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.

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.

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.

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.

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.

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.

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.

Circulating levels of gonadotropins before and after prostate ablation in cancer patients.

UNLABELLED: Abstract Background: The prostate gland synthesizes a host of hormones, prostaglandins and growth factors. It is not clear if such biochemical factors modulate the hypothalamic/pituitary (H-P) gonadal axis. AIM: To determine the influence of the prostate gland on the hypothalamic-pituitary axis feedback system and changes in circulating hormone levels before and after cryoablation of the entire prostate. METHODS: In 37 consecutive patients with localized prostate cancer who underwent total cryoablation we investigated the circulating levels of testosterone, estradiol, progesterone, sex hormone binding globulin (SHBG) luteinizing hormone (LH), follicle stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS), prolactin, insulin-like growth factor-1(IGF-1) and prostatic specific antigen (PSA) from 3 years prior to diagnosis to 3 years after initiating treatment. RESULTS: The levels of LH and FSH were significantly elevated in most patients up to 3 years after surgery. No significant changes were observed for the other hormones, with a decrease in PSA as expected. CONCLUSION: LH and FSH levels rise after ablation of the prostate gland and the levels remain high for up to 3 years after surgery, which suggests that the prostate gland may influence the H-P feedback axis.

Persistent organic pollutants in serum and several different fat compartments in humans.

BACKGROUND: Chemicals that store in lipid-rich compartments have the potential for long-term disruption of metabolic and endocrine processes. Given the evidence that persistent organic pollutants (POPs) also alter systemic metabolic, endocrine, and immune system functions, it follows that elevated chemical concentrations in intra-abdominal fat may alter function, through local chemical signaling, of visceral organs. Despite this potential, there has been little study defining POP concentrations in live human intra-abdominal fat. It is at present uncertain whether POPs distribute equally to all fat compartments, including fat in serum. METHODS: Seven human subjects scheduled for elective surgery for benign lesions or cancer provided consent for removal of samples of subcutaneous and intra-abdominal fat and/or cancerous tissue. These samples were analyzed for 22 chlorinated pesticides and 10 polychlorinated biphenyl (PCB) congeners by GC/ECD plus GC/MS. RESULTS: In only two subjects were the patterns and relative concentrations of PCBs and pesticides about the same in all fat compartments. In the other subjects, there were major differences in levels in subcutaneous as compared to other compartments, but with some higher and some lower. While the pattern of PCBs in the various compartments matched that of the pesticides in some, it was opposite in others. INTERPRETATION: These results demonstrate a complicated distribution of PCB congeners and pesticides in various lipid compartments. The difference may reflect various K(ow)s, different rates of metabolism, and/or different lengths of exposure. But the results suggest that contaminant levels in serum or even subcutaneous fat do not necessarily indicate concentrations and patterns in other kinds of adipose tissue.