Use Of Adjuvant Systemic Therapy Research Articles

The Role of Adjuvant Radiotherapy for the Treatment of Resected High-Risk Stage III Cutaneous Melanoma in the Era of Modern Systemic Therapies.

Modern adjuvant systemic therapies (STs) have revolutionized the management of stage III melanoma. Currently, the role of adjuvant radiotherapy (RT) remains unclear. In this single-center retrospective study, patients with clinically detectable stage III melanoma with high-risk features for lymph node basin (LNB) recurrence and whose tumors were fully resected with complete lymphadenectomy (CLD) between 2010 and 2019 were assessed. We determined the cumulative incidence (CIF) of LNB recurrence and any disease recurrence or progression using competing risk analysis. A total of 108 patients were identified; the median age was 59 years (24-92), and 74 (69%) were men. A total of 51 (42%) received adjuvant RT, 22 (20%) received adjuvant ST, and 35 (32%) received no adjuvant therapy. The advent of ST changed clinical practice, with a significant increase in the use of adjuvant ST and a decrease in the use of RT when comparing practice patterns before and after 2015 (p < 0.001). The 3-year CIF of LNB recurrence was similar in patients treated with adjuvant RT (6.3%) and adjuvant ST (9.8%). The 3-year CIF of any disease recurrence or progression was lower in patients receiving adjuvant ST (24%) compared to those receiving adjuvant RT (52%) or no adjuvant therapy (55%, p = 0.06). Three-year overall survival (OS) was not significantly different in patients treated with ST compared to those not treated with any ST (p = 0.118). Despite ST replacing RT as the dominant adjuvant treatment modality, this change in practice has not resulted in increased LNB recurrence for patients at high risk of LNB recurrence following CLD.

Molecular residual disease (MRD) detection using bespoke circulating tumor DNA (ctDNA) assays in localized soft tissue sarcoma (STS).

11509 Background: Surgery and (neo)adjuvant radiotherapy (RT) are the mainstay curative treatments for localized STS. Despite treatment, up to 50% of STS patients experience metastatic relapse, and routine use of adjuvant systemic therapy (AST) remains controversial. The presence of ctDNA following curative-intent treatment of STS is a potential biomarker for MRD and may identify patients who are likely to benefit from AST. Given the genomic heterogeneity of STS, a histology-agnostic approach to ctDNA detection in this population is desirable. Methods: Patients (pts) with localized, high risk (size ≥ 5cm, grade ≥ 2) STS were enrolled prior to (neo)adjuvant RT and surgery. Pts who received (neo)adjuvant systemic treatment were excluded. Blood samples for ctDNA analysis were collected at diagnosis, post-RT, post-surgery and every 3 months for up to 2 years. Whole exome sequencing (WES) of archival tumor and matched normal were carried out to identify patient-specific, somatic, single nucleotide variants. Personalized and tumor-informed, multiplex PCR next generation sequencing-based ctDNA (Signatera) assays were then developed to track ctDNA in serially collected plasma samples. ctDNA levels were expressed as mean tumor molecules per milliliter (MTM/ml) of plasma. Radiologic surveillance was performed every 3 months following surgery. The primary endpoint was a ctDNA detection rate of &gt;70% at diagnosis. Secondary endpoints included MRD detection after local therapy and correlation of ctDNA levels with disease relapse. Results: A total of 140 plasma samples from 22 pts [18 male and 4 female; median age: 65 years, range: 30 – 84] were obtained. RT was preoperative in 19/22 pts. Of the 22 tumor samples, 20 had adequate tissue quality for WES to enable ctDNA assay design. Tumor histologic subtypes included undifferentiated pleomorphic sarcoma (n = 6), myxofibrosarcoma (n = 5), and liposarcoma (n = 9). A median of 7 plasma samples per patient (range: 2 – 10) were analyzed. ctDNA was detected in 80% of pts (16/20) at diagnosis, with median ctDNA level of 3.4 MTM/mL (range: 0.2 – 1393.9). Of these 16 pts, 15 (94%) became ctDNA negative at the immediate post-surgical timepoint. In addition, ctDNA was detected in 4 pts (80%) prior to or around radiologic relapse with a median lead time of 92 days. Conclusions: Personalized, tumor-informed ctDNA assays can detect MRD after definitive local therapy and/or prior to radiologic recurrence in patients with localized high-risk STS. As such, serial ctDNA monitoring provides prognostic value and may further identify patients that will benefit from AST treatment. Additional studies evaluating ctDNA as a predictive biomarker for AST benefit are ongoing.

Circulating tumor DNA (ctDNA) detection of molecular residual disease (MRD) as a potential biomarker in localized soft tissue sarcoma (STS).

11547 Background: Surgery and (neo)adjuvant radiotherapy are the mainstay curative treatments for localized STS. Despite treatment, approximately 50% of STS patients (pts) experience metastatic relapse and routine use of adjuvant systemic therapy (AST) remains controversial. The presence of ctDNA following curative treatment of STS is a potential biomarker for MRD and may identify patients who benefit from AST. Given the genomic heterogeneity of STS, a histology-agnostic approach to ctDNA detection in this population is desirable. Methods: Pts with localized, high risk (size ≥ 5cm, grade ≥ 2) disease were enrolled prior to (neo) adjuvant radiotherapy and surgery. Blood for ctDNA was collected at diagnosis; post-radiotherapy, post-surgery and every 3 months for up to 2 years. Whole exome sequencing (WES) of archival tumor- and matched buffy coat-DNA were carried out to identify somatic variants. Personalized and tumor-informed, multiplex PCR next generation sequencing-based ctDNA assay (Signatera™ assay) was performed on plasma obtained at the serial timepoints. A sample level positive call required ≥ 2 variants above a confidence calling threshold. Absolute ctDNA levels were expressed as mean tumor molecules per milliliter (MTM/ml) of plasma, based on variant allele frequencies and quantity of cell free DNA. Standard radiologic surveillance (every 3 months) was performed following surgery. The primary endpoint was a ctDNA detection rate of 70% at diagnosis. Secondary endpoints included MRD detection and correlation of ctDNA levels with disease relapse. Results: Seventy-six plasma samples from 10 pts [8 males and 2 females; median age 64 years (range 46–84)] were obtained prospectively. STS subtypes were undifferentiated pleomorphic sarcoma (n = 4), myxofibrosarcoma (n = 2), dedifferentiated liposarcoma (n = 2), myxoid liposarcoma (n = 1), and pleomorphic liposarcoma (n = 1). All tumors successfully underwent WES with adequate data quality for Signatera™ assay design. The personalized ctDNA assay was performed on a median of 7 plasma samples per patient (range: 5 – 10). ctDNA was detected in 7 pts (70%) at diagnosis, with median ctDNA level of 1.6 MTM/ml (range: 0.2 – 137.8), achieving the study primary endpoint. Immediate post-surgery samples were negative in all pts. However, ctDNA was detected in 2 out of 2 pts who developed metastatic disease during follow-up. Conclusions: Personalized tumor-informed ctDNA assays in localized high-risk STS at diagnosis are feasible. In this series, all patients had undetectable levels of ctDNA post-surgery and patients who experienced disease relapse demonstrated a detectable rise in ctDNA levels. Further interrogation of this approach for detection of post-treatment MRD as a possible biomarker of benefit from AST is ongoing.

Gene Expression Profiling in Early Breast Cancer-Patient Stratification Based on Molecular and Tumor Microenvironment Features.

Patients with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) are typically treated with surgery, followed by adjuvant systemic endocrine therapy with or without adjuvant chemotherapy and radiation therapy. Current guidelines regarding the use of adjuvant systemic therapy depend on clinical and pathological factors, such as the morphological assessment of tumor subtype; histological grade; tumor size; lymphovascular invasion; and lymph node status combined with estrogen receptor, progesterone receptor, and HER2 biomarker profiles assessed using immunohistochemistry and in situ hybridization. Additionally, the prognostic and predictive value of tumor-infiltrating lymphocytes and their composition is emerging as a key marker in triple negative (TNBC) and HER2-enriched molecular breast tumor subtypes. However, all these factors do not necessarily reflect the molecular heterogeneity and complexity of breast cancer. In the last two decades, gene expression signatures or profiling (GEP) tests have been developed to predict the risk of disease recurrence and estimate the potential benefit of receiving adjuvant systemic chemotherapy in patients with luminal breast cancer. GEPs have been utilized to help physicians to refine decision-making process, complementing clinicopathological parameters, and can now be used to classify the risk of recurrence and tailoring personalized treatments. Several clinical trials using GEPs validate the increasing value of such assays in different clinical settings, addressing relevant clinical endpoints. Finally, the recent approval of immune checkpoint inhibitors in TNBC and the increasing use of immunotherapy in different molecular BC populations highlight the opportunity to refine current GEPs by including a variety of immune-related genes that may help to improve predicting drug response and finetune prognosis.

Discovery and validation of a genomic signature to identify women with early-stage invasive breast cancer who may safely omit adjuvant radiotherapy after breast-conserving surgery.

512 Background: Adjuvant radiotherapy (RT) is currently the standard of care for women with early-stage invasive breast cancer (BC) treated with breast conserving surgery (BCS). However, some women may have very low risk of recurrence and could safely be spared RT. This study aimed to identify these women using a molecularly-based approach. Methods: We performed an analysis of the SweBCG91-RT cohort, a trial randomizing women with node-negative stage I-II invasive BC +/- RT following breast conserving surgery, with sparse use of adjuvant systemic therapy. Only patients with ER+, HER2- tumors, and not treated with adjuvant systemic therapy, were included in this analysis. Transcriptome-wide profiling of tumors was performed using the Affymetrix Human Exon 1.0 ST microarray. The SweBCG91-RT cohort was divided into a training cohort of 243 patients and a validation cohort of 354 patients. Biological gene sets and individual genes related to locoregional recurrence in patients not receiving RT of the training set were identified, and a 16-gene signature was trained using elastic net regression. The signature, named Profile for the Omission of Local Adjuvant Radiation (POLAR), was locked prior to validation. Results: In the validation cohort, POLAR was prognostic for locoregional recurrence (LRR) in patients not treated with RT (multivariable Cox model adjusting for age, grade, tumor size, and luminal A vs luminal B: HR = 1.7 [1.2,2.3], p &lt; 0.001). Patients categorized as POLAR low-risk had a 10-year locoregional recurrence rate of 7% in the absence of RT. Notably, there was no significant benefit from RT for these POLAR low-risk patients (HR = 1.1 [0.38,3.3], p = 0.83), whereas patients categorized as POLAR high-risk had a significant decreased risk of locoregional recurrence when treated with RT (recurrence rate without RT at 10-years 19%, HR = 0.43 [0.24,0.78], p = 0.0053). Conclusions: These data suggest that the novel POLAR genomic signature based on LRR biology can not only identify patients who have a low risk of LRR without adjuvant RT after BCS but who also would not benefit from RT, thus being prime candidates for RT omission.

Abstract P2-08-20: Long-term outcomes after breast conserving surgery compared with mastectomy in early breast cancer in Korea

Abstract Introduction: In some recent studies, breast conserving surgery (BCS) has been reported to improve survival rates compared with modified radical mastectomy (MRM) in early breast cancer. The purpose of this study was to evaluate long term outcome of Korean women with early breast cancer and compare the recurrence rate and overall survival according to operation methods; BCS vs MRM. Method: In this population-based study, we used information from two databases including the nationwide Korean Breast Cancer Registry (KBCR) and Asan Medical Center (AMC). We identified patients from KBCR who were diagnosed breast cancer stage 1-3 between 1998-2012 and were given either BCS or MRM regardless of axillary staging or dissection or use of adjuvant systemic therapy. To minimize confounding bias caused by variables other than operation method, we used exact match pairing of variables such as age, tumor stage and subtypes except for adjuvant radiotherapy. We compared overall survival (OS) and cancer specific survival (CSS) of BCS group and MRM group. As KBCR is multi-centered and online based registry program, we used a single center database to validate the result of KBCR. We selected patients who were diagnosed with breast cancer stage 1-3 between 1998-2008 from AMC and divided them into BCS group and MRM group. We used exact match pairing of all variables except adjuvant radiotherapy in this cohort as well and compared OS, CSS and disease-free survival (DFS). Result: Of 59121 patients who were selected from KBCR, 26581 patients received MRM and 32540 patients received BCS. 18989 patients in each group were remaining after exact match pairing. After exact matching to adjust variables other than operation method, BCS was significantly associated with better OS and CSS compared with MRM. After exact matching HR for OS and CSS were 1.47 [0.36-1.59 p&amp;lt;0.001], 1.37 [1.20-1.57 p&amp;lt;0.001] respectively. Of 8710 patients who from AMC, 2490 patients were excluded as they had unknown variables we needed to know for exact matching. 3095 patients received MRM and 3125 patients received BCS. 1790 patients in each group were remaining after exact match pairing. In this cohort after exact BCS was also significantly associated with better OS, CSS and DFS compared with MRM. After exact matching HR for OS, CSS and DFS were 1.64 [1.30-2.06 p&amp;lt;0.001], 1.71 [1.33-2.20, p&amp;lt;0.001], 1.37 [1.14-1.64, p&amp;lt;0.001] respectively. Median follow up was 88.6 month before matching and 89.2 month after matching. Conclusion: When we adjusted confounding variables by exact matching BCS showed better overall and cancer specific survival and in AMC database better recurrence free survival compared to MRM in early breast cancer patients. These results suggest that BCS is at least equivalent to mastectomy in terms of recurrence free survival and overall survival and may affect treatment decisions in early breast cancer patients. Citation Format: Hakyoung Kim, Sei Hyun Ahn, Byung Ho Son, Jong Won Lee, Il Yong Chung, Beom Seok Ko, HeeJeong Kim, Jisun Kim, Young Ju Lee, Yungil Shin, Soojeong Choi, Ho Hyun Ryu, Sae Byul Lee. Long-term outcomes after breast conserving surgery compared with mastectomy in early breast cancer in Korea [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-20.

Abstract ML: What would Bill think?

Abstract Since the untimely passing of Bill McGuire in 1992, breast cancer mortality rates have declined by approximately 40% despite stable incidence rates, largely due to mammographic screening and broader application of systemic adjuvant therapy in early stage disease. Continued progress is likely given recently reported clinical trials demonstrating improved survival in metastatic disease, including immune checkpoint blockade in triple negative disease, CDK4/6 inhibitors in ER-positive disease, and second-generation immunconjugates in HER2-positive disease. This remarkable progress in reducing breast cancer mortality has come with a price - broader use of adjuvant chemotherapy in patients with early stage disease who might have been adequately treated and perhaps cured without chemotherapy, and the short and long term side effects that may accompany it - which raises the question - what would Bill think of our progress? How would he challenge us to do better?This lecture will focus on three distinct topics that address some potential challenges: (1) How can gene expression profiles and other diagnostic tests be used to guide the use of adjuvant systemic therapy? (2) is time for reappraisal of active surveillance to detect impending recurrence and prevent it? (3) Are there diagnostic and therapeutic strategies that can be used to identify tumors at highest risk of systemic dissemination, and novel therapeutic strategies that block dissemination? Citation Format: JA Sparano. What would Bill think? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ML.

Abstract P2-14-08: Use of systemic therapy for early stage breast cancer in older adults: Results from the Bridging the Age Gap study

Abstract Background: Older patients with early breast cancer (EBC) are a heterogenous population which is often treated less aggressively than their younger counterparts. This may lead to increased variance in the use of adjuvant systemic therapy and consequent inferior outcomes.Use of adjuvant systemic therapy in a population of older EBC patients was evaluated within a large UK prospective multicentre cohort study (Bridging the Age Gap). Methods: A prospective, multicentre, observational study of women aged over 70 with EBC was conducted between 2013 and 2018 at 57 Institutions in the UK. Women were recruited at diagnosis and baseline demographics, patient and tumour characteristics, treatment details, adverse events and quality of life were recorded for up to 24 months. Simple statistics, Fisher’s exact test, chi-squared and Cox regression were used as appropriate. The interaction between systemic therapy use, tumour and patient characteristics and survival and toxicity outcomes were evaluated using uni- and multivariate analysis and propensity score matching. Results: 3,649 patients were enrolled in the study of whom 3416 were eligible. 2,816 (82.4%) underwent surgery within 6 months of diagnosis. Of those patients undergoing surgery, 2,554 (90.7%) had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 and 2,710 (96.2%) had a modified Charlson comorbidity Index ≥2. Activities of Daily Living (ADL) were impaired in 568 cases (20.2%) and Instrumental Activities of Daily Living (IADL) in 498 (17.7%). 1,876 patients (66.2%) had normal Mini-Mental State Examination (MMSE). In the overall population, 382 patients (13.6%) received chemotherapy. Its use increased substantially in patients with tumours larger than 50 mm (25.2%), involving axillary lymph nodes (23.6%) and grade 3 (27.4%). Chemotherapy was given in 34.6% of patients with ER-negative and in 47.76% of patients with HER2-positive disease. However, its use decreased with age from 20.7% in patients aged 70-74 to 3.6% in those aged ≥80. Chemotherapy was used in 14.1% of patients with ECOG PS 0-1, 15.6% of those with normal ADL score, 15.6% of those with normal IADL score and 14.2% of those with normal MMSE.Of the total cohort of 3416 women, 1520 (44.5%) had high recurrence risk cancer and 381 (25.0%) patients subsequently underwent chemotherapy. The chemotherapy and no chemotherapy groups differed significantly in age, fitness and frailty. Unadjusted all cause mortality was 17.6% for no chemotherapy and 9.3% for chemotherapy patients. Baseline variation in health status was propensity score adjusted yielding a matched cohort of 381 no chemotherapy and 225 chemotherapy patients. Matched all cause mortality was 10.8% for no chemotherapy versus 10.7% for chemotherapy. EBC specific mortality was 7.0% for no chemotherapy and 8.1% for chemotherapy patients. These data suggest that chemotherapy confers little survival benefit in this age group. Conclusions: The use of chemotherapy in this population is consistent with published data, with a substantial proportion of fit older patients with high-risk breast cancer not receiving it. However, undertaking a matched analysis of outcomes suggests that there is little benefit in this age group at short follow-up. Incorporating geriatric assessment may better inform the management of these complex patients in a multidisciplinary setting. Table 1 - Chemotherapy use based on tumour and patient characteristics.CharacteristicsChemotherapy givenYesNoN (%)N (%)Tumour size (mm)≤2093 (7.3)1,182 (92.7)21-50 233 (17.7)1,085 (82.3)≥5050 (25.2)148 (74.7)Unknown6 (24.0)19 (76.0)pN stagepN0 (incl. micrometastases)174 (9.0)1,751 (91.0)pN1116 (18.7)504 (81.3)pN254 (33.5)107 (66.5)pN334 (40.5)50 (59.5)Unknown4 (15.4)22 (84.6)Grade15 (1.3)384 (98.7)2129 (8.6)1,378 (91.4)3239 (27.4)632 (72.6)Unknown9 (18.4)40 (81.6)HistologyInvasive ductal carcinoma287 (14.4)1,701 (85.6)Invasive lobular carcinoma59 (14.6)345 (85.4)Tubular0 (0.0)31 (100.0)Mucinous2 (2.5)78 (97.5)Other29 (10.1)257 (89.9)Unknown5 (18.5)22 (81.5)Receptor statusER statusPositive247 (10.3)2,144 (89.7)Negative129 (34.6)244 (65.4)Unknown6 (11.5)46 (88.5)HER2 statusPositive160 (47.8)175 (52.2)Negative210 (9.1)2,095 (90.9)Inconclusive4 (17.4)19 (82.6)Unknown8 (5.2)145 (94.8)Oncotype DX testYes6 (14.6)35 (85.4)No376 (13.5)2,399 (86.4)Age70-74242 (20.7)928 (79.3)75-79120 (13.4)777 (86.6)80-8418 (3.6)487 (96.4)≥851 (0.4)11 (91.7)ECOG Performance status0301 (15.5)1,646 (84.5)160 (9.9)547 (90.1)23 (3.7)77 (96.2)32 (5.6)34 (94.4)40 (0.0)1 (100.0)Unknown16 (11.0)129 (89.0)ADL score20309 (15.6)1,669 (84.4)1932 (10.6)270 (89.4)≤1815 (5.6)251 (94.4)Unknown26 (9.6)244 (90.4)IADL score8315 (15.6)1,699 (84.4)727 (10.8)222 (89.2)≤67 (2.8)242 (97.2)Unknown33 (10.9)271 (89.1)Modified Charlson comorbidity index0-10 (0.0)0 (0.0)≥2371 (13.7)2,339 (86.3)Unknown11 (10.4)95 (89.6)MMSE&amp;gt;24267 (14.2)1,609 (85.8)20-247 (17.5)33 (82.5)&amp;lt;204 (12.9)27 (87.1)Unknown104 (12.0)765 (88.0) Citation Format: Nicolò Matteo Luca Battisti, Alistair Ring, Mike Bradburn, Lynda Wyld, Age Gap Trial Steering Group. Use of systemic therapy for early stage breast cancer in older adults: Results from the Bridging the Age Gap study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-08.

179PD - Tumor size and overall survival in a cohort of young (≤40 years), nodenegative, systemically untreated breast cancer patients; by the PARADIGM study group

BackgroundIn the 1990s, the use of adjuvant systemic therapy was based on nodal involvement but not on tumor size, as was recommended in the Dutch breast cancer guidelines. Tumor size is an important prognostic variable in breast cancer, although this may not hold true for all molecular subtypes or patient ages. Here, we studied the prognostic value of tumor size for young (≤40 years at diagnosis), systemically untreated, node-negative (N0), breast cancer patients, and assessed whether for any given T-stage survival exceeds 90% at 20 years. MethodsAll female, breast cancer patients, ≤40 years at time of diagnosis (between 1989 and 2000), were selected from the Netherlands Cancer Registry. All lymph node-positive and systemically treated patients were excluded, resulting in a cohort of 2302 women. Clinico-pathological and follow-up data were collected from national databases, patient records, and the original pathology reports. Multivariate cox regression for overall survival was performed using T-stage (TNM 8.0), molecular subtype, and tumor grade (according to Nottingham Histologic Score) as covariates. ResultsSurvival rates at 20-years are shown in Table. Median follow-up was 17 years. Only 1% had a T3 tumor and these patients were excluded from analysis. The 20-yr OS for the 96 (4%) T1a tumors was 81% (not shown). Women with T2 tumors had a significantly lower OS compared to women with T1a (HR 1.9 P=0.024), T1b (HR 1.7 P=> 0.001) and T1c tumors (HR 1.31 P=0.002), adjusted for tumor grade and molecular subtype. No OS data is shown for subgroups with less than 35 patients.Table179PD Overall survival (OS; %) at 20 years by T-stage, molecular subtype and tumor grade (Gr)TableT1bT1cT2AllnOSnOSnOSnOS3597311146961160230268ER+HER2-Gr 1+2Gr 317282464771655697373436813055834926954All79725569ER-HER2-Gr 1+2Gr 36-31-27-706531-205731586641768All61716368HER2+Gr 1+2Gr 331-745436541595722-8153546116956All70545758 ConclusionsT-stage is associated with OS in this patient group. At 20 years follow-up, we found no T-stage with OS rates >90% in N0, systemically untreated patients, meaning that patients regardless of T-stage may benefit from some form of systemic treatment. Legal entity responsible for the studyThe PARADIGM study group. FundingThe Netherlands Organization for Health Research and Development (ZonMW); A Sister’s Hope; De Vrienden van UMC Utrecht. DisclosureS.C. Linn: Research grant / Funding (self): Amgen; Research grant / Funding (self), unrestricted research grant SUBITO study (NCT02810743): Eurocept-pharmaceuticals; Research grant / Funding (institution), research grant NCT02810743 & olaparib;fulvestrant NCT00738777;advisory board olaparib breast cancer: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution), unrestricted research grant for NCT02285179 and study drug (taselisib): Genentech; Advisory / Consultancy, Member of the Scientific Advisory Board of Cergentis (unpaid): Cergentis; Advisory / Consultancy, scientific advisory board for Watson for Oncology (paid to institution): IBM; Research grant / Funding (institution), unrestricted research grant and study drug NCT03283384; research support biomarker study NCT02109913: Novartis; Advisory / Consultancy, Research grant / Funding (institution), scientific advisory board palbociclib; TEAM 2b through unrestricted research grant from Pfizer: Pfizer; Research grant / Funding (institution), Unrestricted research grant paid to institution for ABC study and study drug: Tesaro; Honoraria (institution), Fee for teaching paid to institution: Bayer. All other authors have declared no conflicts of interest.

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update—Integration of Results From TAILORx

This focused update addresses the use of Oncotype DX in guiding decisions on the use of adjuvant systemic therapy. ASCO uses a signals approach to facilitate guideline updating. For this focused update, the publication of the Trial Assigning Individualized Options for Treatment (TAILORx) evaluating noninferiority of endocrine therapy alone versus chemoendocrine therapy for invasive disease-free survival in women with Oncotype DX scores provided a signal. An expert panel reviewed the results of TAILORx along with other published literature on the Oncotype DX assay to assess for evidence of clinical utility. For patients with hormone receptor-positive, axillary node-negative breast cancer whose tumors have Oncotype DX recurrence scores of less than 26, there is little to no benefit from chemotherapy, especially for patients older than age 50 years. Clinicians may recommend endocrine therapy alone for women older than age 50 years. For patients 50 years of age or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the panel recommends that oncologists may offer chemoendocrine therapy to these patients with recurrence scores of 26 to 30. Additional information can be found at www.asco.org/breast-cancer-guidelines.

Tumor deposits in stage III colon cancer

Colorectal cancer (CRC) remains one of the primary causes of cancer mortality worldwide (1). The tumor node metastasis (TNM) classification, which is based on tumor extent, lymph node involvement, and presence of distant metastasis, is still the most commonly used approach to inform patient prognostication and decision making in clinical management. This classification helps to stratify patients into different risk levels of cancer recurrence and survival after curative resection, and guides the appropriate use of systemic adjuvant therapy. Systemic adjuvant therapy can improve the overall survival of patients with stage III colon cancer by around 3–5%, but is associated with a risk of significant side effects and a small risk of death (2,3). Better stratification is therefore needed to distinguish between patients at higher risk of recurrence who are more likely to benefit from adjuvant therapy, and those at lower risk of recurrence who have a better chance of cure by surgery without adjuvant therapy.

Breast Cancer

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 235,000 women in this country in 2013 and is expected to result in approximately 40,000 deaths. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

Breast Cancer

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 266,120 In 2018, along with 63,960 new cases of non-invasive (in situ) breast cancer. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

Abstract 1226: Targeting BTK family in ER+ breast cancer with Ibrutinib for personalized precision medicine: a double-edged sword

Abstract Background: Metastasis is the principal cause of morbidity and mortality from breast cancer. Although current therapies are effective in early-stage of breast cancer, resistance to therapy is common leading to the development of metastasis. The commonest site of metastases is the regional lymph nodes. The presence and the number of involved lymph nodes remains the single best predictor of metastases and an important guide for the use of systemic adjuvant therapy. Identification of the underlying molecular targets of lymph node metastasis and a better understanding how to therapeutically target these will be a significant step in the goal of prevention of metastases. Experimental Design: To determine the key players associated with the development of metastasis in breast cancer, we performed RNA sequencing (Illumina Paired-end RNA-seq) analysis in a cohort of matched pairs of primary and (nodal) metastatic tumors (n=18). Gene expression profiles were analyzed using DESeq2. For targeted therapeutics, we performed orthotopic tumor implantation into mammary fad pads of athymic nude mice of breast cancer models. Results: Our results identified significant differential expression of the Bruton's tyrosine kinase (BTK) family members in nodal metastasis. Among the family members, BTK, BLK, RLK/TXK and JAK3 are expressed at very high levels in the metastatic lesions as compared to matched primary tumors. Among the 51 breast cancer cell lines analyzed, the BTK genes were significantly upregulated in luminal, but not basal cell lines. Categorized by the molecular subtypes of breast cancer, hormone receptor- positive (HR) and /or HER2 overexpressing breast cancer cell lines present higher BTK expression. Among the 51 breast cancer cell lines analyzed, the BTK genes were significantly regulated in both ER+ HER2- (T47D and ZR75.1) and ER+HER2+ (BT-474 and ZR75.30) breast cancer cell lines. Ibrutinib, a selective and irreversible inhibitor of BTK targeting the cysteine-481 residue in the active site, exhibited potent activity in preclinical models of BTK-expressing targets. Ibrutinib decreased primary tumor growth significantly in ER+HER2+ (BT-474) mouse xenograft model in a dose dependent manner (10 mg/kg vs 25 mg/kg; P&amp;lt; 0.05), whereas it promoted the tumor growth in a significant manner in ER+HER2- xenograft models (T47D and ZR75.1; P&amp;lt;0.05). The differences might be due to the differences in model systems due to the HER2 presence. Conclusion: Our data suggests that differential expression of target genes can be used to select agents as treating breast cancer. However, caution is necessary, as, in some situations, this might lead to enhancement of the growth in in vivo in subsets of breast cancer. Citation Format: Yesim Gökmen-Polar, Xiaoping Gu, Edyta Vieth, Sunil Badve. Targeting BTK family in ER+ breast cancer with Ibrutinib for personalized precision medicine: a double-edged sword [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1226. doi:10.1158/1538-7445.AM2017-1226

The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival

Background:The Dutch guidelines advise to start radiation therapy (RT) within 5 weeks following breast-conserving surgery (BCS). However, much controversy exists regarding timing of RT. This study investigated its effect on 10-year disease-free survival (DFS) in a Dutch population-based cohort.Methods:All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003 treated with BCS+RT were included. Two populations were studied. Population 1 excluded patients receiving chemotherapy before RT. Analyses were stratified for use of adjuvant systemic therapy (AST). Population 2 included patients treated with chemotherapy, and compared chemotherapy before (BCS-chemotherapy-RT) and after RT (BCS-RT-chemotherapy). DFS was estimated using multivariable Cox regression. Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were secondary outcomes.Results:Population 1 (n=2759) showed better DFS and DMFS for a time interval of >55 than a time interval of <42 days. Patients treated with AST showed higher DFS for >55 days (hazards ratio (HR) 0.60 (95% confidence interval (CI): 0.38–0.94)) and 42–55 days (HR 0.64 (95% CI: 0.45–0.91)) than <42 days. Results were similar for DMFS, while timing did not affect LRRFS and OS. For patients without AST, timing was not associated with DFS, DMFS and LLRFS, but 10-year OS was significantly lower for 42–55 and >55 days compared to <42 days. In population 2 (n=1120), timing did not affect survival in BCS-chemotherapy-RT. In BCS-RT-chemotherapy, DMFS was higher for >55 than <42 days.Conclusions:Starting RT shortly after BCS seems not to be associated with a better long-term outcome. The common position that RT should start as soon as possible following surgery in order to increase treatment efficacy can be questioned.

Clinical utility of gene-expression signatures in early stage breast cancer.

Breast cancer is a heterogeneous disease, with different subtypes having a distinct biological, molecular, and clinical course. Assessments of standard clinical and pathological features have traditionally been used to determine the use of adjuvant systemic therapy in patients with early stage breast cancer; however, the ability to identify those who will benefit from adjuvant chemotherapy remains a challenge, leading to the overtreatment of some patients. Advances in molecular medicine have substantially improved the accuracy of gene-expression profiling of breast tumours, resulting in improvements in the ability to predict a patient's risk of breast cancer recurrence and likely response to endocrine therapy and/or chemotherapy. These genomic assays, several of which are commercially available, have aided physicians in tailoring treatment decisions for patients at the individual level. Herein, we describe the available data on the clinical validity of the most widely available assays in patients with early stage breast cancer, with a focus on the development, validation, and clinical application of these assays, in addition to the anticipated outcomes of ongoing prospective trials. We also review data from comparative studies of these assays and from cost-effectiveness analyses relating to their clinical use.

Breast Cancer

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 235,000 women in this country in 2013 and is expected to result in approximately 40,000 deaths. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

Abstract P1-10-21: Influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival

Abstract Background In the Netherlands, one of the indicators of quality of care is that radiation therapy (RT) should start within six weeks following breast-conserving surgery (BCS). However, there is still much controversy regarding timing of RT in literature. This study investigated the effect of timing of RT on disease-free survival (DFS) in a Dutch nationwide population-based cohort. Methods All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003, treated with BCS plus RT, of whom the start date of RT was known, were included. Patients who received chemotherapy between surgery and RT were excluded, as this affects delay. Patients were categorised into three groups: &amp;lt;42 days, 42-55 days and &amp;gt;55 days, between surgery and start of RT. The primary outcome was 10-year DFS. Secondary outcomes were 10-year locoregional recurrence-free (LRRFS) and distant metastasis-free survival (DMFS). Multivariable Cox regression was used to correct for confounding. Since adjuvant systemic therapy largely influences DFS, all analyses were stratified for use of adjuvant systemic therapy (chemotherapy and/or endocrine therapy). Results In total, 2,759 patients were included. The median number of days between BCS and RT was 45 (IQR 37-54 days). The hazard ratio (HR) for 10-year DFS was 0.79 (95% CI: 0.65-0.96) for 42-55 days and 0.71 (95% CI: 0.56-0.90) for &amp;gt;55 days, both compared to &amp;lt;42 days. While no significant differences in 10-year LRRFS were found, 10-year DMFS (HR 0.64 [95% CI: 0.45-0.91]) was significantly higher for BCS-RT interval &amp;gt;55 days compared to &amp;lt;42 days. After stratification, no significant differences were found for any outcome in patients not treated with adjuvant systemic therapy, while in patients who were treated with adjuvant systemic therapy, 10-year DFS was significantly improved for 42-55 days (HR 0.70 (95% CI: 0.51-0.97) and &amp;gt;55 days (HR 0.63 (95% CI: 0.42-0.96) compared to &amp;lt;42 days. Significantly improved 10-year DMFS was confirmed after stratification for longer delays (HR 0.69 (95% CI: 0.47-1.00 for 42-55 days) and 0.59 (95% CI: 0.36-0.96) for &amp;gt;55 days, compared to &amp;lt;42 days) 10-year DFS, LRRFS and DMFS for different time intervals between BCS and RT, stratified for use of adjuvant systemic therapy Entire cohort (n=2,759)No adjuvant treatment (n=1,761)Adjuvant treatment (n=998)Time intervalHR [95% CI]*HR [95% CI]*HR [95% CI]*10-year DFS&amp;lt;42 days11142-55 days0.79 [0.65-0.96]0.83 [0.65-1.05]0.70 [0.51-0.97]&amp;gt;55 days0.71 [0.56-0.90]0.77 [0.57-1.03]0.63 [0.42-0.96]10-year LRRFS&amp;lt;42 days11142-55 days0.74 [0.51-1.06]0.79 [0.52-1.21]0.55 [0.28-1.11]&amp;gt;55 days0.90 [0.59-1.37]0.99 [0.61-1.60]0.67 [0.29-1.57]10-year DMFS&amp;lt;42 days11142-55 days0.90 [0.69-1.17]1.13 [0.77-1.66]0.69 [0.47-1.00]&amp;gt;55 days0.64 [0.45-0.91]0.73 [0.44-1.22]0.59 [0.36-0.96]* Corrected for all relevant confounders. HRs in bold are statistically significant (p&amp;lt;0.05). Conclusion and interpretation In conclusion, patients treated with adjuvant systemic therapy following RT showed increasing 10-year DFS and DMFS with longer BCS-RT intervals, which was not the case for patients not receiving adjuvant systemic therapy. Possible explanations for these results have to be explored further. Citation Format: van Maaren MC, Bretveld RW, Jobsen JJ, Veenstra R, Groothuis-Oudshoorn KCGM, Struikmans H, Maduro JH, Strobbe LJA, Poortmans P, Siesling S. Influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-21.

Why Are There So Many Mastectomies in the United States?

Breast-conserving therapy (BCT) and mastectomy result in equivalent long-term survival. Locoregional recurrence rates after BCT have decreased over time and are now similar to those after mastectomy. Contralateral breast cancer rates are declining as well owing to the widespread use of adjuvant systemic therapy. Despite these improved outcomes, increasing rates of bilateral mastectomy for unilateral cancer have been observed in the United States. Medical indications for mastectomy are well defined and present in a minority of patients, and women at increased risk for contralateral cancer are a small proportion of the breast cancer population. Evidence indicates that increasing use of mastectomy is a patient-driven trend that is most pronounced among younger, educated, and well-insured women, and reflects fear of recurrence and in some cases misunderstanding of future cancer risks. Although satisfaction levels are generally high among patients choosing contralateral prophylactic mastectomy, complications and procedure extent may be underestimated. Improved communication strategies are essential to facilitate this complex decision-making process.

10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study

Investigators of registry-based studies report improved survival for breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer. As these studies did not present long-term overall and breast cancer-specific survival, the effect of breast-conserving surgery plus radiotherapy might be overestimated. In this study, we aimed to evaluate 10 year overall and breast cancer-specific survival after breast-conserving surgery plus radiotherapy compared with mastectomy in Dutch women with early breast cancer. In this population-based study, we selected all women from the Netherlands Cancer Registry diagnosed with primary, invasive, stage T1-2, N0-1, M0 breast cancer between Jan 1, 2000, and Dec 31, 2004, given either breast-conserving surgery plus radiotherapy or mastectomy, irrespective of axillary staging or dissection or use of adjuvant systemic therapy. Primary outcomes were 10 year overall survival in the entire cohort and breast cancer-specific survival in a representative subcohort of patients diagnosed in 2003 with characteristics similar to the entire cohort. We estimated breast cancer-specific survival by calculating distant metastasis-free and relative survival for every tumour and nodal category. We did multivariable Cox proportional hazard analysis to estimate hazard ratios (HRs) for overall and distant metastasis-free survival. We estimated relative survival by calculating excess mortality ratios using life tables of the general population. We did multiple imputation to account for missing data. Of the 37 207 patients included in this study, 21 734 (58%) received breast-conserving surgery plus radiotherapy and 15 473 (42%) received mastectomy. The 2003 representative subcohort consisted of 7552 (20%) patients, of whom 4647 (62%) received breast-conserving surgery plus radiotherapy and 2905 (38%) received mastectomy. For both unadjusted and adjusted analysis accounting for various confounding factors, breast-conserving surgery plus radiotherapy was significantly associated with improved 10 year overall survival in the whole cohort overall compared with mastectomy (HR 0·51 [95% CI 0·49-0·53]; p<0·0001; adjusted HR 0·81 [0·78-0·85]; p<0·0001), and this improvement remained significant for all subgroups of different T and N stages of breast cancer. After adjustment for confounding variables, breast-conserving surgery plus radiotherapy did not significantly improve 10 year distant metastasis-free survival in the 2003 cohort overall compared with mastectomy (adjusted HR 0·88 [0·77-1·01]; p=0·07), but did in the T1N0 subgroup (adjusted 0·74 [0·58-0·94]; p=0·014). Breast-conserving surgery plus radiotherapy did significantly improve 10 year relative survival in the 2003 cohort overall (adjusted 0·76 [0·64-0·91]; p=0·003) and in the T1N0 subgroup (adjusted 0·60 [0·42-0·85]; p=0·004) compared with mastectomy. Adjusting for confounding variables, breast-conserving surgery plus radiotherapy showed improved 10 year overall and relative survival compared with mastectomy in early breast cancer, but 10 year distant metastasis-free survival was improved with breast-conserving surgery plus radiotherapy compared with mastectomy in the T1N0 subgroup only, indicating a possible role of confounding by severity. These results suggest that breast-conserving surgery plus radiotherapy is at least equivalent to mastectomy with respect to overall survival and may influence treatment decision making for patients with early breast cancer. None.