days. Growth inhibition of these cells was compared with that of transfected cells treated with only AI or with nontransfected cells treated with DHEAS/AI. Mann-Whitney U test was used to determine statistical significance. RESULTS: Cell death rates of 53.5% (P = .001) and 40.1% (P = .006) were seen in transfected cells treated with DHEAS/AI compared with controls for days 1 and 2, respectively. Nontransfected cells were unaffected by treatment. COMMENTS: ER/PR/AR-negative cells transfected with AR were killed by DHEAS/AI treatment, providing evidence that AR is responsible for this effect. This provides the first AR-targeted hormonal therapy for ER breast cancer.

Risk counseling and management in patients with lobular carcinoma in situ.

BACKGROUND: The understanding of lobular carcinoma in situ (LCIS) has evolved since it was first described. LCIS once was thought to be a premalignant condition, but now it is considered a marker for increased risk for developing invasive breast cancer. We evaluated patient perception of risk, counseling, and subsequent management. METHODS: A community cancer registry of 3,605 cases of breast cancer was reviewed. Fifty-five (1.5%) patients with LCIS as their sole diagnosis were identified and these patients were sent a questionnaire. RESULTS: Forty of 55 patients completed the questionnaire for a 73% response rate. The patients' perception of lifetime risk for invasive cancer was variable. Surgeons performed the majority of counseling. Fourteen patients (35%) were placed on a selective estrogen-receptor modulator. Eleven patients (28%) had bilateral mastectomy. Three patients had unilateral mastectomy. Screening recommendations included an annual mammography (64%), a professional examination (64%), and a monthly self-breast examination (75%). CONCLUSION: A patient's perception of risk for invasive breast cancer after a diagnosis of LCIS is widely variable. Patients will adhere to suggested screening recommendations. Surgeons are performing the majority of counseling and must stay abreast on current recommendations.

Geographic variation in sentinel node adaptation by practicing surgeons in Oregon.

BACKGROUND: The sentinel node biopsy (SNB) technique is an important tool in the diagnosis and treatment of breast cancer and melanoma. However, surgeons in Oregon have not universally adopted its use. METHODS: Mailed questionnaire. RESULTS: The response rate was 32%. Seventy-four (76%) of the surgical respondents perform routine SNB; 49% completed courses, and 32% learned the technique in residency. Sixty-one (89%) performed axillary dissection with their initial cases. It took 21 of 40 (52%) surgeons greater than a year to accrue 20 cases. Of 23 surgeons (24%) not performing SNB, 89% believed it was an important skill to obtain, and 70% thought they would benefit from proctoring opportunities. Six (26%) did not have technological support at their hospital. Surgeons at hospitals with less than 50 beds (P = .001) and at rural hospitals (P = .003) were less likely to perform SNB. CONCLUSION: The majority of urban general surgeons in Oregon use SNB in their practice. However, the incorporation of SNB for surgeons practicing in smaller hospitals and rural settings is less frequent than in the urban environment. As SNB becomes the standard of care, we need to overcome these barriers so that patients can have access to this procedure in their own communities.