OncotypeDX Testing Does Not Benefit Patients with Estrogen and Progesterone Receptor Positive Grade 1 Breast Cancers: A TAILORx Validated Study.

BACKGROUND & OBJECTIVES: We previously described a predictive AAMC model that identifies patients (grade 1, hormonepositive) who would not benefit from OncotypeDX testing. The purpose of this study was to validate the AAMC model by assessing distant recurrence-free interval (DRFI) and invasive disease-free survival (IDFS) using TAILORx clinical trial data. MATERIALS & METHODS: We retrospectively analyzed TAILORx trial data and categorized patients based on the AAMC model. AAMC low-risk patients are those with grade 1 and hormone-positive tumors. Kaplan-Meier curves examined DRFI and IDFS. RESULTS: Of the 9195 cases, 2246 (24.4%) were identified by AAMC as low-risk. Among these AAMC low-risk patients, 55.2% had Recurrence Score (RS) 0-15, 42.3% had RS 15-25, and 2.4% had RS > 25. The 10-year DRFI did not differ for those who received adjuvant chemotherapy versus those who did not (98% vs. 96%, log-rank p = 0.46). Similarly, IDFS was comparable between those who received adjuvant chemotherapy and those that did not (86% vs. 86%, log-rank p = 0.66). Only 2.4% of AAMC low-risk patients were categorized as high-risk (RS > 25). A sensitivity analysis of this discordant group, wherein those with RS > 25 were re-classified into the no-chemotherapy group and assumed to have experienced recurrences at the rate expected without chemotherapy, did not find any difference in DRFI between those who received adjuvant chemotherapy and those who did not (log-rank p = 0.16). CONCLUSION: OncotypeDX testing does not benefit AAMC low-risk patients with hormone-positive grade 1 tumors. Based on these data, 1 in 4 TAILORx participants would not need OncotypeDX testing.

Is Sentinel Lymph Node Biopsy Reliable After Recent Oncoplastic Breast Reduction?

An oncoplastic breast reduction may disrupt normal lymphatic drainage and make subsequent identification of the sentinel lymph nodes (SLNs) unreliable. There are little data on the success rate of sentinel lymph node biopsy (SLNB) after recent oncoplastic breast reduction, and there is no agreement on whether SLNB should be done at the time of the partial mastectomy and reduction for ductal carcinoma in situ (DCIS). The primary goals of this study were to evaluate the identification rate of SLNB after recent oncoplastic or functional breast reduction and to examine recurrence rates in this setting. Results reveal SLNB is feasible in this setting. At least one SLN was found in all patients, and there were no recurrences with an average follow-up of 34 months.

Outcomes of Margin Reexcision after Oncoplastic Breast Reduction.

Tissue rearrangement after an oncoplastic breast reduction may complicate identification of margins during reexcision. Little is known about outcomes of reoperation in this setting. Methods: This is a single-institution, retrospective analysis of outcomes of margin reexcisions after lumpectomy with concurrent oncoplastic Wise-pattern reduction from 2015 to 2020. Outcomes assessed were the rate of successful breast conservation, in-breast recurrence, wound issues or complications, effect on cosmesis, and delay to onset of adjuvant therapy. Results: From 2015 to 2020, 649 patients underwent lumpectomy with oncoplastic Wise-pattern reduction. Forty-seven patients (7.2%) had greater than or equal to one positive margin(s); of these, 28 went directly to mastectomy, and 19 underwent margin reexcision. Residual disease was found in seven of 19 patients (37%) at reexcision. The rate of successful breast-conserving therapy was 95% with a mean follow-up of 31 months. There was one (5%) in-breast recurrence (invasive ductal carcinoma [IDC] occurring 30 months after the original operation); this patient had a mastectomy for treatment of her recurrence. The overall complication rate was 37%. Radiation was administered to 18 patients (95%), and two patients (11%) had delay of radiation past 6 weeks due to wound complications. Of the 14 patients with photographs available, 12 of 14 patients (86%) were blindly assessed to have equivalent or better cosmesis after margin reexcision (versus initial lumpectomy). Conclusion: Margin reexcision after oncoplastic breast reduction with Wise-pattern is feasible and effective, and can be done without compromising the initial cosmetic results.

Recurrence Score Testing Does not Appear to Benefit Patients With Grade 1, Progesterone Receptor-Positive Breast Cancers: An Opportunity to Eliminate Overtreatment and Decrease Testing Costs.

BACKGROUND: We previously described a risk prediction model (Anne Arundel Medical Center [AAMC] model) based on pathology which may eliminate the need for recurrence score (RS) testing in select early-stage breast cancers. There is a concern that patients in discordant risk prediction groups (AAMC vs. RS) may be overtreated or undertreated if RS testing were omitted. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) database for all breast cancer patients between 2004 and 2015. AAMC low-risk was defined as Grade 1 and progesterone receptor-positive (PR + ) tumors, while AAMC high-risk was defined as Grade 3 or estrogen-negative tumors. RS low-risk group was defined as RS < 16 and age ≤ 50 years, or RS ≤ 25 and age > 50 years. RS high-risk group was defined as RS > 25. RESULTS: A total of 71,212 cases were analyzed. Of these, 590 were AAMC low-risk/RS high-risk discordant, while 5,596 were AAMC high-risk/RS low-risk discordant. For AAMC low-risk/RS high-risk discordant, 10-year breast cancer-specific survival (BCSS) did not differ for patients who received adjuvant chemotherapy versus those who did not (93% chemotherapy vs. 99% unknown/no chemotherapy, p = .12). Overall survival (OS) was also comparable (92% chemotherapy vs. 91% unknown/no chemotherapy, p = .42). In the AAMC high-risk/RS low-risk discordant group, 10-year BCSS (92% chemotherapy vs. 96% unknown/no chemotherapy, p = .06) and OS (87% chemotherapy vs. 90% unknown/no chemotherapy, p = .52) did not differ between adjuvant chemotherapy and unknown/no chemotherapy groups. CONCLUSIONS: Adjuvant chemotherapy in the AAMC low-risk/RS high-risk and AAMC high-risk/RS low-risk discordant groups did not improve survival. This supports consideration of omission of RS testing in Grade 1, PR + tumors. Patients with Grade 3 tumors do benefit from RS testing.

The Impact of Genomic Profiling on Adjuvant Therapy Recommendation in Postmenopausal Women with ER-Positive, T1-2 Breast Cancer: Can Genomic Profiling Eliminate the Need for Sentinel Lymph Node Biopsy?

INTRODUCTION: With the advent of genomic assays, sentinel lymph node biopsy (SLNB) may be less impactful in determining adjuvant breast cancer therapy. We evaluated the influence of SLNB on adjuvant therapy recommendation when the Oncotype DX recurrence score (RS) is known. METHODS: We reviewed postmenopausal women with ER-positive/HER2-negative, pT1-2 breast cancers with non-suspicious axillary ultrasound treated with SLNB at the time of cancer resection, from 2011 to 2015. For each case, the recommended adjuvant therapy based on the actual SLNB was compared with recommendations if SLNB had been omitted (presumed negative). RESULTS: Surgical nodal status was N0 in 184 patients (84.8%), Nmi-N1 in 29 patients (13.4%), and N2-3 in 4 patients (1.8%). SLNB resulted in a recommendation for axillary lymph node dissection in 4.1% (n = 9). Axillary surgery resulted in a change in radiation recommendation (nodal radiation considered or recommended) in 15.2% (n = 33). Of the 147 patients with known RS, 95 patients had RS > 18, 29 had RS 18-25, and 23 had RS < 25. When chemotherapy was only recommended for RS > 25, or N2-3 disease, SLNB changed the recommendation to have chemotherapy in one patient (0.7%), and the recommendation of which chemotherapy regimen (second- vs. third-generation) in an additional 5 patients. CONCLUSION: SLNB changed the recommendation for/against chemotherapy, or the chemotherapy regiment recommended, in 4.8% of postmenopausal women with early-stage, ER-positive/HER2-negative breast cancer, and sonographically negative axilla when using RS > 25 or N2-3 disease as an indication for chemotherapy. Preoperative genomic profiling can guide de-escalation of axillary surgery.

A Three-Dimensional Bioabsorbable Tissue Marker for Volume Replacement and Radiation Planning: A Multicenter Study of Surgical and Patient-Reported Outcomes for 818 Patients with Breast Cancer.

BACKGROUND: Accurate identification of the tumor bed after breast-conserving surgery (BCS) ensures appropriate radiation to the tumor bed while minimizing normal tissue exposure. The BioZorb® three-dimensional (3D) bioabsorbable tissue marker provides a reliable target for radiation therapy (RT) planning and follow-up evaluation while serving as a scaffold to maintain breast contour. METHODS: After informed consent, 818 patients (826 breasts) implanted with the BioZorb® at 14 U.S. sites were enrolled in a national registry. All the patients were prospectively followed with the BioZorb® implant after BCS. The data collected at 3, 6, 12, and 24 months included all demographics, treatment parameters, and provider/patient-assessed cosmesis. RESULTS: The median follow-up period was 18.2 months (range, 0.2-53.4 months). The 30-day breast infection rate was 0.5 % of the patients (n = 4), and re-excision was performed for 8.1 % of the patients (n = 66), whereas 2.6 % of the patients (n = 21) underwent mastectomy. Two patients (0.2 %) had local recurrence. The patient-reported cosmetic outcomes at 6, 12, and 24 months were rated as good-to-excellent by 92.4 %, 90.6 %, and 87.3 % of the patients, respectively and similarly by the surgeons. The radiation oncologists reported planning of target volume (PTV) reduction for 46.2 % of the patients receiving radiation boost, with PTV reduction most commonly estimated at 30 %. CONCLUSIONS: This report describes the first large multicenter study of 818 patients implanted with the BioZorb® tissue marker during BCS. Radiation oncologists found that the device yielded reduced PTVs and that both the patients and the surgeons reported good-to-excellent long-term cosmetic outcomes, with low adverse effects. The BioZorb® 3D tissue marker is a safe adjunct to BCS and may add benefits for both surgeons and radiation oncologists.

Ultrasound-Based Nomogram Identifies Breast Cancer Patients Unlikely to Harbor Axillary Metastasis: Towards Selective Omission of Sentinel Lymph Node Biopsy.

BACKGROUND: As tumor biology takes precedence over anatomic staging to determine breast cancer (BC) prognosis, there is growing interest in limiting axillary surgery. There is a need for tools to identify patients at the lowest risk of harboring axillary lymph node (ALN) disease, to determine when omission of sentinel lymph node biopsy (SLNB) may be appropriate. We examined whether a nomogram using preoperative axillary ultrasound (axUS) findings, clinical tumor size, receptor status, and grade to calculate the probability of nodal metastasis (PNM) has value in surgical decision making. METHODS: This was a retrospective analysis of female patients (February 2011-October 2014) with invasive BC who underwent preoperative axUS and axillary surgery. Cases with locally advanced BC, neoadjuvant treatment, or bilateral BC were excluded. PNM was calculated for each case. Using various PNM thresholds, the proportion of cases with ALN metastasis on pathology was examined to determine an optimal PNM cut-point to predict ALN negativity. RESULTS: Of 357 included patients, 72% were node-negative on surgical staging, and 69 (19.6%) had a PNM < 9.3%. Of these 69 patients, 6 had ALN metastasis on surgical pathology, yielding a false negative rate (FNR) of 8.7% for predicting negative ALN when a PNM threshold of < 9.3% was used. CONCLUSION: A nomogram incorporating axUS findings and tumor characteristics identified a sizeable subgroup (19.6%) in whom ALN was predicted to be negative, with an 8.7% FNR. Surgeons can use this nomogram to quantify the probability of ALN metastasis and select patients who may benefit from omitting SLNB.

Treatment delays from transfers of care and their impact on breast cancer quality measures.

PURPOSE: Despite delays between diagnosis and surgery adversely affecting survival, patients frequently transfer their breast cancer care between institutions. This study was performed to assess the prevalence and effect of such transfers of care (TsOC) on the time to surgery, and its impact on current time-dependent breast cancer quality metrics at Commission on Cancer (CoC) and National Accreditation Program for Breast Centers (NAPBC)-accredited institutions. METHODS: Patients having non-metastatic invasive breast cancer diagnosed between 2006 and 2015 at CoC and NAPBC centers ("reporting facilities") in the National Cancer Database were reviewed. TsOC refer to transferring into or out of a reporting facility between diagnosis and surgery. RESULTS: Among 622,793 patients, 36.6% of patients transferred care. TsOC add 7.3, 7.8, 8.7, and 9.8 days in time to surgery, chemotherapy, radiotherapy, and endocrine therapy, respectively (p's < 0.0001). On multivariable analysis, the odds of surgery occurring > 90 days from diagnosis were greatest for patients undergoing unilateral or bilateral mastectomy, Black or Hispanic patients, and those having TsOC (ORs > 1.73, p's < 0.0001). TsOC increase the odds of non-compliance, per patient, for chemotherapy, radiotherapy and endocrine therapy time-dependent measures by 65.4%, 25.6%, and 56.5%, respectively (p < 0.0001). CONCLUSIONS: TsOC for newly diagnosed breast cancers to or from an accredited facility result in delays in time to surgery which can affect compliance with time-dependent quality measures. Facilities frequently receiving transferred patients may be most adversely affected. Although non-compliance with these quality measures is low, institutions and accrediting bodies should be aware of these associations in order to comply with time-dependent standards.

ASBRS Great Debate: Sentinel Node Biopsy in Patients Over 70 Years of Age.

INTRODUCTION: Controversy over the need for sentinel node biopsy (SNB) continues to exist for the optimal treatment of breast cancer in patients ≥ 70 years of age, especially in those with lower-risk disease. Clinicians must balance competing risks to give the best individualized care. METHODS: The American Society of Breast Surgeons (ASBrS) conducted a debate discussing the pros and cons of routinely performing SNB in this age group. Small, randomized studies have been conducted that show no overall survival benefit to axillary intervention (either axillary dissection or SNB) in patients with clinically T1N0 estrogen receptor (ER)- and progesterone receptor (PR)-positive, HER2/neu-negative tumors. There may be a small local recurrence benefit to axillary staging in patients who do not undergo radiation. Alternatively, axillary ultrasound, which carries a low false-negative rate for heavy disease burden, can be used to select patients who can avoid SNB. CONCLUSION: Surgeons must continue to individualize care of breast cancer patients over 70 years of age in whom competing comorbidities may dictate care. No randomized clinical trials (RCTs) have found a survival benefit to axillary staging in this low-risk population. However, in healthy patients, axillary staging may improve local control, provide prognostic information, and help guide decisions regarding adjuvant therapy such as chemotherapy and radiation. Ongoing RCTs are evaluating the benefit of SNB in patients with a negative axillary ultrasound. Until those results are available, clinicians and patients must balance the risk and benefits to determine if SNB adds significant value to their overall care.

Routine Axillary Ultrasound for Patients with T1-T2 Breast Cancer Does Not Increase the Rate of Axillary Lymph Node Dissection Based on Predictive Modeling.

BACKGROUND: Since publication of the American College of Surgeons Oncology Group Z0011 trial results, demonstrating that many patients with nonpalpable axillary lymph nodes and one or two positive sentinel nodes do not require axillary lymph node dissection (ALND), preoperative axillary ultrasound (AUS) has become controversial. Clinicians are concerned that AUS may lead to unnecessary ALND. The authors developed an algorithm (Algorithm 1) in which the number of AUS-suspicious nodes and tumor biology direct management. For estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer with a single AUS-suspicious node and a positive lymph node needle biopsy (LNNB), sentinel lymph node biopsy (SLNB) is performed with a specimen X-ray documenting retrieval of the clipped node. Other patients with positive LNNB receive neoadjuvant chemotherapy. The authors hypothesized that routine AUS and this algorithm could decrease ALND compared with a strategy of no preoperative AUS. METHODS: Decision-tree analysis and Monte Carlo simulation were used to assess the expected number of ALNDs under two strategies (routine AUS vs no AUS). Probabilities were drawn from a literature review and an institutional database. The authors assumed nodal pathologic complete response rates as reported in the literature. Four additional algorithms were created to assess whether any other treatment model could decrease the rate of ALND. RESULTS: Using the routine AUS and the authors' algorithm, the predicted ALND rate was 9%, versus 10% for a strategy of no AUS, with overlapping uncertainty intervals. The remaining treatment algorithms showed similar results. DISCUSSION: Use of AUS may help to tailor patient care without leading to overutilization of ALND, as long as neoadjuvant chemotherapy is administered when appropriate.

Positive Ultrasound-guided Lymph Node Needle Biopsy in Breast Cancer may not Mandate Axillary Lymph Node Dissection.

BACKGROUND: The ACOSOG Z0011 (Z11) trial demonstrated that in patients with nonpalpable axillary lymph nodes (LN) and one to two positive sentinel LN (SLN), axillary LN dissection (ALND) is unnecessary.JAMA 305:569-575, [2011], Ann Surg 264:413-42, [2016] The Z11 trial did not require preoperative axillary ultrasound (axUS). In many centers, preoperative axUS is part of the standard workup of a newly diagnosed breast cancer patient, but in light of the Z11 results, its role is now questioned. METHODS: We retrospectively analyzed newly diagnosed breast cancer patients at two institutions. Inclusion criteria were patients with (1) no palpable lymphadenopathy, (2) abnormal axUS, (3) axillary LN metastasis confirmed preoperatively by axUS-lymph node needle biopsy, (4) no neoadjuvant therapy, and (5) ALND. LN disease burden was dichotomized as N1 versus N2-3. We examined relationships between clinicopathologic factors, including axUS characteristics, and LN disease burden. RESULTS: Of 129 included cases, 67 had N1 disease (51.9%) and 62 had N2-3 disease (48.1%). Factors significantly associated with N1 disease were tumor size ≤2 cm (p = 0.012), nonlobular histology (p = 0.013), and one suspicious LN on axUS (p = 0.008). For patients with both tumor size on imaging ≤2 cm and one abnormal LN on axUS, only 27% had N2-3 disease (p = 0.007). CONCLUSIONS: More than half of patients without palpable adenopathy but with preoperative US-guided biopsy proven axillary LN metastases had N1 disease. For patients with both tumor size ≤2 cm and only 1 abnormal LN on axUS, 73% had N1 disease. This suggests that such patients, if they are otherwise analogous to Z11 patients, may undergo attempt at SLNB.

Prospective Study Comparing Surgeons' Pain and Fatigue Associated with Nipple-Sparing versus Skin-Sparing Mastectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) is more technically challenging than skin-sparing mastectomy (SSM) but offers quality-of-life and cosmetic advantages. However, surgeon physical symptoms related to NSM workload have not been documented. METHODS: This was a prospective study using questionnaires to compare surgeon-reported physical symptoms before, during, and after NSM versus SSM. Surgeons also answered general questions about each mastectomy. Bilateral cases were performed simultaneously by two surgeons, who completed independent questionnaires. RESULTS: Questionnaires were completed after 82 SSMs and 44 NSMs. On a 0-10 scale, surgeons reported NSM was more physically demanding than SSM (7.0 vs. 4.5, p < 0.001). Mean visualization was more difficult (5.7 vs. 3.2, p < 0.001) and mean fatigue score was greater (5.6 vs. 3.1, p < 0.001) after NSM than SSM. The mean increase in neck pain (on a 0-4 scale) was greater for NSM than SSM, both from before-to-during surgery (0.8 vs. 0.2, p = 0.003) and before-to-after surgery (0.9 vs. 0.2, p = 0.002). The mean increase in lower back pain was greater for NSM than SSM, both from before-to-during surgery (0.7 vs. 0.2, p = 0.008) and before-to-after surgery (0.9 vs. 0.2, p = 0.003). Surgeons reported that NSM was more mentally demanding (p < 0.001), complex (p = 0.01), and difficult (p < 0.001) than SSM. CONCLUSION: Surgeons experienced greater physical symptoms, mental strain, and fatigue with NSM than SSM. This raises concern that mild but repetitive pain over the course of a breast surgeon's career may lead to repetitive stress injury.

Optimizing the Use of Gene Expression Profiling in Early-Stage Breast Cancer.

Purpose Gene expression profiling assays are frequently used to guide adjuvant chemotherapy decisions in hormone receptor-positive, lymph node-negative breast cancer. We hypothesized that the clinical value of these new tools would be more fully realized when appropriately integrated with high-quality clinicopathologic data. Hence, we developed a model that uses routine pathologic parameters to estimate Oncotype DX recurrence score (ODX RS) and independently tested its ability to predict ODX RS in clinical samples. Patients and Methods We retrospectively reviewed ordered ODX RS and pathology reports from five institutions (n = 1,113) between 2006 and 2013. We used locally performed histopathologic markers (estrogen receptor, progesterone receptor, Ki-67, human epidermal growth factor receptor 2, and Elston grade) to develop models that predict RS-based risk categories. Ordering patterns at one site were evaluated under an integrated decision-making model incorporating clinical treatment guidelines, immunohistochemistry markers, and ODX. Final locked models were independently tested (n = 472). Results Distribution of RS was similar across sites and to reported clinical practice experience and stable over time. Histopathologic markers alone determined risk category with > 95% confidence in > 55% (616 of 1,113) of cases. Application of the integrated decision model to one site indicated that the frequency of testing would not have changed overall, although ordering patterns would have changed substantially with less testing of estimated clinical risk-high or clinical risk-low cases and more testing of clinical risk-intermediate cases. In the validation set, the model correctly predicted risk category in 52.5% (248 of 472). Conclusion The proposed model accurately predicts high- and low-risk RS categories (> 25 or ≤ 25) in a majority of cases. Integrating histopathologic and molecular information into the decision-making process allows refocusing the use of new molecular tools to cases with uncertain risk.

Intraoperative Assessment of Final Margins with a Handheld Optical Imaging Probe During Breast-Conserving Surgery May Reduce the Reoperation Rate: Results of a Multicenter Study.

BACKGROUND: A multicenter, prospective, blinded study was performed to test the feasibility of using a handheld optical imaging probe for the intraoperative assessment of final surgical margins during breast-conserving surgery (BCS) and to determine the potential impact on patient outcomes. METHODS: Forty-six patients with early-stage breast cancer (one with bilateral disease) undergoing BCS at two study sites, the Johns Hopkins Hospital and Anne Arundel Medical Center, were enrolled in this study. During BCS, cavity-shaved margins were obtained and the final margins were examined ex vivo in the operating room with a probe incorporating optical coherence tomography (OCT) hardware and interferometric synthetic aperture microscopy (ISAM) image processing. Images were interpreted after BCS by three physicians blinded to final pathology-reported margin status. Individual and combined interpretations were assessed. Results were compared to conventional postoperative histopathology. RESULTS: A total of 2,191 images were collected and interpreted from 229 shave margin specimens. Of the eight patients (17 %) with positive margins (0 mm), which included invasive and in situ diseases, the device identified all positive margins in five (63%) of them; reoperation could potentially have been avoided in these patients. Among patients with pathologically negative margins (>0 mm), an estimated mean additional tissue volume of 10.7 ml (approximately 1% of overall breast volume) would have been unnecessarily removed due to false positives. CONCLUSIONS: Intraoperative optical imaging of specimen margins with a handheld probe potentially eliminates the majority of reoperations.

Normal Axillary Ultrasound Excludes Heavy Nodal Disease Burden in Patients with Breast Cancer.

BACKGROUND: Axillary lymph node stage is important in guiding adjuvant treatment for breast cancer. The role of axillary ultrasound (AUS) in axillary staging is uncertain. METHODS: From an institutional database, all newly diagnosed invasive breast carcinomas from February 1, 2011 to October 31, 2014 were identified; exclusions were for stage IV disease, palpable adenopathy, or receipt of neoadjuvant chemotherapy. AUS findings, categorized as suspicious versus not suspicious, were correlated with the number of nodal metastasis from surgical pathology. The false-negative rate of nonsuspicious AUS for identifying ≥3 lymph nodes positive on final pathology was calculated. RESULTS: A total of 513 cancers were included. Overall, 400 AUSs were not suspicious (78%), and 113 were suspicious (22%). The sensitivity and specificity of AUS for predicting ≥3 nodal metastasis were 71 and 83%, respectively. The false-negative rate for detecting ≥3 nodal metastasis was 4%. False-negative rate was higher for lobular versus nonlobular carcinomas (12.0 vs. 2.3%, p = 0.004) and for pT2-pT4 tumors versus pT1 tumors (8.2 vs. 1.7 %, p = 0.005). CONCLUSIONS: Patients with normal axillary physical exam and ultrasound rarely harbor a large nodal disease burden. Randomized trials of sentinel lymph node biopsy versus no axillary surgery in patients with normal AUS must be powered for subgroup analysis of patients with invasive lobular carcinoma and pT2-pT4 tumors. Preoperative identification of nodal metastasis may decrease the need for second surgeries and identify candidates for neoadjuvant chemotherapy. AUS is a noninvasive means of predicting disease burden preoperatively and as such is a powerful tool to individualize treatment plans.

A Validated Model for Identifying Patients Unlikely to Benefit From the 21-Gene Recurrence Score Assay.

BACKGROUND: Predicting recurrence risk and chemotherapy benefit in early-stage breast cancer can be challenging, and Oncotype DX (ODX) is often used to gain insight. However, it is still unclear whether ODX can benefit in all cases. To clarify ODX's usefulness we sought to develop a model using readily available pathologic markers to help clinicians make that determination. PATIENTS AND METHODS: Clinical pathologic data from 221 hormone receptor-positive, HER2-negative invasive breast cancer patients was used to create a model. The model was then validated on a second institution's set of 319 patients. RESULTS: The model has 2 simple rules: low grade and positive progesterone receptor tumors (LG+PR) are low risk, and high grade or low estrogen receptor (ER) (ER < 20%) tumors (HG/LER) are high risk. The TAILORx (Trial Assigning Individualized Options for Treatment (Rx)) trial thresholds of Recurrence Score (RS) ≤ 10, when chemotherapy is of little benefit, and RS ≥ 26 when chemotherapy might be beneficial were used to judge model performance. Impressively, the misclassifications of an HG/LER patient who has an RS ≤ 10 were 0% and 2%, and for LG+PR patients who had an RS ≥ 26 were 0% and 2.6%. In the validation set, 28% (66 of 232) of the indeterminate group (neither in the HG/LER nor the LG+PR groups) had an RS ≤ 10 or an RS ≥ 26; this group might clinically benefit from ODX. CONCLUSION: A simple 2-rule model based on readily available pathologic data was developed and validated, which categorized patients into high and low risk for recurrence. Identification of patients who are unlikely to benefit from ODX testing could result in significant cost avoidance.

A randomized prospective study of lumpectomy margin assessment with use of MarginProbe in patients with nonpalpable breast malignancies.

BACKGROUND: The presence of tumor cells at the margins of breast lumpectomy specimens is associated with an increased risk of ipsilateral tumor recurrence. Twenty to 30 % of patients undergoing breast-conserving surgery require second procedures to achieve negative margins. This study evaluated the adjunctive use of the MarginProbe device (Dune Medical Devices Ltd, Caesarea, Israel) in providing real-time intraoperative assessment of lumpectomy margins. METHODS: This multicenter randomized trial enrolled patients with nonpalpable breast malignancies. The study evaluated MarginProbe use in addition to standard intraoperative methods for margin assessment. After specimen removal and inspection, patients were randomized to device or control arms. In the device arm, MarginProbe was used to examine the main lumpectomy specimens and direct additional excision of positive margins. Intraoperative imaging was used in both arms; no intraoperative pathology assessment was permitted. RESULTS: In total, 596 patients were enrolled. False-negative rates were 24.8 and 66.1 % and false-positive rates were 53.6 and 16.6 % in the device and control arms, respectively. All positive margins on positive main specimens were resected in 62 % (101 of 163) of cases in the device arm, versus 22 % (33 of 147) in the control arm (p < 0.001). A total of 19.8 % (59 of 298) of patients in the device arm underwent a reexcision procedure compared with 25.8 % (77 of 298) in the control arm (6 % absolute, 23 % relative reduction). The difference in tissue volume removed was not significant. CONCLUSIONS: Adjunctive use of the MarginProbe device during breast-conserving surgery improved surgeons' ability to identify and resect positive lumpectomy margins in the absence of intraoperative pathology assessment, reducing the number of patients requiring reexcision. MarginProbe may aid performance of breast-conserving surgery by reducing the burden of reexcision procedures for patients and the health care system.

A prediction model for the presence of axillary lymph node involvement in women with invasive breast cancer: a focus on older women.

Axillary lymph node (ALN) status at diagnosis is the most powerful prognostic indicator for patients with breast cancer. Our aim is to examine the contribution of variables that lead to ALN metastases in a large dataset with a high proportion of patients greater than 70 years old. Using the data from two multicenter prospective studies, a retrospective review was performed on 2,812 patients diagnosed with clinically node-negative invasive breast cancer from 1996 to 2005 and who underwent ALN sampling. Univariate and multivariate logistic regression were used to identify variables that were strongly associated with axillary metastases, and an equation was developed to estimate risk of ALN metastases. Of the 2,812 patients with invasive breast cancer, 18% had ALN metastases at diagnosis. Based on univariate analysis, tumor size, lymphovascular invasion (LVI), tumor grade, age at diagnosis, menopausal status, race, tumor location, tumor type, and estrogen and progesterone receptor status were statistically significant. The relationship between age and involvement of axillary metastases was nonlinear. In multivariate analysis, LVI, tumor size and menopausal status were the most significant factors associated with ALN metastases. Age, however, was not a significant contributing factor for axillary metastases. Tumor size, LVI, and menopausal status are strongly associated with ALN metastases. We believe that age may have been a strong factor in previous analyses because there was not an adequate representation of women in older age groups and because of the violation of the assumption of linearity in their multivariate analyses.

Is oncotype DX recurrence score (RS) of prognostic value once HER2-positive and. low-ER expression patients are removed?

Oncotype DX has been criticized for not providing significantly more prognostic information than histopathologic analysis. Oncotype DX was validated in cohorts that included poor prognostic factors (HER2-positive, low-estrogen receptor [ER] expression), raising the question: if patients with known high recurrence rates are excluded, is the Recurrence Score (RS) still valid? Our purpose was to determine if RS can be predicted with readily available measures. One hundred and twenty samples from August 2006 to November 2010 that underwent Oncotype DX testing were analyzed. Data included RS, ER, progesterone receptor (PR), HER2, and Ki67 status by immunohistochemistry (IHC). IHC data were used to create two linear regression models to predict RS. SAS's JMP-7 was used for statistical analysis. When comparing Oncotype DX- and IHC-derived ER and PR values, there were 21 discordant samples. The linear regression model PRS-F created with IHC data (ER, PR, HER2, Ki67) from all samples (n = 120) had an adjusted R(2) = 0.60 indicating a good model for predicting RS. The PRS-R model was built without low-ER and HER2-positive samples (n = 110). It had an adjusted R(2) = 0.38 indicating poor prediction of RS. Oncotype DX data showed good concordance with IHC for ER- and PR-expression in this cohort. Low-ER samples had high RS. After removing low-ER and HER2-positives, calculating RS with PRS-R from remaining data showed poor predictive power for RS (adjusted R(2) = 0.38). This result questions whether RS is prognostic in this subgroup (who would most benefit from further clarification of recurrence risk) and independent of pathology, or is simply producing random RS values. Data bases available to Genomic Health can resolve this issue.

Does breast tumor heterogeneity necessitate further immunohistochemical staining on surgical specimens?

BACKGROUND: Prognostic and predictive tumor markers in breast cancer are most commonly performed on core needle biopsies (CNB) of the primary tumor. Because treatment recommendations are influenced by these markers, it is imperative to verify strong concordance between tumor markers on CNB specimens and the corresponding surgical specimens (SS). STUDY DESIGN: A prospective study was performed on 165 women (205 samples) with breast cancer diagnosed from January 2009 to July 2011. Tumor type, grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2), and Ki67 expression by immunohistochemical (IHC) testing were retrospectively analyzed in the CNB and SS. Contingency tables and agreement modeling were performed. RESULTS: There was substantial agreement between the CNB and SS for PR% and HER2; moderate agreement for tumor type, grade, and ER%; and fair agreement for Ki67%. In 8% of patients (n = 13), tumor heterogeneity was seen. In heterogeneous tumors the overall concordance between the CNB and SS was worse, especially for HER2. Six of these patients had areas of tumor that were positive for HER2, which were not detected in their CNBs. Nine patients had multiple distinct molecular subtypes within their tumor(s). CONCLUSIONS: The heterogeneous distribution of antigens in breast cancer tumors raises concern that the CNB may not adequately represent the true biologic profile in all patients. There is strong concordance for tumor type, ER, and PR between CNB and SS (although a quantitative decline was noted from CNB to SS); however, HER2 activity does not appear to be adequately detected on CNB in patients with heterogeneous tumors. These data suggest that IHC testing on the CNB alone may not be adequate to tailor targeted therapy in all patients.