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Human epidermal growth factor receptor-2 (HER2) status can be tested with immunohistochemistry (IHC) and in situ hybridization (ISH). The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 testing guidelines suggest initial HER2 testing using IHC and further testing IHC equivocal cases with ISH. However, many institutions perform both IHC and ISH on the same specimen. This study aims to analyze the concordance between HER2 IHC and ISH in order to evaluate the benefit of repeating HER2 testing on the same breast cancer specimens.Patients diagnosed with invasive breast cancer through BreastScreen NSW Sydney West program between January 2018 and December 2020 were identified and their HER2 IHC and HER2 ISH results on core needle biopsy (CNB) and surgical excisions (SE) were retrospectively collected. Specimens with both IHC and ISH results were then analyzed for agreement and concordance using unweighted kappa values. Equivocal IHC (2+) cases were excluded from concordance analysis.Overall, there were 240 invasive breast cancer specimens (CNB and SE) with both IHC and ISH recorded. Concordance between HER2 IHC and ISH was 100% (95% CI: 96.2-100%; κ = 1.00 (P 0.001)). Of the IHC equivocal cases (n = 146), 94.5% were ISH negative.There was perfect positive concordance and agreement between non-equivocal IHC and ISH results. This reinforces that IHC alone can be utilized reliably for testing HER2 status of non-equivocal cases consistent with the 2018 ASCO/CAP guidelines.

To evaluate risk factors (treatment-related, comorbidities, and lifestyle) for breast cancer-related lymphedema (BCRL) within the context of a Prospective Surveillance and Early Intervention (PSEI) model of care for subclinical BCRL.The parent randomized clinical trial assigned patients newly diagnosed with breast cancer to PSEI with either bioimpedance spectroscopy (BIS) or tape measurement (TM). Surgical, systemic and radiation treatments, comorbidities, and lifestyle factors were recorded. Detection of subclinical BCRL (change from baseline of either BIS L-Dex ≥6.5 or tape volume ≥ 5% and 10%) triggered an intervention with compression therapy. Volume change from baseline ≥10% indicated progression to chronic lymphedema and need for complex decongestive physiotherapy. In this secondary analysis, multinomial logistic regressions including main and interaction effects of the study group and risk factors were used to test for factor associations with outcomes (no lymphedema, subclinical lymphedema, progression to chronic lymphedema after intervention, progression to chronic lymphedema without intervention). Post hoc tests of significant interaction effects were conducted using Bonferroni-corrected alphas of .008; otherwise, an alpha of .05 was used for statistical significance.The sample (n = 918; TM = 457; BIS = 461) was female with a median age of 58.4 years. Factors associated with BCRL risk included axillary lymph node dissection (ALND) (p .001), taxane-based chemotherapy (p .001), regional nodal irradiation (RNI) (p ≤ .001), body mass index30 (p = .002), and rurality (p = .037). Mastectomy, age, hypertension, diabetes, seroma, smoking, and air travel were not associated with BCRL risk.Within the context of 3 years of PSEI for subclinical lymphedema, variables of ALND, taxane-based chemotherapy, RNI, body mass index30, and rurality increased risk.

BackgroundThis study compared rates of progression to chronic breast cancer-related lymphedema (defined as a ≥ 10% arm volume change from baseline requiring complex decongestive physiotherapy (CDP)) following an intervention for subclinical lymphedema (S-BCRL) triggered by bioimpedance spectroscopy (BIS) or by tape measurement (TM).Methods and ResultsThis stratified, randomized, international trial enrolled new breast cancer patients undergoing: mastectomy/partial mastectomy, axillary treatment (dissection, sentinel lymph node biopsy >6 nodes or radiation), radiation therapy (chest wall/ breast, supraclavicular fossa), or taxane-based chemotherapy. Following post-surgery eligibility reassessment, centralized, 1:1 randomization to prospective surveillance by BIS or TM occurred. S-BCRL detection triggered a 4-week, 12-hour per day, compression sleeve and gauntlet intervention. The primary outcome (n=209), rates of post-intervention progression to CDP, were assessed over three years. Between June 24, 2014 and September 11, 2018, 1,200 patients were enrolled, 963 randomized (BIS n=482;TM n=481) and 879 analyzed (BIS n=442;TM n=437). Median follow-up was 32.9 months (IQR=22,35). BIS patients triggered an intervention at a lower rate than TM patients (20.1%, n=89 vs 27.5%, n=120, p = 0.011). Median months to trigger was longer with BIS than TM (9.7; 95%CI,8.2-12.6 vs 3.9; 95%CI,2.8-4.5, p = 0.001). Overall, 14.4%(n=30) progressed post-intervention, with reduced likelihood for BIS patients than TM patients (7.9%, n=7 vs 19.2%, n=23; RR=0.41; 95%CI,0.13-0.81; absolute reduction 11.3%; 95%CI,2.3%-20.3%; p = 0.016).ConclusionsAs compared to TM, BIS provides a more precise identification of patients likely to benefit from an early compression intervention.Condensed AbstractThis stratified, multi-site, international trial enrolled newly diagnosed breast cancer patients, randomized them to prospective surveillance by bioimpedance spectroscopy (BIS) or tape measurement (TM), and screened them for lymphedema development at frequent intervals for three years after surgery. When subclinical lymphedema was detected a 4-week, 12-hour per day, compression sleeve and gauntlet intervention was implemented. Overall, 14.4% (n=30) progressed post-intervention to chronic lymphedema, with reduced likelihood for BIS patients than TM patients (7.9%, n=7 vs 19.2%, n=23; RR=0.41; 95%-CI,0.13-0.81; absolute reduction 11.3%; 95%-CI,2.3%-20.3%; p = 0.016). BIS best supported intervention success for prevention of chronic lymphedema compared to TM.

Chronic lymphedema following breast cancer (BC) affects individuals physically, functionally, psychologically, and financially. Despite national guidelines and evidence-based research supporting a prospective surveillance and early intervention model of care (PSM), bridging the gap between research and clinical practice has been difficult.As part of an international randomized controlled trial (RCT), Australian women with BC from four hospitals were recruited, monitored for lymphedema at regular intervals over a 3-year period, and were provided a compression garment if intervention was triggered. The reach, effectiveness, adoption, implementation and maintenance (RE-AIM) evaluation framework was used retrospectively to assess a PSM at the individual and organizational level for those who had completed at least 2-year follow-up (N = 219) in the RCT.The application of the RE-AIM framework retrospectively demonstrated an extensive reach to patients across public and private settings; the effectiveness of prospective surveillance and early intervention was achieved through low progression rates to clinical lymphedema (1.8%), and all hospital sites initially approached adopted the research study. Key implementation strategies necessary for effectiveness of this model of care included education to health professionals and patients, staff acceptability, and development of a referral and care pathway. Maintenance dimensions were evaluated both at the individual level with 92-100% adherence rates for all nonoptional study appointments over the 2-year period, and at the organizational-level, PSM was sustained after recruitment ceased for the research study.The PSM for lymphedema in BC can be successfully implemented using the RE-AIM framework applied retrospectively. The implementation of the PSM used in the RCT has assisted in changing clinical practices and improving the quality and effectiveness of the health care system.

The American College of Surgeons Oncology Group Z0011 Trial demonstrated that early breast cancer patients with positive axillary sentinel lymph nodes treated with breast-conserving surgery and breast radiotherapy had no additional oncologic benefit of proceeding to an axillary lymph node dissection (ALND). The extent to which practice has changed in Australia remains unclear. The aim of this study was to investigate the effect of the Z0011 trial on the management of positive axillary sentinel nodes at an Australian institutional level. We reviewed all breast cancer cases treated at the Sydney Adventist Hospital over a 10-year period from 1 January 2008 to 31 December 2017. Patients who fulfilled the Z0011 trial criteria were selected. These patients were divided into two groups according to the year of surgery, before and after 1 January 2011 when the Z0011 study was published. Clinicopathologic data and axillary surgical management were compared. Of the 237 patients fulfilling the Z0011 trial criteria, there were 73 patients before and 158 patients after 1 January 2011. In the earlier group the rate of proceeding to an ALND following a positive sentinel node was 78.1% compared to 43.7% in the latter group (P < 0.0001). There was a significant decline in the rate of ALND over this 10-year period (r = -0.79, P = 0.006). The Z0011 trial has influenced the surgical management of the axilla leading to a significant reduction in the rate of an ALND in patients fulfilling the Z0011 trial criteria at our institution.

Purpose To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome. Patients and Methods Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted. Results Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor. Conclusion V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.

Background: Merkel cell carcinoma is an aggressive primary cutaneous neuroendocrine carcinoma. Patients remain at high risk of locoregional and distant relapse despite treatment. Most studies support the incorporation of locoregional adjuvant radiotherapy in reducing the risk of relapse. Methods: Between 1980 and 2002, 86 patients diagnosed with Merkel cell carcinoma were treated with curative intent at Westmead Hospital, Sydney. Multivariate analysis was performed using Cox regression analysis. Disease-free survival and overall survival was calculated using Kaplan–Meier survival curves. Results: Median age at diagnosis was 75 years (range 46–89 years) in 49 men and 37 women. Median duration of follow up was 31 months (range 6–153 months). Fifty-one (59%) patients presented with a primary lesion, 19 (22%) with a primary lesion and clinical nodal disease and 16 (19%) with lymph node metastases from an unknown primary. A total of 47 of 86 (55%) relapsed with regional nodal relapse, the commonest site of first relapse. Local relapse was similar for patients undergoing surgery (5/37; 14%) compared with surgery and adjuvant radiotherapy (3/25; 12%). Nodal relapse occurred in 14 of 36 (37%) treated with surgery compared with 7 of 38 (18%) patients treated with surgery and adjuvant radiotherapy. Patients treated with surgery and adjuvant radiotherapy experienced a better median disease free survival compared to those undergoing surgery alone (10.5 months vs 4 months; P

Electroporation therapy (EPT) is a novel treatment modality that uses brief, high-intensity, pulsed electrical currents to enhance the uptake of chemotherapeutic agents, vaccines and genes into cells. This technique is potentially useful for patients with secondary and, possibly, some primary tumours. Nineteen patients with metastatic melanoma were enrolled in a phase two, randomized, open-label study comparing intralesional bleomycin+EPT with intralesional bleomycin alone. Of 18 study lesions, 13 (72%) showed a complete response, one (5%) showed a partial response, three (18%) showed no change and one (5%) showed disease progression over a period of greater than 12 weeks. This represents a 78% objective response rate, which was significantly greater than the 32% response rate observed in the 19 patients with tumours treated with intralesional bleomycin alone (chi=7.94, 1 df, P=0.005). An additional 36 lesions, not enrolled in the study, were also treated with bleomycin+EPT. Of the total of 54 lesions treated with bleomycin+EPT, there was a 72% objective response rate. EPT treatment was well tolerated and was performed on an outpatient basis.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy. Nodal status has prognostic significance.We sought to analyze for factors predictive of survival and explore the significance of lymph node status and indication for sentinel lymph node biopsy in patients with MCC.A review was undertaken of 136 patients presenting with MCC at our institution between 1980 and 2008. Patient and tumor characteristics, treatment, and patterns of relapse were analyzed.Ninety patients presented with stage I disease, and 46 presented with stage II disease. The median follow-up time was 21 months. In all, 74 patients developed relapse with the commonest site of relapse in the regional lymph nodes. A total of 24 patients developed nodal relapse without prior treatment of the nodal basin. The 5-year survival was 62% and the median disease-free interval was 16 months. Radiotherapy was associated with a better disease-free survival (P.001) and overall survival was worse as the number of involved lymph nodes increased (P = .03).This was a retrospective review with a prolonged accrual time.A high rate of nodal relapse occurred in patients with stage I disease who had undergone treatment of the primary site only. These patients may have benefited from sentinel lymph node biopsy and subsequent treatment of the nodal basin if micrometastatic disease was present, as the number of involved nodes impacted negatively on survival. Conversely, sentinel lymph node biopsy may be used to select those patients with clinical stage I disease who may avoid elective nodal treatment. Radiotherapy should have a routine role in the management of MCC.

Hypothesis Metastatic melanoma to the liver is not incurable; complete surgical resection can achieve long-term survival in selected patients. Background Metastases to the liver are diagnosed in 10% to 20% of patients with American Joint Committee on Cancer stage IV melanoma. Surgical resection has not been generally accepted as a therapeutic option, as most patients will have other sites of disease that limit their survival to a median of only 4 to 6 months. However, there is little information on outcomes following resection in those patients with disease limited to the liver. Patients and Methods Review of the prospective melanoma databases at the John Wayne Cancer Institute, Santa Monica, Calif, and the Sydney Melanoma Unit, Sydney, Australia, identified 1750 patients with hepatic metastases, of whom 34 (2%) underwent exploration with intent to resect the metastases. Prognostic factors within the group of patients who underwent resection were examined by univariate and multivariate analysis, and median disease-free survival (DFS) and overall survival (OS) were calculated. Results Of 34 patients undergoing exploratory celiotomy, 24 (71%) underwent hepatic resection and 10 (29%) underwent exploration but not resection. Eighteen patients (75%) underwent complete surgical resection, while the remaining 6 underwent palliative or debulking procedures with incomplete resection. The operative resections included lobectomy (n=14), segmentectomy (4), nonanatomic resection (5), and extended lobectomy (1). The median number of resected lesions was 1, and median lesion size was 5 cm (range, 0.7-22 cm). The median disease-free interval between initial diagnosis of melanoma and development of hepatic metastases was 58 months (range, 0-264 months). Median DFS and OS estimates in the 24 patients who underwent surgical resection were 12 months (range, 0-147 months) and 28 months (range, 2-147months), respectively. Five-year DFS and OS in this group were 12% and 29%. Macroscopically, complete resection of disease ( P = .001) and histologically negative resection margins ( P = .03) significantly improved DFS by univariate analysis. Patients rendered surgically free of disease also tended to have improved OS ( P = .06). Median OS was 28 months for patients who underwent surgical resection compared with 4 months for patients who underwent exploration only ( P Conclusions Resection of metastatic melanoma to the liver may improve DFS and OS in selected patients, similar to resection of other metastatic sites. Therefore, patients with limited metastatic sites, including the liver, who can be rendered free of disease should be considered for complete surgical resection, as their prognosis is otherwise dismal.