Clinical Impact of Intraoperative Margin Assessment in Breast-Conserving Surgery With a Novel Pegulicianine Fluorescence-Guided System: A Nonrandomized Controlled Trial.

Importance: Positive margins following breast-conserving surgery (BCS) are often identified on standard pathology evaluation. Intraoperative assessment of the lumpectomy cavity has the potential to reduce residual disease or reexcision rate following standard of care BCS in real time. Objective: To collect safety and initial efficacy data on the novel pegulicianine fluorescence-guided system (pFGS) when used to identify residual cancer in the tumor bed of female patients undergoing BCS. Design, Setting, and Participants: This prospective single-arm open-label study was conducted as a nonrandomized multicenter controlled trial at 16 academic or community breast centers across the US. Female patients 18 years and older with newly diagnosed primary invasive breast cancer or ductal carcinoma in situ DCIS undergoing BCS were included, excluding those with previous breast cancer surgery and a history of dye allergies. Of 283 consecutive eligible patients recruited, 234 received a pegulicianine injection and were included in the safety analysis; of these, 230 were included in the efficacy analysis. Patients were enrolled between February 6, 2018, and April 10, 2020, and monitored for a 30-day follow-up period. Data were analyzed from April 10, 2020, to August 5, 2021. Interventions: Participants received an injection of a novel imaging agent (pegulicianine) a mean (SD) of 3.2 (0.9) hours prior to surgery at a dose of 1 mg/kg. After completing standard of care (SOC) excision, pFGS was used to scan the lumpectomy cavity to guide the removal of additional shave margins. Main Outcomes and Measures: Adverse events and sensitivity, specificity, and reexcision rate. Results: Of 234 female patients enrolled (median [IQR] age, 62.0 [55.0-69.0] years), 230 completed the trial and 1 patient with a history of allergy to contrast agents had an anaphylactic reaction and recovered without sequelae. Correlation of pFGS with final margin status on a per-margin analysis showed a marked improvement in sensitivity over standard pathology assessment of the main lumpectomy specimen (69.4% vs 38.2%, respectively). On a per-patient level, the false-negative rate of pFGS was 23.7% (9 of 38), and sensitivity was 76.3% (29 of 38). Among 32 patients who underwent excision of pFGS-guided shaves, pFGS averted the need for reexcision in 6 (19%). Conclusions and Relevance: In this pilot feasibility study, the safety profile of pegulicianine was consistent with other imaging agents used in BCS, and was associated with a reduced need for second surgery in patients who underwent intraoperative additional excision of pFGS-guided shaves. These findings support further development and clinical performance assessment of pFGS in a prospective randomized trial. Trial Registration: ClinicalTrials.gov Identifier: NCT03321929.

Age-Independent Preoperative Chemosensitivity and 5-Year Outcome Determined by Combined 70- and 80-Gene Signature in a Prospective Trial in Early-Stage Breast Cancer.

BACKGROUND: The Neoadjuvant Breast Symphony Trial (NBRST) demonstrated the 70-gene risk of distant recurrence signature, MammaPrint, and the 80-gene molecular subtyping signature, BluePrint, precisely determined preoperative pathological complete response (pCR) in breast cancer patients. We report 5-year follow-up results in addition to an exploratory analysis by age and menopausal status. METHODS: The observational, prospective NBRST (NCT01479101) included 954 early-stage breast cancer patients aged 18-90 years who received neoadjuvant chemotherapy and had clinical and genomic data available. Chemosensitivity and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed. In a post hoc subanalysis, results were stratified by age (≤ 50 vs. > 50 years) and menopausal status in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors. RESULTS: MammaPrint and BluePrint further classified 23% of tumors to a different subtype compared with immunohistochemistry, with more precise correspondence to pCR rates. Five-year DMFS and OS were highest in MammaPrint Low Risk, Luminal A-type and HER2-type tumors, and lowest in MammaPrint High Risk, Luminal B-type and Basal-type tumors. There was no significant difference in chemosensitivity between younger and older patients with Low-Risk (2.2% vs. 3.8%; p = 0.64) or High-Risk tumors (14.5% vs. 11.5%; p = 0.42), or within each BluePrint subtype; this was similar when stratifying by menopausal status. The 5-year outcomes were comparable by age or menopausal status for each molecular subtype. CONCLUSION: Intrinsic preoperative chemosensitivity and long-term outcomes were precisely determined by BluePrint and MammaPrint regardless of patient age, supporting the utility of these assays to inform treatment and surgical decisions in early-stage breast cancer.

Distinct Neoadjuvant Chemotherapy Response and 5-Year Outcome in Patients With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Tumors That Reclassify as Basal-Type by the 80-Gene Signature.

PURPOSE: The 80-gene molecular subtyping signature (80-GS) reclassifies a proportion of immunohistochemistry (IHC)-defined luminal breast cancers (estrogen receptor-positive [ER+], human epidermal growth factor receptor 2-negative [HER2-]) as Basal-Type. We report the association of 80-GS reclassification with neoadjuvant treatment response and 5-year outcome in patients with breast cancer. METHODS: Neoadjuvant Breast Registry Symphony Trial (NBRST; NCT01479101) is an observational, prospective study that included 1,069 patients with early-stage breast cancer age 18-90 years who received neoadjuvant therapy. Pathologic complete response (pCR) and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed in 477 patients with IHC-defined ER+, HER2- tumors and in a reference group of 229 patients with IHC-defined triple-negative breast cancer (TNBC). RESULTS: 80-GS reclassified 15% of ER+, HER2- tumors (n = 73) as Basal-Type (ER+/Basal), which had similar pCR compared with TNBC/Basal tumors (34% v 38%; P = .52), and significantly higher pCR than ER+/Luminal A (2%; P < .001) and ER+/Luminal B (6%; P < .001) tumors. The 5-year DMFS (%, [95% CI]) was significantly lower for patients with ER+/Basal tumors (66% [52.6 to 77.3]), compared with those with ER+/Luminal A tumors (92.3% [85.2 to 96.1]) and ER+/Luminal B tumors (73.5% [44.5 to 79.3]). Importantly, patients with ER+/Basal or TNBC/Basal tumors that had a pCR exhibited significantly improved DMFS and OS compared with those with residual disease. By contrast, patients with ER+/Luminal B tumors had comparable 5-year DMFS and OS whether or not they achieved pCR. CONCLUSION: Significant differences in chemosensitivity and 5-year outcome suggest patients with ER+/Basal molecular subtype may benefit from neoadjuvant regimens optimized for patients with TNBC/Basal tumors compared with patients with ER+/Luminal subtype. These data highlight the importance of identifying this subset of patients to improve treatment planning and long-term survival.

Addition of chemotherapy to local therapy in women aged 70 years or older with triple-negative breast cancer: a propensity-matched analysis.

BACKGROUND: There is a scarcity of data exploring the benefits of adjuvant or neoadjuvant chemotherapy in the treatment of breast cancer in older women. We aimed to explore the effect of adding chemotherapy to local therapy on overall survival in older women with triple-negative breast cancer. METHODS: For this propensity-matched analysis, we used data from the National Cancer Database, a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. We included data from women aged 70 years or older with surgically treated, American Joint Committee on Cancer (AJCC) Stage I-III invasive triple-negative breast cancer diagnosed from 2004 to 2014. Patients with T1aN0M0 disease and those with incomplete data on oestrogen receptor status, progesterone receptor status, or HER2 status were excluded. To reduce bias, patients were subdivided into three groups: those who were recommended chemotherapy but did not receive it; those who received chemotherapy; and those for whom chemotherapy was not recommended and not given. The primary outcome was overall survival. Multivariate Cox regression analysis and propensity score matching were done to minimise bias. FINDINGS: Between Jan 1, 2004, and Dec, 31, 2014, 16 062 women with triple-negative breast cancer in the database met the inclusion criteria for this analysis. Median follow-up was 38·3 months (IQR 20·7-46·1, range 0-138·0; 95% CI 37·8-38·7). Collectively, the 5-year overall survival estimate of the 16 062 patients in the study cohort was 62·3% (95% CI 59·7-64·4). 5-year estimated overall survival was 68·5% (95% CI 66·4-70·6) for patients receiving chemotherapy, 61·1% (59·0-63·2) for patients recommended but not given chemotherapy, and 53·7% (51·8-55·8) for patients not recommended chemotherapy and not given chemotherapy (pooled log rank p<0·0001). Multivariate Cox regression analysis of a propensity score-matched sample comparing those who received chemotherapy with those who were recommended but not given chemotherapy (n=1884 matched pairs) identified improved overall survival with chemotherapy (hazard ratio [HR] 0·69 [95% CI 0·60-0·80]; p<0·0001). After stratifying the propensity score matching sample, this benefit persisted for node-negative women (HR 0·80 [95% CI 0·66-0·97]; p=0·007), node-positive women (0·76 [0·64-0·91]; p=0·006), and those with a comorbidity score greater than 0 (HR 0·74 [95% CI 0·59-0·94]; p=0·013). INTERPRETATION: These data support consideration of chemotherapy in the treatment of women aged 70 years or older with triple-negative breast cancer. FUNDING: None.

For-profit hospital ownership status and use of brachytherapy after breast-conserving surgery.

BACKGROUND: Little is known about the relationship between operative care for breast cancer at for-profit hospitals and subsequent use of adjuvant radiation therapy (RT). Among Medicare beneficiaries, we examined whether hospital ownership status is associated with the use of breast brachytherapy--a newer and more expensive modality--as well as overall RT. METHODS: We conducted a retrospective study of female Medicare beneficiaries who received breast-conserving surgery for invasive breast cancer in 2008 and 2009. We assessed the relationship between hospital ownership and receipt of brachytherapy or overall RT by using hierarchical generalized linear models. RESULTS: The sample consisted of 35,118 women, 8.0% of whom had breast-conserving operations at for-profit hospitals. Among patients who received RT, those who underwent operation at for-profit hospitals were more likely to receive brachytherapy (20.2%) than patients treated at not-for-profit hospitals (15.2%; odds ratio [OR] for for-profit versus not-for-profit: 1.50; 95% confidence interval [95% CI] 1.23-1.84; P < .001). Among women aged 66-79 years, there was no relationship between hospital ownership status and overall use of RT. Among women ages 80-94 years of age--the group least likely to benefit from RT due to shorter life expectancy--undergoing breast-conserving operations at a for-profit hospital was associated with greater overall use of RT (OR 1.22; 95% CI 1.03-1.45, P = .03) and brachytherapy use (OR 1.66; 95% CI 1.18-2.34, P = .003). CONCLUSION: Operative care at for-profit hospitals was associated with increased use of the newer and more expensive RT modality, brachytherapy. Among the oldest women who are least likely to benefit from RT, operative care at a for-profit hospital was associated with greater overall use of RT, with this difference largely driven by the use of brachytherapy.

Patterns of use and short-term complications of breast brachytherapy in the national medicare population from 2008-2009.

PURPOSE: Brachytherapy has disseminated into clinical practice as an alternative to whole-breast irradiation (WBI) for early-stage breast cancer; however, current national treatment patterns and associated complications remain unknown. PATIENTS AND METHODS: We constructed a national sample of Medicare beneficiaries ages 66 to 94 years who underwent breast-conserving surgery from 2008 to 2009 and were treated with brachytherapy or WBI. We used hospital referral regions (HRRs) to assess national treatment variation and an instrumental variable analysis to compare complication rates between treatment groups, adjusting for patient and clinical characteristics. We compared overall, wound and skin, and deep-tissue and bone complications between brachytherapy and WBI at 1 year of follow-up. RESULTS: Of 29,648 women in our sample, 4,671 (15.8%) received brachytherapy. The percent of patients receiving brachytherapy varied substantially across HRRs, ranging from 0% to over 70% (interquartile range, 7.5% to 23.3%). Of women treated with brachytherapy, 34.3% had a complication compared with 27.3% of women undergoing WBI (P < .001). After adjusting for patient and clinical characteristics, 35.2% of women treated with brachytherapy (95% CI, 28.6 to 41.9) had a complication compared with 18.4% treated with WBI (95% CI, 15.5 to 21.3; P value for difference, <.001). Brachytherapy was associated with a 16.9% higher rate of wound and skin complications compared with WBI (95% CI, 10.0 to 23.9; P < .001), but there was no difference in deep-tissue and bone complications. CONCLUSION: Brachytherapy is commonly used among Medicare beneficiaries and varies substantially across regions. After 1 year, wound and skin complications were significantly higher among women receiving brachytherapy compared with those receiving WBI.

Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer.

The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3-6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P < 0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.

Do sentinel node micrometastases predict recurrence risk in ductal carcinoma in situ and ductal carcinoma in situ with microinvasion?

BACKGROUND: Because the implications of micrometastases found on sentinel node biopsy (SNB) for ductal carcinoma in situ (DCIS) or ductal carcinoma in situ with microinvasion (DCISM) are largely unknown, we wished to determine if SNB pathology predicted recurrence risk in DCIS/DCISM. METHODS: Retrospective chart review identified patients with DCIS/DCISM who underwent SNB. SNB findings and all local and distant recurrences were determined. RESULTS: A total of 322 patients underwent SNB for DCIS/DCISM. There were 13 local recurrences (4.0%) and 1 (.03%) distant recurrence at a median follow-up of 47.9 months (range 0 to 110.6), 12 in patients with negative SNBs; 1 patient had a positive SNB. There were 4 recurrences after mastectomy and 9 after lumpectomy. In 29 patients with positive SNBs, there was only 1 recurrence (3.4%). CONCLUSIONS: Positive SNBs in patients with DCIS or DCISM are not associated with higher risk of local or distant recurrence. Other features of DCIS and DCISM may be important in predicting recurrence risk.

Sentinel node biopsy is important in mastectomy for ductal carcinoma in situ.

BACKGROUND: There is uncertainty about the utility of sentinel node biopsy (SNB) for ductal carcinoma in situ (DCIS) and its potential to avoid axillary lymph node dissection (ALND) in patients undergoing mastectomy for DCIS. METHODS: A review was conducted of 179 patients who underwent mastectomy with sentinel node biopsy for DCIS without invasion or microinvasion on premastectomy pathology review. RESULTS: The sentinel node identification rate was 98.9% (177/179). Twenty (11.3%) of 177 mastectomies for DCIS had a positive SNB: two micrometastasis (pN1mi) and 18 isolated tumor cells [pN0(i+)]. Unsuspected invasive cancer was found in 20 (11.2%) of 179 mastectomies, eight T1mic, five T1a, three T1b, and four T1c tumors. Sentinel nodes were identified in 19 of 20 patients with invasive cancer and four were positive: one pN1mi and three pN0(i+). Eighteen of 19 patients with unsuspected invasive cancer were able to avoid axillary dissection on the basis of SNB results. Of the 159 patients whose final pathology revealed DCIS without invasion, a sentinel node was identified in 158 (99.4%). The SNB was positive in 16 patients (10.1%): one pN1mi and 15 pN0(i+). Three patients underwent ALND on the basis of positive SNBs and in each the SNB was the only positive node. CONCLUSIONS: 11% of patients undergoing mastectomy for DCIS were found to have invasive cancer on final pathology. The use of SNB during mastectomy for DCIS allowed nearly all such patients to avoid axillary dissection. These results support routine use of SNB during mastectomy for DCIS.

Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer.

PURPOSE: To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. EXPERIMENTAL DESIGN: Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response. RESULTS: Eight of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). Five (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% versus 97%; P = 0.001). CONCLUSIONS: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.

Sentinel lymph node biopsy for occult breast cancer detected during breast reduction surgery.

Breast reduction surgery is considered a relative contraindication to a sentinel node biopsy because of the possibility that lymphatics have been interrupted by the procedure. We describe six patients who underwent successful sentinel lymph node biopsy for occult carcinomas detected after breast reduction surgery. A subsequent skin-sparing mastectomy, along with a sentinel lymph node biopsy, was performed. Reconstruction was possible in five of six patients. Sentinel lymph node biopsy should not be considered a contraindication after breast reduction surgery.

Treatment of breast cancer during pregnancy.

The management of breast cancer during pregnancy is one of the great clinical challenges in oncology. Patients are best served by care provided through a multidisciplinary team including surgeons, oncologists, obstetricians and genetics counsellors with experience in caring for similar women. The risks of diagnostic and therapeutic interventions can be mitigated by the consideration of known side effects of therapy on the fetus and the mother. However, because of the limited amount of clinical experience available, the potential risks to the patient, to the fetus and to the pregnancy are difficult to quantify. Treatment decisions need to be tailored carefully to the individual, respecting both her clinical circumstances and her personal preferences.