Search

Background: HER2-positive versus HER2-negative ductal carcinoma in situ (DCIS) of the breast has been associated with an increased risk of local recurrence after breast-conserving surgery (BCS) and radiotherapy (RT). In recognition of this, the NASBP-B43 trial was designed to determine if two doses of trastuzumab would improve local control with BCS plus RT in HER2-positive DCIS. The trial demonstrated a non-statistically significant advantage with the addition of trastuzumab in reducing ipsilateral breast recurrence (IBR). The predictive 7-gene DCIS biosignature, DCISionRT with Residual Risk Subtype (PreludeDxTM, Laguna Hills, CA) has been shown to classify DCIS patients into two distinct groups of patients with substantially different rates of IBR following BCS plus RT. Based upon these differences in outcome, we assessed the IBR rate in patients with HER2(+) DCIS treated with BCS and RT who were or were not in the Residual Risk Subtype group defined using DCISionRT, while accounting for the varying clinicopathologic profile of the patients. Materials & Methods: DCISionRT was evaluated in a subset of 178 women with HER2(+) DCIS treated with BCS and RT as part of a multinational cohort of 926 patients from the United States, Sweden, and Australia, who were used in the validation studies for DCISionRT. Central pathology review and biosignature testing were performed at a CLIA-certified lab (Laguna Hills, CA). HER2(+) DCIS was defined as patients with a HER2(3+) immunohistochemistry >10% per ASCO/CAP guidelines. The IBR rate was calculated for the overall group of HER2(+) patients and those in the Residual Risk group. Individual patient outcome and biosignature results were analyzed using Kaplan Meier and Cox Proportional Hazard analyses. Results: The biosignature classified 113 of the 178 (63%) HER2(+) women into the Residual Risk group (DS>2.8 with RRt). Patients in the Residual Risk group had a significantly greater IBR (HR=8.3; 95%CI: 1.1,50, p=.012) over 10-years, with a corresponding 10-year total IBR rate of 16.2% (95%CI: 9.7%, 26.5%) versus 1.6% (95%CI: 0.2%, 10.9%) for all other HER2(+) patients. In univariate analysis, younger patients tended to have higher IBR rate after BCS plus RT, but only Residual Risk was significantly associated with IBR rate after BCS plus RT. Moreover, multivariable analysis demonstrated that the Residual Risk group was eight times more likely to recur after BCS and RT, while clinicopathologic factors (age, grade, tumor size) were not associated with higher IBR rates. Conclusion: The DCISionRT Residual Risk group was predictive for 10-year IBR risk after BCS plus RT in women with HER2(+) DCIS. Approximately 40% of patients with HER2(+) DCIS would be expected to achieve low rates of recurrence with BCS and RT, while about 60% of these women (classified in the Residual Risk group) would have higher recurrence rates and may benefit from further therapy, such as HER2-directed therapies. These findings suggest that if the results of the B43 trial were re-analyzed using the predictive 7-gene biosignature (DCISionRT with Residual Risk Subtype), better clarity could be gained on the true impact of trastuzumab on IBR rates in patients with HER2(+) DCIS and the patients most likely to benefit from this additional therapy. Table 1. Univariate and Multivariable Cox Proportional Hazards Analyses. Citation Format: Frank Vicini, Chirag Shah, Rachel Rabinovitch, Pat Whitworth, Julie A. Margenthaler, Brian J. Czerniecki, DAVID J. DABBS, Sheila Weinmann, Michael Leo, G Bruce Mann, Fredrik Wärnberg, jess Savala, Steven C. Shivers, Karuna Mittal, Troy Bremer. Characterization of recurrence risk after lumpectomy and radiotherapy in HER2-positive ductal carcinoma in situ of the breast, using 7-gene predictive biosignature: Implications for the NSABP-B43 trial results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-06.

Background: For women with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS), the benefit of adjuvant radiation therapy (RT) remains controversial. Since there is level 1 evidence supporting the role of RT in reducing the risk of local recurrence, current guidelines generally recommend RT for all women having BCS even though the absolute benefit is variable. In response to the need for prognostic and predictive tools to better assess risk and RT benefit, a 7-gene predictive biosignature (DCISionRT, PreludeDx, Laguna Hills, CA) was developed. The test provides a validated score (DS) for assessing 10-year risk of recurrence and RT benefit using individual tumor biology, as assessed by clinical and pathologic biomarkers. The primary objective of the PREDICT registries is to understand the decision impact such a tool has on treatment decisions. Prospective Clinical Trial Design: This is a multicenter, prospective, observational registry for women diagnosed with DCIS in Australia. After DCIS diagnosis, sites will send the most representative tissue block or sections mounted on charged slides to the PreludeDx lab for biosignature testing. Treating physicians will complete a treatment recommendation survey before and after receiving the biosignature test results. Test results, treatment recommendations, patient preferences and clinicopathologic features will be stored in a de-identified registry for participating institutions from a variety of geographic regions across Australia. Women will then be followed for up to 10 years with completion of a follow-up form. The study has been approved by the North Shore Local Health District Human Research Ethics Committee, St Leonards, NSW, Australia. Universal Trial Number (UTN): U1111-1266-0439; ANZCTR: ACTRN12621000695808; ClinicalTrials.gov: NCT04916808. Eligibility Criteria: The study includes females age 26 or older who are candidates for BCS and eligible for RT and/or systemic treatment. Subjects must not have been previously treated for DCIS or have previous or current invasive or micro-invasive breast cancer. Specific Aims: The primary endpoints are changes in treatment recommendations for surgical, radiation and hormonal therapy. Secondary endpoints are identification of key drivers for treatment recommendations, including age, size, grade, necrosis, hormone receptor status, patient preference and biosignature status. Statistical Methods: Changes in pre- and post-DCISionRT treatment recommendations will be analyzed using McNemar’s test (alpha level = 0.05). Multivariate logistic regression will be used to determine odds ratios of clinicopathologic factors leading to pre- and post-test treatment recommendations. Pre-test covariates include patient age, tumor size, palpability, margin status, hormone receptor status, nuclear grade, tumor necrosis, family history of breast cancer, race, ethnicity and patient preference, as well as physician specialty (surgeons vs. radiation oncologists) and post-test covariates will also include the DCISionRT Decision Score (DS). Differences in recurrence-free and overall survival will be assessed by Kaplan-Meier survival analysis using the log-rank test and/or the Cox Proportional Hazards model. Statistical analyses will be carried out using R (https://www.r-project.org) or SAS. An early interim analysis based on the first 200 enrolled patients is currently underway. Present and Planned Accrual: We are planning to enroll up to 1,500 women from up to 100 sites across Australia. A similar registry has recently completed enrollment of 2,500 women from 68 sites in the US. Citation Format: Yvonne Zissiadis, G Bruce Mann, David Speakman, Christobel Saunders, Christopher Pyke, Daniel De Viana, Melissa Bochner, James R. French, Marcus Dreosti, Sally Baron-Hay, Alexandra Feetham, Kim Kirkham, Shane Ryan, Karuna Mittal, Steven C. Shivers, Troy Bremer. The PREDICT Registry Australia: A prospective registry to evaluate the clinical utility of a 7-gene predictive biosignature on treatment decisions in patients with ductal carcinoma in situ [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-11-03.

Background: Early biologic response to endocrine therapy, such as changes in Ki67 labeling index (LI), has been suggested to predict long-term outcomes in hormone sensitive breast cancer. The addition of a CDK4/6 inhibitor to endocrine therapy has been shown to augment biological response in breast cancer. Pre-operative Endocrine Prognostic Index (PEPI) scores, generated based on post-treatment Ki67 LI, have been shown to predict patient outcomes. EndoPredict® is a multigene assay that predicts the risk of distant recurrence in patients with operable estrogen receptor (ER)-positive HER2-negative breast cancer. This study was conducted to evaluate the efficacy of the neoadjuvant endocrine therapy plus palbociclib versus neoadjuvant endocrine therapy plus placebo. Patients and Methods: This is a phase III randomized, double-blind study of neoadjuvant hormonal therapy plus palbociclib versus neoadjuvant hormonal therapy plus placebo in untreated pre/peri- and post-menopausal women with operable, hormone receptor-positive (ER and/or progesterone receptor), HER2-negative breast cancer. The other major inclusion criteria included tumor size ≥ 15mm, T1c-3N0-1, Ki67 LI ≥14% by central assessment, and no previous history of radiotherapy or systemic therapy for breast cancer. Patients were randomly assigned 1:1 to receive 16 weeks of hormonal therapy plus palbociclib or hormonal therapy plus placebo. Hormonal therapy consisted of letrozole for post-menopausal patients and tamoxifen plus LH-RH agonist for pre/peri-menopausal patients. The co-primary endpoints included PEPI score and EPclin Risk Score, a score combining EndoPredict® molecular score with clinical factors. These scores were sequentially analyzed on a modified intent-to-treat basis according to the gatekeeping procedure: if statistical significance was detected on the PEPI score, the statistical significance of EPclin Risk Score would be assessed. The sample size was 100 patients in each arm, which was calculated with < 5% type I error rate (two sided) and 80% power. Results: Between 16 July 2019 – 7 July 2021, 141 eligible patients were randomized from 25 participating institutes in Japan, Korea, Taiwan, Hong Kong and Australia. One hundred twenty-six patients completed the treatment duration and surgical samples were collected to evaluate endpoints. All randomized patients were evaluable for safety assessment. Randomization was well-balanced in terms of age, menopausal status and cancer stage. The proportion of patients who had a low, moderate, or high PEPI score was 15.2%, 50.0% and 34.8% in the hormonal therapy plus palbociclib arm and 13.3%, 55.0% and 31.7% in the hormonal therapy plus placebo arm, respectively. There was no statistically significant difference in PEPI score between two arms (one-sided p-value=0.563). The proportion of patients who had a high risk EPclin Risk Score seemed lower in the palbociclib arm than in the placebo arm (62.1% vs 68.3%) although hypothesis testing was not performed on EPclin Risk Score because statistical significance was not detected on the PEPI score. No new safety signals were found in the study. Permanent discontinuation from the study in association with adverse events was reported for 7 (9.7%) patients in the hormonal therapy plus palbociclib arm and for 0 patients in the hormonal therapy plus placebo arm. Conclusions: The addition of palbociclib to neoadjuvant hormonal therapy did not improve efficacy measured by PEPI score. In palbociclib arm, the rate of patients who had a high risk EPclin Risk Score after treatment was lower than in placebo arm. Translational researches are ongoing to analyze molecular changes by treatments. The role of chemotherapy after neoadjuvant therapy is under investigation. Clinical trial identification: NCT03969121 Funding: Pfizer Inc. Citation Format: Takayuki Ueno, Louis W.C. Chow, Wonshik Han, Chiun Sheng Huang, G Bruce Mann, Satoshi Morita, Hironori Haga, Elham Fakhrejahani, Takayuki Kobayashi, Kenichi Inoue, Mariko Tokiwa, Hirofumi Suwa, Tomoyuki Aruga, Sachiko Minamiguchi, Yosuke Yamada, Yuko Tanabe, Masahiro Takada, Toshinari Yamashita, Hiroji Iwata, Chi-Feng Chung, Sachiko Takahara, Eriko Tokunaga, Shigeru Imoto, Eun Sook Lee, Yasuaki Sagara, Jee Hyun Kim, Richard H DeBoer, Hyun-Ah Kim, Hung Wen Lai, Ming-Feng Hou, Michelle White, Yoshiko Umeyama. Neoadjuvant hormonal therapy plus palbociclib versus hormonal therapy plus placebo in women with operable, hormone sensitive and HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-01.

Background: Prognostic and predictive tools are needed to optimize treatment for women diagnosed with ductal carcinoma in situ (DCIS). While radiotherapy (RT) is standard of care for DCIS after breast conserving surgery (BCS), those at low-risk for ipsilateral breast recurrence (IBR) risk may be treated without RT. Low-risk has been defined as the absence of high risk clinicopathologic (CP) factors, including larger (>2 cm), palpable, or high nuclear grade (NG) tumors, and younger age (< 50 yrs). However, prospective trials have failed to identify low risk patients (pts) who do not clinically benefit from RT after BCS (RTOG 9804). DCISionRT® (PreludeDxTM, CA) is a 7-gene predictive biosignature providing a validated score (DS) to assess the 10-yr IBR risk and RT benefit, using individual tumor biology and CP factors. This study assessed total 10-yr IBR rates, RT benefit, and number needed to treat (NNT) for risk groups defined by biosignature and CP criteria. Methods: DCIS patients (n=926) from four international cohorts (median follow up 8.5 yrs, 1-3rd quartile 5.8 – 10.2 yrs) treated with BCS (negative margins), with (n=641) and without RT (n=335), had formalin-fixed paraffin-embedded tissues analyzed at a CLIA lab (PreludeDx, Laguna Hills, CA) for DCISionRT with a Residual Risk subtype (RRt). A biosignature Low Risk group (DS≤2.8 without RRt) was contrasted to a High Risk group comprising Elevated Risk (DS>2.8 without RRt) and Residual Risk (DS>2.8 with RRt) groups. Low-risk CP groups were RTOG 9804-like (NG1-2, non-palpable, negative margins, screening detected) or (age >50 and NG 1-2). Total 10-yr IBR rates were evaluated using Cox Proportional Hazards and Kaplan Meier analysis by treatment, biosignature and CP risk groups. NNT was determined with 10-yr IBR rate differences with RT. Results: The biosignature classified 37% (n=338) of women as Low Risk and 63% (n=588) as High Risk. Among women who did not receive RT, biosignature Low Risk pts had lower IBR than biosignature High Risk pts (5.6% vs. 25.7%, p Conclusion: In a large multicenter population, DCISionRT was a better predictor of 10-yr prognosis and RT benefit than CP criteria alone. Pts with biosignature Low Risk disease, comprising about 1/3 of CP high-risk pts, had no significant RT benefit. Whereas pts with biosignature High Risk disease, comprising about 1/2 of CP low-risk pts, significantly benefited from RT, highlighting the lack of accuracy of these CP factors in assessing RT benefit. Table 1. Ten-Year Risk of Ipsilateral Breast Recurrence (IBR) Citation Format: Rachel Rabinovitch, Frank Vicini, Chirag Shah, Julie A. Margenthaler, Brian J. Czerniecki, Pat Whitworth, DAVID J. DABBS, G Bruce Mann, Fredrik Wärnberg, Sheila Weinmann, Michael Leo, Jess Savala, Steven C. Shivers, Karuna Mittal, Troy Bremer. PD15-07 7-gene predictive biosignature improves risk stratification for breast ductal carcinoma in situ patients compared to clinicopathologic criteria, identifying a low risk group not clinically benefiting from adjuvant radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-07.

Australia introduced COVID-19 infection prevention and control measures in early 2020. To help prepare health services, the Australian Government Department of Health commissioned a modelled evaluation of the impact of disruptions to population breast, bowel, and cervical cancer screening programmes on cancer outcomes and cancer services. We used the Policy1 modelling platforms to predict outcomes for potential disruptions to cancer screening participation, covering periods of 3, 6, 9, and 12 mo. We estimated missed screens, clinical outcomes (cancer incidence, tumour staging), and various diagnostic service impacts. We found that a 12-mo screening disruption would reduce breast cancer diagnoses (9.3% population-level reduction over 2020–2021) and colorectal cancer (up to 12.1% reduction over 2020–21), and increase cervical cancer diagnoses (up to 3.6% over 2020–2022), with upstaging expected for these cancer types (2, 1.4, and 6.8% for breast, cervical, and colorectal cancers, respectively). Findings for 6–12-mo disruption scenarios illustrate that maintaining screening participation is critical to preventing an increase in the burden of cancer at a population level. We provide programme-specific insights into which outcomes are expected to change, when changes are likely to become apparent, and likely downstream impacts. This evaluation provided evidence to guide decision-making for screening programmes and emphasises the ongoing benefits of maintaining screening in the face of potential future disruptions.

Supplementary Methods

Supplementary Tables S1-5

Supplementary Table S8

Supplementary Table S7

Supplementary Table S6

Supplementary Figures

Supplementary Table S9

Background: The benefit of adjuvant radiation therapy (RT) for women with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS) remains controversial. Since there is level-I evidence supporting the role of RT in reducing the risk of local recurrence, current guidelines generally recommend adjuvant RT for all women having BCS. However, the absolute benefit of RT is variable in women with DCIS and so it is important to develop prognostic and predictive tools to better assess risk and RT benefit. The DCISionRT Test (PreludeDx, Laguna Hills, CA) is a biologic signature that provides a validated score (DS) for assessing 10-year risk of recurrence and RT benefit using individual tumor biology, as assessed by clinical and pathologic biomarkers. The primary objective of the PREDICT registries is to understand the decision impact such a tool would have on treatment decisions. Prospective Clinical Trial Design: This is a multicenter, prospective, non-interventional (observational) cohort study for women diagnosed with DCIS of the breast. After diagnosis of DCIS, sites will send the most representative tissue block or sections mounted on charged slides to PreludeDx for DCISionRT testing. Treating physicians complete a treatment recommendation survey before and after receiving DCISionRT test results. Test results, treatment recommendations, patient preferences and clinicopathologic features will be stored in a de-identified registry for participating institutions from a variety of geographic regions across Australia. Women will then be followed for up to 10 years with completion of a follow-up form. The study has been approved by the North Shore Local Health District Human Research Ethics Committee, St Leonards, NSW, Australia. Universal Trial Number (UTN): U1111-1266-0439; ANZCTR: ACTRN12621000695808; ClinicalTrials.gov: NCT04916808. Eligibility Criteria: The study includes females age 26 or older who are candidates for BCS and eligible for RT and/or systemic treatment. Subjects must not have been previously treated for DCIS or have previous or current invasive or micro-invasive breast cancer. Specific Aims: The primary endpoints are changes in treatment recommendations for surgical, radiation and hormonal therapy. Secondary endpoints are identification of key drivers for treatment recommendations, including age, size, grade, necrosis, hormone receptor status and patient preference. Statistical Methods: Changes in pre- and post-DCISionRT treatment recommendations will be analyzed using McNemar's test (alpha level = 0.05). Multivariate logistic regression will be used to determine odds ratios of clinicopathologic factors leading to pre- and post-test treatment recommendations. Pre-test covariates include patient age, tumor size, palpability, margin status, hormone receptor status, nuclear grade, tumor necrosis, family history of breast cancer, race, ethnicity and patient preference, as well as physician specialty (surgeons vs. radiation oncologists) and post-test covariates will also include the DCISionRT Decision Score (DS). Differences in recurrence-free and overall survival will be assessed by Kaplan-Meier survival analysis using the log-rank test and/or the Cox Proportional Hazards model. Statistical analyses will be carried out using R (https://www.r-project.org) or SAS. An early interim analysis based on the first 200 enrolled patients is planned. Present and Planned Accrual: We are planning to enroll up to 1,500 women from up to 100 sites across Australia. A similar registry in the US has enrolled 1,985 women from 64 sites towards a goal of 2,500. Citation Format: Yvonne Zissiadis, G Bruce Mann, Steven C Shivers, Troy Bremer. The PREDICT registry Australia: A prospective registry study to evaluate the clinical utility of the DCISionRT test on treatment decisions in patients with DCIS following breast conserving surgery [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-11-01.

Supplementary Figure Legend

Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown.Experimental Design: We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (n = 55) and mutation data (n = 20).Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%–90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (P = 0.002/0.035), ER-negative (P = 0.02/0.02), and ERBB2-amplified tumors (P < 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P < 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with TP53 mutation (P = 0.03) but not with PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both P < 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels.Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor. Clin Cancer Res; 23(17); 5210–7. ©2017 AACR.

Figures S1 and S2, Tables S1 and S2 Supplementary Information Supplementary Table 1. DCIS cases assessed for tumour lymphocytes Supplementary Table 2. DCIS cases assessed for PD-L1 protein expression Supplementary Figure 1. Cohort summary Supplementary Figure 2. TILs in DCIS cases comparing primary with recurrence tumours.

Germline genetic testing is an increasingly important component of treatment decision-making for clinicians and patients with breast cancer. To address increased demand and expedite access to genetic testing for these patients, the Parkville Familial Cancer Centre (PFCC) in Victoria, Australia, implemented a breast mainstream genetic testing program. The program educates and supports breast cancer specialists to provide eligible patients with pre-test information, gain consent, and arrange genetic testing during their routine cancer appointments. This study aimed to explore breast cancer specialists’ experiences and opinions of the education program and of facilitating mainstream genetic testing for their patients. Specialists who had attended the mainstream genetic testing education were invited to complete an online survey about the training provided through the education program and their experience of deploying mainstream genetic testing in their practice. Descriptive statistics were compiled, and content analysis used for open text responses. Forty-five breast cancer specialists (breast surgeons, medical oncologists, radiation oncologists and breast care nurses) responded (45% response rate). Most participants had discussed (87%) and consented (80%) patients for mainstream genetic testing. Most specialists (81%) rated their confidence levels as high or very high for consenting patients to mainstream genetic testing. The majority (89%) indicated that they believed mainstream genetic testing should be part of their role and felt well supported by the PFCC (90%). This research demonstrates that the breast cancer specialists were satisfied by the education they received and the PFCC has successfully integrated mainstream genetic testing for breast cancer patients.

PURPOSE Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p

The human eye can distinguish as many as 10,000 different colours but is far less sensitive to variations in intensity1, meaning that colour is highly desirable when interpreting images. However, most biological samples are essentially transparent, and nearly invisible when viewed using a standard optical microscope2. It is therefore highly desirable to be able to produce coloured images without needing to add any stains or dyes, which can alter the sample properties. Here we demonstrate that colorimetric histology images can be generated using full-sized plasmonically active microscope slides. These slides translate subtle changes in the dielectric constant into striking colour contrast when samples are placed upon them. We demonstrate the biomedical potential of this technique, which we term histoplasmonics, by distinguishing neoplastic cells from normal breast epithelium during the earliest stages of tumorigenesis in the mouse MMTV-PyMT mammary tumour model. We then apply this method to human diagnostic tissue and validate its utility in distinguishing normal epithelium, usual ductal hyperplasia, and early-stage breast cancer (ductal carcinoma in situ). The colorimetric output of the image pixels is compared to conventional histopathology. The results we report here support the hypothesis that histoplasmonics can be used as a novel alternative or adjunct to general staining. The widespread availability of this technique and its incorporation into standard laboratory workflows may prove transformative for applications extending well beyond tissue diagnostics. This work also highlights opportunities for improvements to digital pathology that have yet to be explored. Colour contrast is added to unstained histological samples by using surface plasmon polaritons whose properties depend on the sample’s dielectric constant.

BackgroundAustralia introduced COVID-19 infection prevention and control measures in early 2020. To help prepare health services the Australian Government Department of Health commissioned a modelled evaluation of the impact of disruptions to population breast, bowel and cervical cancer screening programs on cancer outcomes and cancer services.MethodsWe used the Policy1 modelling platforms to estimate outcomes for potential disruptions to cancer screening participation, covering periods of 3, 6, 9 and 12 months. We estimated missed screens, clinical outcomes (cancer incidence, tumour staging), and various diagnostic service impacts.ResultsWe estimated that a 12-month screening disruption would reduce breast cancer diagnoses (9.3% population-level reduction over 2020-2021) and colorectal cancer (up to 12·1% reduction over 2020-21), and increase cervical cancer diagnoses (up to 3·6% over 2020-2022), with upstaging expected for these cancer types.ConclusionsFindings illustrate that maintaining screening participation is critical to sustaining a reduced cancer burden. We provide program-specific insights into which outcomes are expected to change, when changes are likely to become apparent, and likely downstream impacts. This evaluation provided evidence to guide decision-making for screening programs, and emphasises the ongoing benefits of maintaining screening in the face of potential future disruptions.FundingAustralian Government Department of Health

For more than two decades attempts have been made to identify a subset of women diagnosed with lesions with uncertain malignant potential (B3 lesions) who could safely be observed rather than being treated with surgical excision and/or chemoprevention. Various histopathological, clinical and imaging parameters for risk recommendation have been evaluated, with little impact on clinical practice. The primary reason for surgery is to rule out an upgrade lesion to either ductal carcinoma in situ (DCIS) or invasive breast cancer (IBC). While on average 30% of these patients are upgraded after diagnostic biopsy, a large number are over treated,making this an important harm of screening.Here we evaluated stromal lymphocytes from B3 biopsies (n=264) as a predictive biomarker for upgrade. A higher number of stromal lymphocytes were observed in upgraded B3 lesions than non-upgraded (p< 0.01, zero inflated binomial model) for both ductal and papillary lesions (n=174). This observation was validated in an independent cohort (pIn conclusion, we can identify a subset of the patients at risk of upgrade with high specificity. Assessing the tumour microenvironment including stromal lymphocytes may contribute to reducing unnecessary surgeries in the clinic.

To describe a new international dataset for pathology reporting of ductal carcinoma in situ (DCIS), variants of lobular carcinoma in situ (LCIS) and low-grade lesions (encapsulated papillary carcinoma, solid papillary carcinoma in situ, Paget's disease) produced by the International Collaboration on Cancer Reporting (ICCR).The ICCR, a global alliance of pathology bodies, uses a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Their aim is to support quality pathology reporting and engender understanding between the breast surgeon, pathologist, and oncologist for optimal and uniform patient management globally. Here we describe the dataset for DCIS, some variants of LCIS (namely the pleomorphic and the florid variants), and low-grade lesions by a multidisciplinary panel of internationally recognized experts. The agreed dataset comprises 12 core (required) and five noncore (recommended) elements suitable for both developed and low-income jurisdictions, derived from a review of current evidence. Areas of contention were addressed using a pragmatic approach in the absence of evidence. Use of all core elements is the minimum reporting standard for any individual case. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or noncore.This first internationally agreed dataset for DCIS, variants of LCIS, and low-grade lesions reporting will enable their standardization of pathology reporting and enhance clinicopathological communication leading to improved patient outcomes. Widespread adoption will also facilitate international comparisons, multinational clinical trials, and help to improve the management of breast disease globally.

Objective: To determine the government and out‐of‐pocket community costs (out‐of‐hospital medical services and prescription medicines) associated with screen‐detected and community‐detected cancers (i.e. cancers detected outside of Australia's organised screening program [BreastScreen]). Methods: We analyse administrative data on government‐subsidised medical services and prescription medicines for 568 Victorian women diagnosed with breast cancer or ductal carcinoma in situ (DCIS). Using multivariable regression analysis, we estimate the government and out‐of‐pocket community costs incurred in the three years after diagnosis for screen‐detected cancers and community‐detected cancers. Additionally, we estimate the government costs associated with diagnosis within and outside of BreastScreen. Results: Average government costs for breast cancer diagnosis were similar within and outside of BreastScreen [$808 (lower limit 676; upper limit 940) vs $837 (95%CI 671; 1,003) respectively]; however, women with community‐detected cancers incurred an additional $254 (95%CI 175; 332) out‐of‐pocket. Controlling for differences in known cancer characteristics, compared to screen‐detected cancers, community‐detected breast cancers were associated with an additional $2,622 (95%CI 644; 4,776) in government expenditure in the three years following diagnosis. Adverse cancer characteristics that were more prevalent in community‐detected cancers (high grade, lymph node involvement, HER2 positive receptor status) were associated with increased government and out‐of‐pocket costs. Conclusions: Community‐detected breast cancers were associated with increased government and out‐of‐pocket costs. Implications for public health: These costs should be considered when evaluating current and alternative breast cancer screening strategies.

BACKGROUND: Survivorship care plans (SCPs) have been used to address ongoing health problems associated with the diagnosis and treatment of early-stage breast cancer. OBJECTIVES: The aim of this article was to determine whether nurse-led consultations using SCPs, as compared with a standard medical consultation, identify more side effects and supportive care needs and lead to appropriate referral patterns. METHODS: The study audited 160 retrospective medical clinic and nursing SCP records in a sample of patients receiving treatment for early-stage breast cancer at a tertiary-level breast service in Australia. FINDINGS: Breast care nurses (BCNs) undertaking SCPs at a nurse-led consultation were significantly more likely than physicians to record symptoms related to menopausal/hormonal therapy, psychosocial/mental health, lifestyle, bone health, and sexuality. BCNs were also significantly more likely to refer patients for concerns related to psychosocial/mental health, lifestyle, and sexuality.

Background: POSNOC is a UK-ANZ multicentre, non-inferiority, randomised trial comparing systemic therapy alone with systemic therapy plus Axillary Treatment (Axillary radiotherapy or ALND) for women with ≤2 macrometastases at SNB. The primary outcome is axillary recurrence within 5 years. This paper describes screening, recruitment and compliance data. Methods: Sites were requested on a monthly basis to upload screening data and provide reasons for non-recruitment of eligible patients into the trial. Sites entered in the online database whether the patients were compliant with their randomisation allocation. Results: The study opened in July 2014 and completed target recruitment of 1900 women (24% of those screened) in July 2021, at 95 sites in the UK and 20 sites in Australia and New Zealand. The reason for non-enrolment was unknown in 1300 women. Of the remaining 4774 women with known reasons, who were screened but not randomised, the most common reasons for non-recruitment were due to either patients (n=2219, 46.5%) or their clinicians (n=782, 16.4%) favouring axillary treatment, or patients (n=490, 10.3%) or their clinicians (n=170, 3.6%) not wishing to have axillary treatment. Over the course of the study, there was an increase in the proportion of patients wanting axillary treatment and declining the trial (Mean % patients declined 2015 – 17.9%, 2021 – 39.1%). Mean number of participants recruited per site per month was 0.24 (SD 0.18) overall, 0.25 (SD 0.19) in the UK, and 0.19(SD 0.15) in ANZ. The mean was < 0.3 in 79 sites and >0.9 in only one site. Recruitment rate remained consistent throughout the study (mean 25.3 per month) except for during the first 6 months of recruitment (5.7) and during the COVID pandemic Apr-Sep 2020 (7.5). Of 89 (4.8%) participants non-compliant with allocation, n=45 (50.6%) received systemic therapy alone and n=44 (49.4%) received systemic therapy plus axillary treatment. There was no fluctuation in the direction of non-compliance during the study duration. There was increasing uptake of axillary radiotherapy to treat the axilla instead of ALND over the course of the study in patients receiving axillary treatment (Number who had ART of all who had axilla treatment2014-2017 - 248/454 (54.6 %); 2018-2021 – 315/449 (70.2%)). Conclusion: Recruitment and compliance with randomised allocation remained consistent over a seven-year period. POSNOC with in-built radiotherapy QA will provide definitive data on axillary management in patients undergoing mastectomy or BCS with ≤2 macrometastases on SNB. Citation Format: Amit Goyal, Cydney Bruce, Shabina Sadiq, Mickey Lewis, Alan Montgomery, G Bruce Mann, Heath Badger, Kathryn Monson, Valerie Jenkins, Lesley Fallowfield, Malcolm Reed, David Dodwell, Patricia Fairbrother, Tara Homer, Luke Vale, Roeum Butt, Elizabeth Miles, Shelley Dowey, Lucy Matthews, Hugh Jarrett, Juliet Jackson, Arfan Ali. Recruitment, clinical equipoise, patient acceptance and compliance in the UK-ANZ POSNOC trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-01-07.

Background: The benefits and harms of breast screening may be better balanced through a risk-stratified approach. We conducted a systematic review assessing the accuracy of questionnaire-based risk assessment tools for this purpose. Methods: Population: asymptomatic women aged ≥40 years; Intervention: questionnaire-based risk assessment tool (incorporating breast density and polygenic risk where available); Comparison: different tool applied to the same population; Primary outcome: breast cancer incidence; Scope: external validation studies identified from databases including Medline and Embase (period 1 January 2008–20 July 2021). We assessed calibration (goodness-of-fit) between expected and observed cancers and compared observed cancer rates by risk group. Risk of bias was assessed with PROBAST. Results: Of 5124 records, 13 were included examining 11 tools across 15 cohorts. The Gail tool was most represented (n = 11), followed by Tyrer-Cuzick (n = 5), BRCAPRO and iCARE-Lit (n = 3). No tool was consistently well-calibrated across multiple studies and breast density or polygenic risk scores did not improve calibration. Most tools identified a risk group with higher rates of observed cancers, but few tools identified lower-risk groups across different settings. All tools demonstrated a high risk of bias. Conclusion: Some risk tools can identify groups of women at higher or lower breast cancer risk, but this is highly dependent on the setting and population.

There is an unmet need to identify women diagnosed with ductal carcinoma in situ (DCIS) with a low risk of in-breast recurrence (IBR) after breast conserving surgery (BCS), which could omit radiation therapy (RT), and also to identify those with elevated IBR risk remaining after BCS plus RT. We evaluated a novel biosignature for a residual risk subtype (RRt) to help identify patients with elevated IBR risk after BCS plus RT.Women with DCIS treated with BCS with or without RT at centers in the US, Australia, and Sweden (n = 926) were evaluated. Patients were classified into 3 biosignature risk groups using the decision score (DS) and the RRt category: (1) Low Risk (DS ≤2.8 without RRt), (2) Elevated Risk (DS2.8 without RRt), and (3) Residual Risk (DS2.8 with RRt). Total and invasive IBR rates were assessed by risk group and treatment.In patients at low risk, there was no significant difference in IBR rates with or without RT (total, P = .8; invasive IBR, P = .7), and there were low overall 10-year rates (total, 5.1%; invasive, 2.7%). In patients with elevated risk, IBR rates were decreased with RT (total: hazard ratio [HR], 0.25; P.001; invasive: HR, 0.28; P = .005); 10-year rates were 20.6% versus 4.9% (total) and 10.9% versus 3.1% (invasive). In patients with residual risk, although IBR rates decreased with RT after BCS (total: HR, 0.21; P.001; invasive: HR, 0.29; P = .028), IBR rates remained significantly higher after RT compared with patients with elevated risk (HR, 2.5; 95% CI, 1.2-5.4; P = .018), with 10-year rates of 42.1% versus 14.7% (total) and 18.3% versus 6.5% (invasive).The novel biosignature identified patients with 3 distinct risk profiles: Low Risk patients with a low recurrence risk with or without adjuvant RT, Elevated Risk patients with excellent outcomes after BCS plus RT, and Residual Risk patients with an elevated recurrence risk remaining after BCS plus RT, warranting potential intensified or alternative treatment approaches.

Background: NCCN treatment guidelines support de-escalation of radiotherapy (RT) for “low risk” patients with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS) for which improved specificity in identifying patients with low in-breast recurrence (IBR) rates who are unlikely to benefit from RT is needed. “low risk” has been defined as the absence of “high risk” clinicopathological (CP) factors, which include younger age (2.8 without RRt) and Residual Risk groups (DS>2.8 with RRt), where 10-yr total IBR rates were evaluated using Cox Proportional Hazards and Kaplan Meier analysis by treatment, biosignature Risk group, and CP criteria. Results: The biosignature classified 37% of women treated with BCS as Low Risk (n=338) and 63% (n=588) were classified into the combined Elevated/Residual Risk group. Among patients who did not receive RT, those in the Elevated/Residual Risk group had higher IBR rates (p Citation Format: Rachel Rabinovitch, Frank A. Vicini, Chirag Shah, Julie Margenthaler, Brian Czerniecki, Pat Whitworth, Sheila Weinmann, Michael C. Leo, Fredrik Wärnberg, G. Bruce Mann, Steven C. Shivers, David Dabbs, Karuna Mittal, Troy Bremer. Guiding de-escalation of treatment for patients with DCIS using a predictive 7-gene biosignature: Identification of a clinically low-risk patient group [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B016.

Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application.Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team.233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p 0.001) were the strongest discriminators of risk.Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.

Background There is increasing interest in risk-based breast cancer screening, including interventions to improve outcomes for women with mammographically dense breasts. Methods Policy1-Breast is a continuous-time, multiple-cohort micro-simulation whole-population model which incorporates breast cancer risk, life-course breast density, menopause, hormone therapy use and screening participation. Outcomes include cancer diagnoses and characteristics (invasive/DCIS, tumour size, grade), mode of detection (screen-detected/interval/other) and mortality (breast cancer and other cause). Policy1-Breast validates well against key observed clinical outcomes in Australia. We estimate changes in outcomes within and outside the BreastScreen program upon the introduction of a hypothetical screening test with improved sensitivity for women with dense breasts. Results We estimate that introducing in year 2020 a screening test for women in the highest quintile of breast density at age 50 that halves the masking effect of their breast density would, by 2026-2030, increase diagnosis rates of population-level invasive cancers ( 10%) and screen-detected cancers (20%) and decrease rates of interval cancers (17%) and community-detected cancers (6%). Conclusions Targeted screening tests with improved sensitivity for women with dense breasts are expected to markedly reduce interval cancers and other cancers diagnosed outside the BreastScreen program, while increasing all cancer diagnoses due to increased rates of screen-detected cancers. Key messages Specialised breast cancer screening tests directed at women with very high breast density are expected to reduce interval cancers and increase overall cancer diagnoses. Population simulation models such as Policy1-Breast can complement trial evidence by evaluating a range of scenarios and estimating short and long-term implications.

Policy decisions regarding breast cancer screening and treatment programmes may be misplaced unless the decision process includes the appropriate utilities and disutilities of mammography screening and its sequelae. The objectives of this study were to critically review how economic evaluations have valued the health states associated with breast cancer screening, and appraise the primary evidence informing health state utility values (cardinal measures of quality of life). A systematic review was conducted up to September 2018 of studies that elicited or used utilities relevant to mammography screening. The methods used to elicit utilities and the quality of the reported values were tabulated and analysed narratively. 40 economic evaluations of breast cancer screening programmes and 10 primary studies measuring utilities for health states associated with mammography were reviewed in full. The economic evaluations made different assumptions about the measures used, duration applied and the sequalae included in each health state. 22 evaluations referenced utilities based on assumptions or used measures that were not methodologically appropriate. There was significant heterogeneity in the utilities generated by the 10 primary studies, including the methods and population used to derive them. No study asked women to explicitly consider the risk of overdiagnosis when valuing the health states described. Utilities informing breast screening policy are restricted in their ability to reflect the full benefits and harms. Evaluating the true cost-effectiveness of breast cancer screening will remain problematic, unless the methodological challenges associated with valuing the disutilities of screening are adequately addressed.

Breast cancer (BC) diagnosed after a negative mammogram but prior to the next screening episode is termed an 'interval BC' (IBC). Understanding the molecular differences between IBC and screen-detected BCs (SDBC) could improve mammographic screening and management options. Therefore, we assessed both germline and somatic genomic aberrations in a prospective cohort. Utilising the Lifepool cohort of >54 000 women attending mammographic screening programs, 930 BC cases with screening status were identified (726 SDBC and 204 IBC). Clinico-pathological and family history information were recorded. Germline and tumour DNA were collected where available and sequenced for BC predisposition and driver gene mutations. Compared to SDBC, IBCs were significantly associated with a younger age at diagnosis and tumour characteristics associated with worse prognosis. Germline DNA assessment of BC cases that developed post-enrolment (276 SDBCs and 77 IBCs) for pathogenic mutations in 12 hereditary BC predisposition genes identified 8 carriers (2.27%). The germline mutation frequency was higher in IBC versus SDBC, although not statistically significant (3.90% versus 1.81%, p = 0.174). Comparing somatic genetic features of IBC and SDBC matched for grade, histological subtype and hormone receptor revealed no significant differences, with the exception of higher homologous recombination deficiency scores in IBC, and copy number changes on chromosome Xq in triple negative SDBCs. Our data demonstrates that while IBCs are clinically more aggressive than SDBC, when matched for confounding clinico-pathological features they do not represent a unique molecular class of invasive BC, but could be a consequence of timing of tumour initiation and mammographic screening. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0–8) were treated with daily tamoxifen (20 mg) and venetoclax (200–800 mg). Apart from uncomplicated “on-target” lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. Significance: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors. See related commentary by Drago et al., p. 323. This article is highlighted in the In This Issue feature, p. 305

Longitudinal data estimate that 1 in 353 Australian children under 12 experience parental cancer diagnosis; and this number is increasing (1). These children are at increased risk of adverse psychosocial outcomes (2), however, effective family communication about a parental cancer diagnosis may support child coping (2) especially when developmentally appropriate language is used (3). Parents report communicating with their children about their diagnosis is a major challenge and want more instructive guidance from health professionals (HPs) about meeting their children's needs (4). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Background:Although evaluations of breast cancer screening programs frequently estimate quality-adjusted life-year (QALY) losses by stage, other breast cancer characteristics influence treatment and vary by mode of detection - i.e. whether the cancer is detected through screening (screen-detected), between screening rounds (interval-detected) or outside screening (community-detected). Here, we estimate the association between early-stage invasive breast cancer (ESIBC) characteristics and treatment-related QALY losses.Methods:Using clinicopathological and treatment information from 675 women managed for ESIBC, we estimated the average five-year treatment-related QALY loss by detection group. We then used regression analysis to estimate the extent to which known cancer characteristics and the detection mode, are associated with treatment and treatment-related QALY losses.Results:Community-detected cancers had the largest QALY loss (0.76 QALYs [95% CI 0.73;0.80]), followed by interval-detected cancers (0.75 QALYs [95% CI 0.68;0.82]) and screen-detected cancers (0.69 QALYs [95%CI 0.67;0.71]). Adverse prognostic factors more common in community-detected and interval-detected breast cancers (large tumours, lymph node involvement, high grade) were largely associated with QALY losses from mastectomies and chemotherapy. Receptor-positive subtypes, more common in screen-detected cancers, were associated with QALY losses related to endocrine therapy.Conclusions:The associations between ESIBC characteristics and treatment-related QALY losses should be considered when evaluating breast cancer screening and treatment strategies.

Mammographic density (MD) influences breast cancer risk, but how this is mediated is unknown. Molecular differences between breast cancers arising in the context of the lowest and highest quintiles of mammographic density may identify the mechanism through which MD drives breast cancer development. Women diagnosed with invasive or in situ breast cancer where MD measurement was also available (n = 842) were identified from the Lifepool cohort of >54,000 women participating in population-based mammographic screening. This group included 142 carcinomas in the lowest quintile of MD and 119 carcinomas in the highest quintile. Clinico-pathological and family history information were recorded. Tumor DNA was collected where available (n = 56) and sequenced for breast cancer predisposition and driver gene mutations, including copy number alterations. Compared to carcinomas from low-MD breasts, those from high-MD breasts were significantly associated with a younger age at diagnosis and features associated with poor prognosis. Low- and high-MD carcinomas matched for grade, histological subtype, and hormone receptor status were compared for somatic genetic features. Low-MD carcinomas had a significantly increased frequency of TP53 mutations, higher homologous recombination deficiency, higher fraction of the genome altered, and more copy number gains on chromosome 1q and losses on 17p. While high-MD carcinomas showed enrichment of tumor-infiltrating lymphocytes in the stroma. The data demonstrate that when tumors were matched for confounding clinico-pathological features, a proportion in the lowest quintile of MD appear biologically distinct, reflective of microenvironment differences between the lowest and highest quintiles of MD.

BackgroundDecreased cancer incidence and reported changes to clinical management indicate that the COVID-19 pandemic will result in diagnostic and treatment delays for cancer patients. We aimed to develop a flexible model to estimate the impact of delayed diagnosis and treatment initiation on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation.MethodsThe stage-shift model estimates population-level health economic outcomes by weighting disease stage-specific outcomes by the distribution of stages at treatment initiation, assuming delays lead to stage-progression. It allows for extrapolation of population-level survival data using parametric distributions to calculate the expected survival in life years. The model was demonstrated based on an analysis of the impact of 3 and 6-month delays for stage I breast cancer, colorectal cancer and lung cancer patients, and for T1 melanoma, based on Australian data. In the absence of patient-level data about time to stage progression, two approaches were explored to estimate the proportion of patients that would experience a stage shift following the delay: 1) based on the relation between time to treatment initiation and overall survival (breast, colorectal and lung cancer), and 2) based on the tumour growth rate (melanoma). The model is available on http://stage-shift.personex.nl/.ResultsA shift from stage I to stage II due to a 6-month delay is least likely for colorectal cancer patients, with an estimated proportion of 3% of the stage I patients diagnosed in 2020 progressing to stage II, resulting in 11 excess deaths after 5 years and a total of 96 life years lost over a 10-year time horizon. For breast and lung cancer, progression from stage I to stage II due to a 6-month delay were slightly higher at 5% (breast cancer) and 8% (lung cancer), resulting in 25 and 43 excess deaths after 5 years, and 239 and 373 life years lost over a 10-year time horizon, respectively. For melanoma, with 32% of T1 patients progressing to T2 disease following a 6-month delay, the model estimated 270 excess death after 5 years and 2584 life years lost over a 10-year time horizon.ConclusionsUsing a conservative 3-month delay in diagnosis and treatment initiation due to the COVID-19 pandemic, this study predicts nearly 90 excess deaths and $12 million excess healthcare costs in Australia over 5 years for the in 2020 diagnosed patients for 4 cancers. If the delays increase to 6 months, excess mortality and cost approach nearly 350 deaths and $46 million in Australia. More accurate data on stage of disease during and after the COVID-19 pandemic are critical to obtain more reliable estimates.

BACKGROUND: Reoperation rates after breast-conserving surgery are highly variable and the best techniques for optimizing margin clearance are being evaluated. The aim was to identify the reoperation rate at our centre and identify influential factors, including a change in guidelines on margin recommendations and the introduction of in-theatre specimen X-ray. METHODS: A retrospective review of medical records was undertaken to identify 562 patients who underwent breast conservation at The Royal Melbourne Hospital and Royal Women's Hospital between 2013 and 2015. All cases that underwent subsequent re-excision or total mastectomy were captured and factors influencing margin excision recorded. RESULTS: Reoperation was undertaken in 19.5% of patients (110; 86 re-excisions and 24 total mastectomies). There was a reduction in reoperation rate from 25% to 17% (P = 0.01) with adoption of the margin guidelines in 2014, but no significant reduction with the introduction of in-theatre specimen X-ray in 2015 (21% versus 16%, P = 0.14). On multivariate analysis, factors that significantly influenced reoperation rates were the presence of multifocality on mammogram (odds ratio (OR): 5.3, 95% confidence interval (CI): 1.6-16.7, P < 0.01); lesion size on mammogram (OR: 2.2 per 10 mm, 95% CI: 1.4-3.6, P < 0.01); smaller excision specimen weight (OR: 0.5 per 25 g of resection, 95% CI: 0.3-0.8, P < 0.01); and pure ductal carcinoma in situ on final pathology (OR: 5.9, 95% CI: 1.9-16.7, P < 0.01). CONCLUSION: Optimizing reoperation rates following breast-conserving surgery remains a surgical challenge, particularly in patients with in situ or multifocal disease. Adoption of international margin guidelines reduced reoperation rates at our centre; however, introduction of intraoperative specimen X-ray had no influence.

The Oncotype DX® assay was developed to address the need for optimizing the selection of adjuvant systemic therapy for patients with estrogen receptor (ER)-positive, lymph node-negative breast cancer. It has ushered in the era of genomic-based personalized cancer care for ER-positive primary breast cancer and is now widely utilized in various parts of the world. Together with several other genomic assays, Oncotype DX has been incorporated into clinical practice guidelines on biomarker use to guide treatment decisions. The Oncotype DX result is presented as the recurrence score which is a continuous score that predicts the risk of distant disease recurrence. The assay, which provides information on clinicopathological factors, has been validated for use in the prognostication and prediction of degree of adjuvant chemotherapy benefit in both lymph node-positive and lymph node-negative early breast cancers. Clinical studies have consistently shown that the Oncotype DX has a significant impact on decision making in adjuvant therapy recommendations and appears to be cost-effective in diverse health care settings. In this article, we provide an overview of the validation and clinical impact studies for the Oncotype DX assay. We also discuss its potential use in the neoadjuvant setting, as well as the more recent prospective validation trials, and the economic and utility implications of studies that use a lower cutoff score to define low-risk disease.

BACKGROUND: Adjuvant therapy for breast cancer is routinely discussed and recommended in multi-disciplinary meetings (MDMs). Current literature explores how treatments received by patients differ from national guidelines; however, it does not explore whether treatment is concordant with MDMs. This study provides an Australian perspective on the uptake of MDM recommendations and reasons for non-concordance. METHODS: A retrospective cohort study of patients with breast cancer presented at The Royal Melbourne Hospital MDM in 2010 and 2014 to investigate the concordance between MDM recommendations and treatment received. RESULTS: The study group comprised 441 patients (161 from 2010 and 280 from 2014). A total of 375 patients were included in the analyses. Overall, 82% of patients had perfect concordance between recommended and received treatment for all modes of adjuvant therapy. Concordance to endocrine therapy was higher for invasive cancers than ductal carcinoma in situ (97% versus 81%, P

Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown. Experimental Design: We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (n = 55) and mutation data (n = 20). Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%–90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (P = 0.002/0.035), ER-negative (P = 0.02/0.02), and ERBB2-amplified tumors (P < 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P < 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with TP53 mutation (P = 0.03) but not with PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both P < 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels. Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor. Clin Cancer Res; 23(17); 5210–7. ©2017 AACR.

The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P=0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P=0.005), including a significant positive association with amplification or gain of ERBB2 (P

Objective To explore the communication and resource needs of mothers diagnosed with breast cancer treated with curative intent in communicating with their young children and to identify gaps in the resources and support provided to these women. Methods Data were collected via semi-structured telephone interviews from 13 mothers who were diagnosed with breast cancer while parenting a young child (age 3-12 years), and 10 health professionals in Victoria, Australia. Data were analysed qualitatively using the Framework Method. Results and conclusion Mothers and health professionals prioritised communication with children about the cancer diagnosis; however, health professionals and mothers differed in their views of parents' communication needs both in terms of the nature of the support/information needed and the delivery of this support/information. Mothers wanted easily accessible resources that were both instructive and practical. Mothers also emphasised quality over quantity of support. Health professionals were mostly aware of mothers' needs, however, emphasised less instructive support and information. This study highlights the need for improved coordination and tailoring of psychosocial resources and supports for these parents and families communicating about a cancer diagnosis with their young children.

Background Mammographic screening reduces breast cancer mortality but may lead to the overdiagnosis and overtreatment of low-risk breast cancers. Conservative management may reduce the potential harm of overtreatment, yet little is known about the impact upon quality of life. Objectives To quantify women's preferences for managing low-risk screen detected ductal carcinoma in situ (DCIS), including the acceptability of active monitoring as an alternative treatment. Methods Utilities (cardinal measures of quality of life) were elicited from 172 women using visual analogue scales (VASs), standard gambles, and the Euro-Qol-5D-5L questionnaire for seven health states describing treatments for low-risk DCIS. Sociodemographics and breast cancer history were examined as predictors of utility. Results Both patients and non-patients valued active monitoring more favourably on average than conventional treatment. Utilities were lowest for DCIS treated with mastectomy (VAS: 0.454) or breast conserving surgery (BCS) with adjuvant radiotherapy (VAS: 0.575). The utility of active monitoring was comparable to BCS alone but was rated more favourably as progression risk was reduced from 40% to 10%. Disutility for active monitoring was likely driven by anxiety around progression, whereas conventional management impacted other dimensions of quality of life. The heterogeneity between individual preferences could not be explained by sociodemographic variables, suggesting that the factors influencing women's preferences are complex. Conclusions Active monitoring of low-risk DCIS is likely to be an acceptable alternative for reducing the impact of overdiagnosis and overtreatment in terms of quality of life. Further research is required to determine subgroups more likely to opt for conservative management.

There are currently no single disruptors to breast cancer screening akin to the impact of human papillomavirus testing and vaccination on cervical cancer screening. However, there is a groundswell of interest to review the BreastScreen Australia program to consider more risk-based screening protocols and to establish whether to routinely inform women about their breast density. We propose a framework for a considered, evidence-based review. Population-level effectiveness of breast cancer screening is ultimately measured through its impact on breast cancer mortality, and this has been realised in Australia. Effectiveness can also be measured through treatment intensity, estimated overdiagnosis, false-positive screens and health economics measures. Key levers to improve such population-level outcomes include screening participation, screening test sensitivity and specificity, risk assessment and screening protocols. We propose that the review of the program should fall under an evidence-based, consensus-guided framework comprising four complementary elements: improved evidence on current program performance for population risk subgroups; regularly updated evidence on key levers for change; clinical trials and population simulation modelling working in tandem; and consensus-based decision making about the degree of improvement required to justify change. Informing women about their breast density is feasible and would be valued by some BreastScreen clients to help understand the accuracy of their screening test. However, without agreed protocols for screening women with dense breasts, increases in supplemental screening as observed in other settings would, in Australia, shift screening costs to clients and Medicare. This would reduce equity of access to population screening, and maintaining BreastScreen’s usual standard of monitoring and quality management (such as screen-detected and interval cancer diagnoses, and imaging and biopsy rates) would require data linkage between BreastScreen and other services. The proposed framework assesses screening effectiveness in the era of personalised medicine, allows review of multiple factors that may together warrant change, and gives full, evidence-based consideration of the benefits, harms and costs of various approaches to breast cancer screening. To be effective, the framework requires a coordinated approach to generating the evidence required for policy makers, with time to prepare appropriate health services.