Combined 70- and 80-gene signatures identify tumors with genomically luminal biology responsive to neoadjuvant endocrine therapy and are prognostic of 5-year outcome in early-stage breast cancer.

BACKGROUND: As more patients with early-stage breast cancer receive neoadjuvant endocrine therapy (NET), there is a need for reliable biomarkers that can identify patients with HR+ HER2- tumors who are likely to benefit from NET. NBRST (NCT01479101) compared the prognostic value of the 70-gene risk classification and 80-gene molecular subtyping signatures with conventional pathological classification methods in response to neoadjuvant therapy. We evaluated the association of these signatures with clinical response and 5-year outcome of patients treated with NET. METHODS: 1091 patients with early-stage breast cancer scheduled to receive neoadjuvant therapy were prospectively enrolled into NBRST, and a sub-analysis of 67 patients treated with NET was performed. Patients received standard of care genomic testing using the 70-gene and 80-gene signatures and were treated with NET, per physician's discretion. The primary endpoint was pathologic partial response (pPR) and secondary endpoints were distant metastasis-free survival (DMFS) and overall survival (OS). Clinical benefit was defined as having a pPR or stable disease (SD) with NET. RESULTS: Overall, 94.4% of patients with genomically (g) Luminal A-Type (50.0% pPR and 44.4% SD) and 95.0% with Luminal B-Type tumors (55.0% pPR and 40.0% SD) exhibited clinical benefit. At 5 years, patients with gLuminal B tumors had significantly worse DMFS (75.6%, 95% CI 50.8-89.1) than patients with gLuminal A (91.1%; 95% CI 74.8-97.1; p = 0.047), with a similar trend for OS, albeit not significant (81.0%, 95% CI 56.9-92.4 and 91.1%, 95% CI 74.8-97.1, respectively; p = 0.13). CONCLUSIONS: Genomic assays offer a broader understanding of the underlying tumor biology, which adds precision to pathology as a preoperative risk classifier. Patients with 70-gene signature Low Risk, gLuminal A tumors treated with endocrine therapy alone have excellent 5-year outcomes. Most patients with genomically-defined Luminal A- and B-Type tumors respond well to NET, suggesting these patients may be safely treated with NET, while those with gLuminal B tumors will also require post-operative chemotherapy or CDK4/6 inhibitors to improve long-term outcomes. Overall, these findings demonstrate that genomic classification, defined by the combined 70- and 80-gene signatures, is associated with tumor response and prognostic of long-term outcomes.

Genomic Classification of HER2-Positive Patients With 80-Gene and 70-Gene Signatures Identifies Diversity in Clinical Outcomes With HER2-Targeted Neoadjuvant Therapy.

PURPOSE: The prospective Neoadjuvant Breast Registry Symphony Trial compared the 80-gene molecular subtyping signature with clinical assessment by immunohistochemistry and/or fluorescence in situ hybridization in predicting pathologic complete response (pCR) and 5-year outcomes in patients with early-stage breast cancer. METHODS: Standard-of-care neoadjuvant chemotherapy combined with trastuzumab or trastuzumab plus pertuzumab was given to patients with human epidermal growth factor receptor 2 (HER2)-positive tumors (n = 295). pCR was the primary end point, with secondary end points of distant metastasis-free survival and overall survival at 5 years. RESULTS: Among clinically defined HER2-positive (cHER2) tumors, the 80-gene assay identified 29.5% (87 of 295) as Luminal-Type (cHER2/gLuminal), 14.9% (44 of 295) as Basal-Type (cHER2/gBasal), and 55.6% (164 of 295) as HER2-Type (cHER2/genomically classified as HER2 [gHER2]). Patients with cHER2/gHER2 tumors had a higher pCR rate (61.6%) compared with non-gHER2 tumors (26.7%; P < .001). Dual targeting for cHER2/gHER2 tumors yielded a higher pCR rate (75%) compared with those treated with single HER2-targeted therapy (54%; P = .006). For cHER2/gBasal tumors, the 42.9% pCR rate observed with dual targeting was not different from that with trastuzumab alone (46.4%; P = .830). Among those with cHER2/gBasal tumors, 5-year distant metastasis-free survival (68.6%; 95% CI, 49.1 to 81.9) was significantly worse than in patients with cHER2/gLuminal tumors (88.9%; 95% CI, 78.0 to 94.6) and cHER2/gHER2 tumors (87.4%; 95% CI, 80.2 to 92.2; P = .010), with similar corresponding overall survival differences. CONCLUSION: The 80-gene assay identified meaningful genomic diversity in patients with cHER2 disease. Patients with cHER2/gHER2 tumors, who benefitted most from dual HER2-targeted therapy, accounted for approximately half of the cHER2 cohort. Genomically Luminal tumors had low pCR rates but good 5-year outcomes. cHER2/gBasal tumors derived no benefit from dual therapy and had significantly worse 5-year prognosis; these patients merit special consideration in future trials.

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.

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.

TARGIT-R (Retrospective): 5-Year Follow-Up Evaluation of Intraoperative Radiation Therapy (IORT) for Breast Cancer Performed in North America.

BACKGROUND: Intraoperative radiation therapy (IORT) has been investigated for patients with low-risk, early-stage breast cancer. The The North American experience was evaluated by TARGIT-R (retrospective) to provide outcomes for patients treated in "real-world" clinical practice with breast IORT. This analysis presents a 5-year follow-up assessment. METHODS: TARGIT-R is a multi-institutional retrospective registry of patients who underwent lumpectomy and IORT between the years 2007 and 2013. The primary outcome of the evaluation was ipsilateral breast tumor recurrence (IBTR). RESULTS: The evaluation included 667 patients with a median follow-up period of 5.1 years. Primary IORT (IORT at the time of lumpectomy) was performed for 72%, delayed IORT (after lumpectomy) for 3%, intended boost for 8%, and unintended boost (primary IORT followed by whole-breast radiation) for 17% of the patients. At 5 years, IBTR was 6.6% for all the patients, with 8% for the primary IORT cohort and 1.7% for the unintended-boost cohort. No recurrences were identified in the delayed IORT or intended-boost cohorts. Noncompliance with endocrine therapy (ET) was associated with higher IBTR risk (hazard ratio [HR], 3.67). Patients treated with primary IORT who were complaint with ET had a 5-year IBTR rate of 3.9%. CONCLUSION: The local recurrence rates in this series differ slightly from recent results of randomized IORT trials and are notably higher than in previous published studies using whole-breast radiotherapy for similar patients with early-stage breast cancer. Understanding differences in this retrospective series and the prospective trials will be critical to optimizing patient selection and outcomes going forward.

Complications after Perforated versus Nonperforated Acellular Dermal Matrix Use in Direct-to-Implant Breast Reconstruction: A Propensity Score Analysis.

Acellular dermal matrices (ADMs) were first incorporated into direct-to-implant (DTI) breast reconstruction by the senior author in 2001 and have since become foundational to implant-based reconstruction. ADM composition has evolved recently and now includes perforated types, which some speculate decrease the likelihood of seroma. The authors performed a retrospective review of perforated (P-ADM) and nonperforated (NP-ADM) ADM-assisted direct-to-implant breast reconstruction patients to evaluate differences in complication rates. METHODS: Retrospective review of direct-to-implant breast reconstruction patients operated on by a single surgeon (CAS) from 2011 to 2018 was conducted. Patient and operative characteristics, including ADM type, were recorded. A propensity score matching algorithm accounting for potentially confounding variables was developed, followed by univariate analysis to evaluate the association between ADM perforation and postoperative complications. RESULTS: The review began with 409 patients (761 breasts). Following exclusion of patients with missing demographic information, lack of ADM in their reconstruction, and follow-up times of less than 4 weeks, 364 patients (680 breasts) were included for analysis. A total of 530 (77.94%) and 150 (22.06%) breasts received NP-ADM and P-ADM, respectively. After propensity score matching, there were 294 breasts, composed of equal numbers of P-ADM and NP-ADM recipients. Univariate analysis showed no association between ADM type and any postoperative complication. CONCLUSIONS: The complication profile of direct-to-implant breast reconstruction appears to be unaffected by the use of P-ADM or NP-ADM. Current understanding of the association between ADM type and clinical outcomes would benefit from multi-institution, prospective, randomized trials.

Is the Vectra 3D Imaging System a Reliable Tool for Predicting Breast Mass?

BACKGROUND: In selecting breast implants for breast reconstruction, current preoperative planning largely relies on 2-dimensional measurements, which are often limited in suboptimal accuracy and objectivity. Although the introduction of 3-dimensional imaging modalities has further improved preoperative planning, they require in-depth analysis of accuracy if they are to be considered as a standardized part of preoperative planning. Thus, the present study analyzes the reliability of the Vectra 3D Imaging System in predicting breast mass and explores potential confounding variables that may limit its accuracy. METHODS: A retrospective review of 202 breasts that received direct-to-implant reconstruction by a single surgeon between February 2015 and February 2019 was conducted. Variables recorded included Vectra predicted mass (VPM; in grams), mastectomy mass (MM; in grams), ptosis grade, and body mass index (BMI). Body mass index was classified as follows: underweight (BMI < 20 kg/m), normal (20 kg/m ≤ BMI < 25 kg/m), overweight (25 kg/m ≤ BMI < 30 kg/m), and obese (BMI ≥ 30 kg/m). Cup size was approximated as follows: A and smaller (MM ≤250 g), B (250 g < MM ≤ 450 g), C (450 g < MM ≤ 600 g), and D and larger (MM ≥ 600 g). Correlation between MM and VPM was evaluated using 2-tailed Pearson correlation coefficients (r), and associated formula was derived from a linear model. Equality of variances was assessed with the Bartlett test. Correlation coefficients calculated for ptosis and BMI categories were then compared with the overall correlation coefficient. Significance was set at α = 0.05, and analyses were conducted in R 3.6.0, version 1.70. RESULTS: There was a strong correlation between MM and VPM (R = 0.90, P < 0.0001). The following equation was derived to predict MM: [MM] = 0.8 × [VPM] + 32 (adjusted r = 0.81). The Bartlett test indicated that VPM varies significantly across cup sizes (P < 0.0001). Comparison of correlation coefficients for ptosis and BMI categories revealed a significantly reduced correlation coefficient for pseudoptosis (0.90 vs 0.75, P = 0.0425). CONCLUSIONS: The present study suggests that the reliability of Vectra in predicting breast mass varies across cup sizes and that there exists a significantly decreased association between VPM and MM among pseudoptotic breasts. These are important considerations when using this technology in surgical planning.

Nipple sparing mastectomy techniques: a literature review and an inframammary technique.

Nipple sparing mastectomy (NSM) has quickly become an accepted technique for patients with selected cancers and for risk reducing surgery. Much of its surgical acceptance over the last decade has been based on the low risk of nipple areolar complex (NAC) occurrence in breast cancer patients. Improved patient satisfaction due to improved cosmetic outcomes with reconstruction have also driven its popularity. We reviewed current English journals to determine the NSM techniques which achieve the lowest complications, best outcomes, and best patient satisfaction. We researched studies showing reductions in complications with improved surgical techniques and patient selection which have been implicated in improved results. In the studies reviewed, incision placement, away from the nipple, resulted in the lowest rates of ischemic nipple complications and the best cosmetic outcomes. The effect of other factors such as surgeon experience and thickness of skin flap development were more difficult to prove. Leaving a 2-3 mm rim of tissue around the nipple bundle was shown to help preserve the nipple vascularity. Lower complication rates with improved outcomes and patient satisfaction were reported in the literature in patients with B or smaller cup sizes, non-smokers, and patients with lower body mass index (BMI). Incision placement, away from the nipple, with preservation of a 2-3 mm rim of tissue around the nipple bundle along with careful patient selection were the most significant variables reviewed which helped to lower complications rates of NSM. Coordinated surgical planning with the breast and plastic surgeons to determine the best surgical approach for each individual patient is necessary to obtain the best results. Although short-term oncologic follow-up seems to be acceptable, longer follow-up will still be needed to define the best breast cancer surgical candidates for the nipple sparing approach.

Short-Term Complications Associated With Acellular Dermal Matrix-Assisted Direct-to-Implant Breast Reconstruction.

BACKGROUND: Although direct-to-implant breast reconstruction is a more concise procedure than 2-stage expander/implant reconstruction, it is less frequently performed. Skeptics of direct-to-implant reconstruction cite risk of postoperative complications as a reason for its rejection. To determine whether these perceptions are valid, we evaluated our 13-year experience of acellular dermal matrix (ADM)-assisted, direct-to-implant breast reconstruction. We report complication and reoperation rates associated with this technique as well as predictors for these outcomes. METHODS: This retrospective study included all patients who underwent immediate, ADM-assisted, direct-to-implant, breast reconstruction from December 2001 to May 2014 at 2 practices. Postoperative complications, defined as those occurring within the first 12 months after reconstructive surgery, were evaluated. Univariate/multivariate analyses were performed to determine the influence of patient-, breast-, and surgery-related characteristics on the development of complications. RESULTS: A total of 1584 breast reconstructions (721 bilateral, 142 unilateral) in 863 patients were performed; 35% were oncologic, and 65% were prophylactic reconstructions. Complication rate was 8.6% and included skin necrosis (5.9%), infection (3.0%), implant loss (2.9%), seroma (1.1%), and hematoma (0.9%). Reoperative rate in breasts with complications was 3.2%. Age 50 years or older, smoking, nonnipple-sparing mastectomy, and implant size of 600 mL or greater strongly predicted the development of complications (P < 0.001). CONCLUSIONS: Our cumulative 13-year experience demonstrates that immediate, ADM-assisted, direct-to-implant breast reconstruction is safe, effective, and reliable. Complication and reoperation rates are less than 10% and are comparable to those reported for 2-stage procedures in the published literature.

Acellular Dermal Matrix-Assisted Direct-to-Implant Breast Reconstruction and Capsular Contracture: A 13-Year Experience.

BACKGROUND: Use of acellular dermal matrix for implant-based breast reconstruction appears to be associated with a lower incidence of capsular contracture compared with standard reconstruction. The majority of acellular dermal matrix studies were, however, of short duration; thus, long-term incidence of capsular contracture with acellular dermal matrix use is unknown. METHODS: Patients undergoing acellular dermal matrix-assisted breast reconstruction from December of 2001 to May of 2014 at two institutions were evaluated. Cumulative incidence of capsular contracture was determined by the performing surgeon. A retrospective chart review was performed on prospectively gathered data on patient-, breast-, surgery-, and implant-related characteristics that were analyzed as potential risk factors for the development of capsular contracture. RESULTS: A total of 1584 breast reconstructions in 863 patients were performed. Mean follow-up of patients was 4.7 years; 45 percent of patients had greater than or equal to 5 years of follow-up. The cumulative incidence of capsular contracture was 0.8 percent. Smaller implant size (<400 ml) and postoperative radiotherapy were significantly associated with an increased risk of capsular contracture, but the incidence of capsular contracture was 1.9 percent in irradiated breasts. All capsular contractures developed within the first 2 years, with no new events with longer follow-up. CONCLUSIONS: In this long-term study, the cumulative incidence of capsular contracture with acellular dermal matrix-assisted reconstruction remains low, even in irradiated breasts. Capsular contracture appears to be an early event, and longer follow-up does not appear to increase the incidence, suggesting that acellular dermal matrix may truly mitigate the development of capsular contracture as opposed to delaying its occurrence. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

An 8-year experience of direct-to-implant immediate breast reconstruction using human acellular dermal matrix (AlloDerm).

BACKGROUND: The advent of skin- and nipple-sparing mastectomy in conjunction with the use of human acellular dermal matrix to provide lower pole coverage has made direct-to-implant immediate breast reconstruction following mastectomy feasible. The purpose of this study was to evaluate long-term complications associated with this technique. METHODS: All human acellular dermal matrix-assisted direct-to-implant immediate reconstructions performed over an 8-year period were included in this analysis. Patient charts were reviewed for type of mastectomy (oncologic or prophylactic), incision type, complications during follow-up, length of follow-up, rate and type of revision surgery in breasts without postoperative complications, contralateral procedures, and adjuvant radiotherapy. RESULTS: A total of 466 breasts (260 patients) were reconstructed; 68 percent were prophylactic and 32 percent were oncologic cases. Twenty-one breasts (4.5 percent) received radiotherapy. Mean implant size placed was 412.8 ± 24.7 cc (range, 150 to 600 cc). Mean follow-up was 28.9 ± 21.3 months (range, 0.3 to 97.7 months). The overall complication rate was 3.9 percent (implant loss, 1.3 percent; skin breakdown/necrosis, 1.1 percent; hematoma, 1.1 percent; human acellular dermal matrix exposure, 0.6 percent; capsular contracture, 0.4 percent; and infection, 0.2 percent). Type, incidence, and overall rate of complications did not differ significantly between prophylactic and oncologic breasts. Irradiated breasts had a fourfold higher rate of complications. In 354 breasts with more than 1 year of follow-up (mean, 36.7 ± 18.6 months; range, 12.1 to 97.7 months), there were no long-term complications. CONCLUSIONS: Human acellular dermal matrix-assisted direct-to-implant breast reconstruction following mastectomy is safe and reliable, with a low overall long-term complication rate. The low incidence of capsular contracture supports the growing body of evidence that human acellular dermal matrix mitigates capsular contracture.

Melanoma presenting as circulating tumor cells associated with failed angiogenesis.

The ability of cancer cells to promote angiogenesis has been associated with a transition from a micrometastatic phenotype to a state in which large solid metastases can form. We describe a case of metastatic melanoma that presented with large numbers of circulating tumor cells and tissue infiltration without large solid metastases. Immunohistochemistry and reverse transcriptase-PCR was used to study the expression of melanoma tumor markers in circulating tumor cells. A tumor cell line was established from the patient and analyzed for adhesion molecule expression, expression of vascular endothelial growth factor, and the ability to inhibit solid tumor formation by other melanoma cells implanted as a xenograft. Examination of the circulating tumor cells confirmed they were of melanoma origin. Analysis of the tumor cell line obtained from this patient demonstrated intact expression of alpha and beta integrins but poor production of vascular endothelial growth factor, and also the ability to inhibit solid tumor formation of third-party melanoma tumors, suggesting a strong antiangiogenic activity. Our results indicate that lethal metastatic melanoma can occur even if tumor angiogenesis is defective, an observation that has implications for potential limits of antiangiogenic therapies.

Subcutaneous mastectomy and immediate reconstruction for prevention of breast cancer for high-risk patients.

Breast cancer is the most common malignant tumor among females in the USA, with one out of eight American females developing breast cancer in their lifetimes. The latest studies show that 212,920 new cases of invasive cancer developed in 2006, which is 2.5 times more common than the incidence of lung cancer, and that 40,970 females will die from this disease each year. Therefore, awareness of this cancer is an important health issue, with more women beginning to assess their risk of breast cancer, either informally or with instruments such as the GAIL model. The availability of genetic testing for BRCA-1 and BRCA-2 has revealed many women who are at significantly increased risk. Many aggressive surveillance programs have been developed using advanced MRI and ultrasound, and reductions in breast cancer risk of 50% or more have been proven using chemoprevention strategies with tamoxifen and raloxifene. However, many women are starting to seriously consider prophylactic mastectomy for near-total reduction of breast cancer risk. At our institution, we have developed a procedure for prophylactic subcutaneous mastectomy via an inframammary incision that spares the nipple and is combined with immediate silicone implant reconstruction with the assistance of Alloderm. In this article we will describe the procedure and some of the important issues surrounding its implementation from our experience.