Ipsilateral Invasive Recurrence Research Articles

Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study

Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Tertiary lymphoid structures in breast ductal carcinoma insitu correlate with adverse pathological parameters.

To investigate tertiary lymphoid structures (TLSs) in ductal carcinoma insitu (DCIS) of the breast and their correlation with pathological features, immune cell markers and clinical outcomes. Morphological identification of TLSs in 198 DCIS cases incorporated B and T cell zones with high endothelial venules. TLS positivity was defined as ≥ 1 TLSs in lesional areas, while TLS area percentage was divided into two categories: low (TLSs < 5%) and high (TLSs ≥ 5%). Previously reported biomarkers included ER, PR, HER2, CD68, CD163, CD4, CD8 and PD-L1. TLSs were observed in 24.7% (49 of 198) of cases, with a mean diameter of 0.44 mm (median=0.4 mm, range=0.12-1.43 mm). TLSs were significantly associated with higher nuclear grade, presence of necrosis, hormone receptor negativity/HER2 positivity, triple negativity, tumour infiltrating lymphocytes (TILs) and immune related biomarkers such as FOXP3, CD163, CD4 and CD4/CD8 ratio (all P< 0.05). There were no significant associations between TLSs and recurrence, but a combination of TLSshigh with FOXP3+ , CD4high , CD4/CD8 ratiohigh and CD68high individually, compared with all other combinations, disclosed significantly poorer disease-free survival (DFS) for ipsilateral invasive recurrence (IIR) on both Kaplan-Meier and multivariable Cox regression analyses (all P< 0.05). TLSs in DCIS were associated with unfavourable prognostic features, TILs and immune cell markers in our study. TLSshigh /FoxP3+ , TLSshigh /CD4high , TLSshigh /(CD4/CD8) ratiohigh and TLSshigh /CD68high were independent factors for poorer DFS for IIR. Further exploration of the pathological significance of TLSs may provide a clinical basis for their recognition as an important structure and functional unit in the tumour immune microenvironment.

Abstract IA027: DCIS or cancer? Why all the confusion?

Abstract Many women diagnosed with DCIS in the United States report they are confused about their chances of developing an invasive breast cancer or metastatic cancer. They are told that DCIS is not cancer but it holds the possibility of becoming a cancer. Nevertheless, DCIS is treated in much the same way as a small invasive cancer. Surgical options include lumpectomy alone, lumpectomy with radiotherapy, unilateral or bilateral mastectomy. Much of the confusion is generated by the current paradigm that separates DCIS and invasive cancer into distinct conditions. The mortality of DCIS is 3% over 20 years and that prevention of local invasive recurrence post-DCIS does not reduce breast cancer mortality. If the invasive recurrence were the real cancer then preventing it would reduce the risk of dying but this has not been shown. Further, the risk of an invasive in-breast recurrence following DCIS is the same as the risk of an invasive in-breast recurrence following invasive breast cancer. In the Banting database, the 15-year risk of invasive local recurrence following DCIS was 15.6%, following stage I breast cancer was 15.3% and following stage II breast cancer was 15.9%. In the Banting database, the 15-year risk of ipsilateral invasive recurrence was 14% for DCIS patients who receives radiotherapy and was 29% for DCIS patients who did not received radiotherapy – a difference of 15%. In the Banting database, the 15-year risk of ipsilateral invasive recurrence was 14% for Stage I/II patients who received radiotherapy and was 27% for Stage I/II patients who did not receive radiotherapy – a difference of 13%. The benefit of radiotherapy is the same in both groups. Similarly, the benefit of unilateral mastectomy versus lumpectomy on preventing local invasive recurrence is the same for DCIS patients as it is for early-stage invasive breast cancer patients. In our SEER-based analysis of 812,851 women with breast cancer, the 25-year actuarial risk of contralateral invasive breast cancer was 10.1% for patients with DCIS and was 9.9% for patients with invasive breast cancer. Based on this finding, the benefit of performing a contralateral mastectomy at the time of diagnosis is the same for both groups. We accept lumpectomy as standard of care for invasive breast cancer even though the risk of invasive ipsilateral recurrence is much higher after lumpectomy than after mastectomy. We consider contralateral mastectomy as an option for women with invasive cancer, but as overtreatment for women with DCIS even though the risk of contralateral breast cancer is almost exactly the same. The benefit of radiotherapy is the same for patients with DCIS and stage I/II breast cancer, but we are more likely to consider it overtreatment for DCIS patients. Much of the confusion can be resolved if we consider both types of cancer to be different points on the spectrum. Breast cancer is heterogeneous; DCIS is one end of the spectrum. Accepting this fact will make the rationale behind treatment decisions easier to explain. Citation Format: Steven A. Narod. DCIS or cancer? Why all the confusion? [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 IA027.

Abstract A016: Identification of methylated regions in ductal carcinoma in situ and association with disease progression

Abstract Background: The advent of breast screening has led to a 4-fold increase in the diagnosis of ductal carcinoma in situ (DCIS). Studies following the clinical outcomes of patients show variable progression free survival rates, with only up to 35% of patients progressing to invasive disease without treatment. This highlights the need to find a biomarker to accurately predict which DCIS lesions will recur as invasive tumors. Epigenetics changes are events which occur early in tumorigenesis, this makes DNA methylation a potential biomarker of DCIS progression. However, a lack of DCIS methylation profiling with long term follow-up data exists. This study investigates genome-wide methylation profiles in women with primary DCIS and associates the data with their overall recurrence free survival. Methods: DCIS was macrodissected from 89 formalin-fixed paraffin embedded (FFPE) to extract tumor enriched DNA from patients with DCIS and long term follow up. 39 women had developed an ipsilateral invasive recurrence (classified as cases) and 50 had no evidence of recurrent disease (classified as controls). Genome wide methylation was assessed using the human methylation EPIC BeadChip which, interrogates over 850,000 methylation sites. Data was assessed for quality both at the sample and probe level by the wateRmelon. Further analysis was performed in ChAMP to identify differentially methylated regions (DMR) and by DMRcate packages in R to identify variably methylated regions (VMR). Genes annotated in the most significant VMRs were analysed through Metascape, a web-based tool to perform functional gene set enrichment analysis (GSEA). A cox proportional hazards model was used to calculate the association between the methylation of the VMRs and recurrence free survival. This model was adjusted for DCIS receptor status and grade. Results: 59 samples passed data quality assessment (35 controls and 24 cases). 10 differentially methylated regions were identified. The most significant of which, was a hypomethylated region on chromosome 4, containing CDKL2 (p = 0.001), known to promote the epithelial-mesenchymal transition in breast cancer progression. 5813 VMRs were identified across the genome, (P-value range between 0 and 10-321). 82% of the VMRs aligned to the body of the gene or the surrounding regulatory features. GSEA revealed that VMRs were predominantly involved in pathways involved in cell adhesion (GO:0007156) Assessment of the significant VMRs by COX proportional hazards model showed that a VMR on chromosome 6p was associated with the development of invasive disease after adjusting for oestrogen receptor, human epidermal growth factor 2 status and grade (p=0.001). Conclusions: This preliminary study shows altered sites of methylation could be observed across the genome, in DCIS. The function of the VMRs is currently being investigated to understand how methylation in this region predisposes to invasive recurrence of DCIS. Correlation of methylation status and RNA expression data will be used to understand the biological relevance. Citation Format: Vandna Shah, Maria Roman-Escorza, Karen Clements Clements, Lennart Mulder, Esther H. Lips, Jelle Wesseling, Sarah Pinder, Alastair M. Thompson, Elinor J. Sawyer. Identification of methylated regions in ductal carcinoma in situ and association with disease progression [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 A016.

149 (PB-062) Poster - Primary results of ANZ 1002 : Post-operative Radiotherapy Omission in Selected Patients with Early breast Cancer Trial (PROSPECT) following pre-operative breast MRI

Background: We aimed to determine if preoperative MRI could identify patients in whom the ipsilateral invasive recurrence (IIR) rate was sufficiently low without RT, such that RT might be safely omitted. Here we report primary analysis, and imaging/biopsy findings for occult lesions.

Primary results of ANZ 1002: Post-operative radiotherapy omission in selected patients with early breast cancer trial (PROSPECT) following pre-operative breast MRI.

572 Background: Selective use of radiotherapy (RT) after surgery for early breast cancer (EBC) has been an elusive goal. The role of breast MRI in localised EBC is controversial. We aimed to determine if preoperative MRI could identify patients with EBC in whom the ipsilateral invasive recurrence (IIR) rate was sufficiently low without RT, such that RT might be safely omitted. Here we report primary and secondary outcomes, and imaging/biopsy findings for occult lesions. Methods: PROSPECT is a prospective single-arm study. Criteria for omission of RT included age at least 50, nil/minimal or mild Background Parenchymal Enhancement (BPE) on MRI, unifocal pT1N0 cancer, not Triple Negative (TNBC), no LVI. All patients who underwent PROSPECT MRI were included in the analysis. Imaging findings on MMG, US and MRI were documented and all biopsies were recorded. Pathology of lesions identified by MRI was described. The primary outcome was the IIR at 5 years of those treated without RT. An IIR rate of 5% or less was considered acceptable. The protocol specified primary analysis occurred after the 100th patient reached 5 years follow up in May 2021. Results: Between 9/2011 and 5/2019, 443 patients had MRI after diagnosis. BPE was nil/minimal or mild in 344 patients. MRI detected 194 occult lesions in 144 (33%) patients; 139 (72%) were ipsilateral. 61 MMG/US occult malignant lesions - 36 invasive and 25 DCIS - were identified in 48 patients (11% of total cohort). Of 38 ipsilateral lesions in 32 patients (7% of total cohort), 23 were DCIS, 4 were T1a, 7 T1b and 4 T1c. 201 patients were treated on trial without RT. The median age was 63 years (range: 50 to 84), median tumour size 11 mm (range: 2 to 20), grade 1 (104), grade 2 (86) or grade 3 (11). The rate of IIR at 5 years was 1% (1/101). There were 2 IIRs at 4.6 and 7.7 years follow up, 1 regional recurrence, and 1 patient with both a regional and distant recurrence with 1 breast cancer death. There was 1 contralateral (CL) breast cancer, 1 CL DCIS, 2 other cancer diagnoses and 1 death from other causes. Of 242 patients undergoing MRI but not in the main study, median age was 63 range: 50-80, median tumour size, 13mm (range: 4-145). 9 underwent mastectomy (2% of total cohort). Followup is complete for 235. There was 3 IIR, 3 CL primary and no distant metastases or breast cancer deaths. Conclusions: Breast MRI in selected, low risk patients identified occult malignancy in 11% of patients. At a median of 5 years follow up the IIR and other breast cancer events was very low. This suggests that local recurrences may be due to occult breast cancers, and MRI may allow the identification of truly localised cancers for which radiation may be safely omitted. The event rate for the entire cohort was very low, suggesting that identification of occult malignancy in apparently unifocal EBC is beneficial. Confirmatory trials are needed. Clinical trial information: 12610000810011.

Local treatment options for young women with ductal carcinoma in situ: A systematic review and meta-analysis comparing breast conserving surgery with or without adjuvant radiotherapy, and mastectomy

PurposeYoung age is associated with poor prognosis in ductal carcinoma in situ (DCIS) of female breast and controversy exists regarding the optimal treatment modality for young patients. We aimed to compare treatment outcomes among breast conserving surgery (BCS), BCS with adjuvant radiotherapy (BCS + RT), and total mastectomy (MT) for young DCIS women. MethodsPubMed, Cochrane, and Embase were searched for studies reporting comparative results among BCS, BCS + RT, or MT in ≤50 years old (y/o) DCIS females. Study quality was assessed and meta-analysis with subgroup analysis was performed to pool the effect sizes of the outcomes-of-interest. ResultsWe included 3 randomized control trials and 18 observational studies. For DCIS women ≤50 y/o, RT following BCS significantly reduced the risk for ipsilateral breast tumor recurrence (IBTR) (HR = 0.66, 95% CI 0.50–0.87). However, the benefit was less robust in extremely young patients and with long follow-ups. RT revealed no statistically significant preventive effect on ipsilateral invasive recurrence (HR = 1.38, 95% CI 0.98–1.94). On the other hand, MT yielded the lowest IBTR (BCS + RT vs MT: HR = 4.4, 95% CI 2.06–9.40), both in ipsilateral DCIS recurrence and ipsilateral invasive recurrence. There was great heterogeneity and could not reach an evident conclusion concerning survival outcomes. ConclusionThis study highlighted the varying effect of RT for young DCIS females. The local control benefit of MT was definite without survival differences observed. Our study provided a moderate certainty of evidence to guide the treatment for young DCIS women. Further age-specific prospective trial is warranted.

Prognostic Risk Assessment and Prediction of Radiotherapy Benefit for Women with Ductal Carcinoma In Situ (DCIS) of the Breast, in a Randomized Clinical Trial (SweDCIS).

Simple SummaryDespite clinical advancements in the diagnosis and treatment of DCIS, tailoring individual treatment for women diagnosed with DCIS remains an unmet clinical need. Definitive predictive tools that can predict who will or not benefit from radiation therapy (RT) after breast conserving surgery (BCS) remains elusive. Here, we used a prospective–retrospective design to validate DCISionRT®, using data from the SweDCIS randomized clinical trial. DCISionRT identified women with elevated recurrence risk who benefited substantially from RT after BCS. In addition, the test identified women with low recurrence risk and little benefit from RT. These results support our conclusions that knowledge of the individual risk and benefit from RT provided by the test can help clinicians and patients make individualized treatment decisions for women diagnosed with DCIS.Prediction of radiotherapy (RT) benefit after breast-conserving surgery (BCS) for DCIS is crucial. The aim was to validate a biosignature, DCISionRT®, in the SweDCIS randomized trial. Women were randomly assigned to RT or not after BCS, between 1987 and 2000. Tumor blocks were collected, and slides were sent to PreludeDxTM for testing. In 504 women with complete data and negative margins, DCISionRT divided 52% women into Elevated (DS > 3) and 48% in Low (DS ≤ 3) Risk groups. In the Elevated Risk group, RT significantly decreased relative 10-year ipsilateral total recurrence (TotBE) and 10-year ipsilateral invasive recurrence (InvBE) rates, HR 0.32 and HR 0.24, with absolute decreases of 15.5% and 9.3%. In the Low Risk group, there were no significant risk differences observed with radiotherapy. Using a cutoff of DS > 3.0, the test was not predictive for RT benefit (p = 0.093); however, above DS > 2.8 RT benefit was greater for InvBE (interaction p = 0.038). Recurrences at 10 years without radiotherapy increased significantly per 5 DS units (TotBE HR:1.5 and InvBE HR:1.5). Continuous DS was prognostic for TotBE risk although categorical DS did not reach significance. Absolute 10-year TotBE and InvBE risks appear sufficiently different to indicate that DCISionRT can aid physicians in selecting individualized adjuvant DCIS treatment strategies. Further analyses are planned in combined cohorts to increase statistical power.

Abstract PS16-03: Clonal relatedness of LCIS with synchronous and asynchronous invasive disease

Abstract Background: Lobular carcinoma in situ (LCIS) is typically clinically undetectable but is being increasingly diagnosed as a result of breast screening mammography and is often found associated with other breast pathologies such as invasive lobular breast cancer (ILC), invasive carcinoma of ductal /no special type (IDC) and ductal carcinoma in situ (DCIS). It is also considered a risk factor for the development of subsequent invasive breast disease. The aim of this study was to understand the genetic relationship between LCIS that presents with synchronous DCIS, IDC and/or ILC in order to ascertain whether the components have common precursors and also to understand the clonal relationship between LCIS and subsequent invasive disease. Methods: 25 cases of LCIS with synchronous ILC, 7 cases of LCIS with synchronous DCIS &amp; IDC, and 8 pure LCIS that developed a subsequent invasive recurrence were identified from the GLACIER study (MREC 06/Q1702/64). DNA was extracted from archival paraffin embedded tissue and underwent copy number analysis using either the Oncoscan™ Array (Affymetrix) or HumanCytoSNP FFPE-12 BeadChip (Illumina). Four of 7 cases of LCIS with synchronous DCIS &amp; IDC also underwent targeted sequencing using a custom 121 breast cancer-associated gene panel (SureSelectXT HS kit, Agilent Technologies). Clonal relatedness was assessed using a novel methodology based on the presence of shared copy number aberration breakpoints and mutations. Results: Of the 25 synchronous LCIS and ILC cases, 17 appeared related, 4 were ambiguous (sharing the typical lobular signature of 1q gain and 16q loss) and 4 demonstrated no evidence of relatedness. Of the 7 cases with synchronous LCIS, DCIS and IDC, all had copy number data available and 4 had mutation data available. In 3 cases the synchronous LCIS, DCIS and IDC were clonally related according to copy number and for two there was mutation data that supported this (one sharing PIK3CA and CDH1 mutations, the other a TP53 mutation). In two cases the LCIS was not related to the DCIS or IDC, but the DCIS and IDC were related to each other; while in one case LCIS was related to IDC but not to the DCIS by copy number but all components shared the same CHEK2 mutation. Finally in one case none of the three components were related to each other by copy number but the LCIS and IDC shared a PIK3CA mutation, albeit at much lower allele frequency in LCIS than in IDC. Of the 8 patients with pure LCIS, 4 developed an ipsilateral invasive recurrence of various combinations of morphologies: 1 ILC &amp; LCIS, 1 ILC &amp; DCIS, 1 IDC &amp; DCIS, 1 ILC &amp; IDC, and 4 a contralateral recurrence (1 tubular, 1 IDC, 2 ILC), with a median time to recurrence of 69 months (range 34-175). The primary LCIS was related to at least one component of the recurrent disease in all four ipsilateral cases; in two the primary LCIS and all components of the recurrent disease were related, and in the remainder we observed a variety of putative evolutionary patterns. Conclusions: The majority (68%) of cases of synchronous LCIS and ILC appeared to be clonally related by copy number. 50% of cases of co-existing LCIS and IDC appeared to have a common clonal origin by either copy number or targeted sequencing. As these are genomically stable tumours, copy number data may also be underestimating relatedness. In the four cases of pure primary LCIS that developed an ipsilateral recurrence, different subtypes of breast cancer were noted as the recurrence morphology, supporting the historical view that LCIS is a risk lesion rather than a true precursor. However, in all cases the preceding LCIS was found to be related to at least one component of the subsequent invasive tumour including DCIS and IDC. This data shows that clonal relatedness between LCIS and both synchronous and asynchronous invasive disease and DCIS is more complex than previously thought, with LCIS acting as a precursor lesion even in some cases of IDC. Citation Format: Elinor Sawyer, Mateja Sborchia, Anargyros Megalios, Vandna Shah, Salpie Nowinski, Cloe Vassart, Anita Grigoriadis, Alastair Thompson, Ian Tomlinson, Rebecca Roylance, Sarah Pinder. Clonal relatedness of LCIS with synchronous and asynchronous invasive disease [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-03.

Local Recurrence after Treatment of Ductal Carcinoma In Situ: A Comprehensive Overview.

Patients with DCIS have an excellent long-term prognosis with a 10-year breast cancer-specific survival around 98%. Treatment has the goal to prevent the development of an invasive breast cancer and to minimize the risk for a second breast cancer event, and published studies have shown a substantial decrease in invasive local recurrence rates over time. Approximately 50% of the local recurrences after BCS for a primary DCIS are invasive and 8.5% of them node-positive. Experiencing an ipsilateral invasive recurrence after a primary DCIS does significantly increase the risk of breast cancer death, while this is not seen after a DCIS recurrence. Radical surgery remains crucial to minimize the risk of local recurrence, and adjuvant radiotherapy reduces the risk of local recurrence by at least 50%. At recurrence, a repeat-BCS should be considered as it offers a good local control in properly selected patients and an overall and breast cancer-specific survival comparable to that seen after mastectomy.

Breast ductal Carcinoma in situ associated with microinvasion induces immunological response and predicts ipsilateral invasive recurrence.

Although microinvasion (Mi) is often thought to be an interim stage between ductal carcinoma in situ (DCIS) and established invasive ductal carcinoma, survival outcomes and biological behaviour of DCIS-Mi are still poorly understood. This study investigated the potential influence of Mi on disease-free survival (DFS) and assessed its correlations with clinicopathological parameters, prognosis, molecular, and immune markers. CD4, CD8, forkhead box P3 (FOXP3), CD68, CD163, programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression in pure DCIS and DCIS-Mi, from a cohort of 198 patients, were determined by immunohistochemistry. DFS, clinicopathological parameters, immune markers, and biomarker expression were correlated with presence of Mi. Twelve out of 198 DCIS cases were associated with Mi. DCIS-Mi was significantly linked with ipsilateral invasive recurrence (p = 0.032). Kaplan-Meier analysis revealed that DCIS-Mi had worse DFS for ipsilateral invasive recurrence (p = 0.011) and this was affirmed by multivariate Cox regression analysis (95% CI 1.181-9.010, HR = 3.262, p = 0.023). DCIS-Mi was associated with higher densities of immune infiltrates positive for CD4 (p = 0.037), FOXP3 (p = 0.037), CD163 (p = 0.01), and PD-L1 (p = 0.015). This study demonstrated that DCIS-Mi was correlated with high densities of immune infiltrates and predicted ipsilateral invasive recurrence.

HER2-Overexpressing Ductal Carcinoma In Situ Associated with Increased Risk of Ipsilateral Invasive Recurrence, Receptor Discordance with Recurrence.

The impact of HER2 status in ductal carcinoma in situ (DCIS) on the risk of progression to invasive ductal carcinoma (IDC) has been debated. We aim to use a national database to identify patients with known HER2 status to elucidate the effect of HER2 overexpression on ipsilateral IDC (iIDC) development. We performed survival analysis on patient-level data using the U.S. NCI's Surveillance Epidemiology and End Results program. We identified patients diagnosed with DCIS who underwent lumpectomy and had known HER2 status. Competing risks analysis was performed. A total of 1,540 patients had known HER2 status and met inclusion criteria. Median age at diagnosis was 60, median follow-up time was 44.5 months. A total of 417 (27.1%) patients were HER2 positive and 1,035 (67.2%) were HER2 negative. Twenty-two (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% for HER2-negative and borderline patients, and 3.9% for HER2-positive patients. On multivariate competing risks regression, two factors were significant for iIDC: radiation (protective) therapy within 24 months (HR, 0.05; P = 0.00006) and HER2 overexpression (increased likelihood; HR, 2.72; P = 0.044). Patients with HER2-positive DCIS were more likely to have recurrences with receptor discordance. HER2 may serve as a prognostic factor for invasive recurrence and was the only lesion-related factor to significantly relate to iIDC development. It may also be associated with receptor discordance of recurrences. Further large studies will be needed to confirm these results.

Higher densities of tumour-infiltrating lymphocytes and CD4+ T cells predict recurrence and progression of ductal carcinoma in situ of the breast.

Host immunity influences cancer progression and therapeutic response. We investigated the potential of tumour-infiltrating lymphocytes (TILs) around ductal carcinoma in situ (DCIS) in predicting recurrence and progression. CD4, CD8, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in DCIS from 198 patients was determined by immunohistochemistry. We correlated disease-free survival (DFS), clinicopathological parameters and biomarker expression with TIL density and CD4/CD8 ratio. High TIL density was associated with high nuclear grade (P<0.001), DCIS PD-L1 expression (P=0.008), TIL PD-L1 expression (P<0.001), oestrogen (ER) negativity (P<0.001), progesterone (PR) negativity (P<0.001), human epidermal growth factor receptor 2 (HER2) positivity (P=0.002) and triple negativity (P=0.001). TIL PD-L1 expression was associated with triple-negative DCIS (P=0.028). TIL density was associated with molecular subtypes (P<0.001). High CD4+ T cell density was associated with high nuclear grade (P=0.001), microinvasion (P=0.037), ER negativity (P<0.001), PR negativity (P=0.001), HER2 positivity (P=0.004), triple negativity (P=0.023) and PD-L1 expression in TILs (P<0.011). High CD4/CD8 ratio was associated with PD-L1 expression in DCIS (P=0.035) and TILs (P<0.001). DCIS with higher TIL density disclosed worse DFS (P=0.012) and was affirmed with multivariate analysis [95% confidence interval (CI)=1.109-2.554, hazard ratio (HR)=1.683, P=0.014]. Poorer DFS for ipsilateral invasive recurrence was found for DCIS with higher CD4+ T cell density (P=0.006) or CD4/CD8 ratio (P=0.02), confirmed by multivariate analysis for the former (95% CI=1.369-10.196, HR=3.736, P=0.01) and latter (95% CI=1.311-7.935, HR=3.225, P=0.011). DCIS with higher TIL density was associated with poorer prognostic parameters and predicted recurrence, while both CD4+ T cell density and CD4/CD8 ratio were associated with both recurrence and ipsilateral invasive recurrence.

Evaluation of predictor risk factors and calculation of a margin index for ipsilateral invasive recurrence following treatment of DCIS: A 15‐year observational study

Evaluation of predictor risk factors and calculation of a margin index for ipsilateral invasive recurrence following treatment of DCIS: A 15‐year observational study

Abstract P2-16-10: Disease free survival rate with dose dense Doxorubicin and Cyclophosphamide followed by weekly Paclitaxel with Trastuzumab and Pertuzumab (ddACTHP) in patients with HER2-positive early stage breast cancer: A single institution experience

Abstract Background: Trastuzumab and pertuzumab (HP) with standard chemotherapy is approved for use in the neoadjuvant setting. We performed a retrospective analysis of patients (pts) treated with dose-dense doxorubicin and cyclophosphamide (AC) → paclitaxel, trastuzumab, pertuzumab (THP) in the neoadjuvant setting followed by adjuvant anti-HER2 therapy. Here we report the invasive disease-free survival (iDFS) rate, defined as the time from surgery to the first documented event of ipsilateral invasive local recurrence, ipsilateral locoregional invasive recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause Methods: We abstracted medical records of patients who were treated with pertuzumab-based therapy in the neoadjuvant setting from September 1, 2013 to March 1, 2016. Charts were analyzed for pt demographics, stage of breast cancer, surgical data, pathologic complete response (pCR)(ypT0/is ypN0) and information on systemic therapy. Results: Charts from 236 pts were reviewed. One patient was excluded as she developed metastatic disease during NAC and did not have surgery. Median follow up was 3.8 years. Median age was 49 years (range 26-79 years). Of 235 pts, 215 (91%) had operable breast cancer (T1-3, N0-1, M0) of which 10 (4%) had clinical stage I disease (T1N0)]; 225 (96%) had stage II/III (T2-4d N0-3 M0); 18 (8%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 9 (3.8%) had inflammatory breast cancer (T4d, any N, M0). 153 (65%) and 82 (35%) had hormone receptor (HR)-positive and negative diseases, respectively. All patients had HER2-positive breast cancer defined as immunohistochemistry (IHC) 3+ and/or fluorescent in-situ hybridization (FISH) of ≥ 2.0. Median number of preoperative HP cycles was 5.5 (range 1-9). 121pts (51%) underwent mastectomy, 113 pts (48%) underwent lumpectomy, 1 patient underwent axillary dissection only. Out of 235 evaluable pts, 146 (62%) had pCR; 80/153 (52%) with HR-positive and 65/82 (78%) with HR-negative diseases had pCR, respectively. After a median follow-up of 3.8 years, there were 21 iDFS events and 10 OS events (n=9-Breast cancer, n=1-Acute Myeloid Leukemia). The 3-year iDFS was 91% (95% C.I. 88-95%) for all, 94% (95% C.I. 90-98%) for pts w/ pCR, and 87% (95% C.I. 80-95%) for pts w/ non pCR (p-value=0.051). The 3-year OS was 96% (95% C.I. 94-99%) for all, 98% (95% C.I. 95-100%) for pts w/ pCR, and 93% (95% C.I. 88-99%) for pts w/ non pCR (p-value=0.12) Conclusions: At our single center experience, the iDFS and OS for patients who received neoadjuvant ddACTHP followed by adjuvant anti-HER2 treatment was 91% and 96%, respectively. Patients with pCR had better outcomes than those with residual disease. Citation Format: Jasmeet C Singh, Sujata Patil, Larry Norton, Mark Robson, Chau Dang. Disease free survival rate with dose dense Doxorubicin and Cyclophosphamide followed by weekly Paclitaxel with Trastuzumab and Pertuzumab (ddACTHP) in patients with HER2-positive early stage breast cancer: A single institution experience [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 P2-16-10.

Abstract P4-07-04: Genomic analysis of paired DCIS and subsequent recurrence to assess clonal relatedness in screen detected DCIS

Abstract In order to understand the clonal relatedness of DCIS and subsequent recurrence, 40 patients with primary DCIS that developed a subsequent ipsilateral event (28 invasive and 12 pure DCIS) and 17 with a subsequent contralateral event, were identified within the Sloane project, a prospective national cohort study of DCIS embedded in the UK Breast Screening Programme. Median follow up was 5.4 years. All cases were reviewed by a breast histopathologist and macro-dissected to separate the DCIS or invasive disease from the normal tissue. DNA was extracted using the AllPrep DNA/RNA FFPE Kit (Qiagen). Somatic copy number aberrations were assessed using the HumanCytoSNP-12 BeadChip Kit (Illumina) and ASCAT. Targeted sequencing of a custom panel of 120 breast cancer-associated genes was performed using the SureSelect XT low input Target Enrichment System (Agilent Technologies). Prior to undertaking clonal related analysis, the relatedness of the samples was confirmed by cryptic relatedness analysis in PLINK v1.07. Clonal relatedness was assessed using two methods. The first used copy number data, available for all samples, where each breakpoint was compared between the pairs of tumours from the same individual and a concordance score calculated based on the presence of shared and unique breakpoints. The second used targeted sequencing, available on 23 paired ipsilateral cases and 7 contralateral paired recurrences, that was run through the previously described Clonality package (Biometrics. 2018). The results of the clonal relatedness analysis are summarized in below. Evidence of clonal relatedness on copy number and / or mutation analysisEquivocal on mutation analysisNot clonal on mutation or copy number analysisNot clonal by copy numberPrimary DCIS &amp; Ipsilateral invasive recurrence (28 pairs)1648Primary DCIS &amp; Ipsilateral DCIS recurrence (12 pairs)1101Primary DCIS &amp; Contralateral recurrence (16 pairs)1213Recurrent synchronous DCIS and invasive disease (12 pairs)1110 There were 2 cases where mutation data showed clear evidence of clonal relatedness but copy number did not, suggesting that the copy number approach may underestimate relatedness. There was also a proportion of cases where the pairs shared only one mutation and it was not possible to ascertain conclusively whether they were related, particularly when the shared mutation was a common driver mutation in PIK3CA that could have arisen by chance in unrelated samples. Of the 28 primary DCIS that developed ipsilateral invasive recurrence, 8 cases (29%) showed no evidence of clonal relatedness by one or other method. Of these 3 recurred in the original tumour bed, 3 in a different quadrant and in 2 the site of recurrence was unknown. Of the 12 primary DCIS that developed an ipsilateral DCIS recurrence 92% showed evidence of clonal relatedness and also recurred earlier than the invasive recurrences, mean time to recurrence 2.9 years compared to 4.15 years for recurrent invasive disease (P=0.04, Student’s t-test). The mutations that were most commonly shared between the primary and recurrence were PIK3CA and TP53, followed by KMT2C, CAD and DNAH2. As expected, the majority of the contralateral cases were unrelated. Of the 28 cases of DCIS that recurred ipsilaterally with invasive disease 16 had synchronous DCIS at the time of detection of the invasive disease and in 12 cases we were able to analyse the two synchronous components separately. In all cases the synchronous recurrent DCIS and invasive components showed evidence of clonal relatedness. This study shows synchronous DCIS and IDC are clonally related as is DCIS that recurs as DCIS in the majority of cases. However, 29% of DCIS that recurred as invasive disease showed no evidence of clonal relatedness. It remains to be seen whether exome sequencing of the unrelated lesions would reveal evidence of relatedness or whether they are truly new primaries. Citation Format: Vandna Shah, Anargyros Megalios, Rana Shami, Mathini Sridharan, Carolina Salinas de Souza, Tapsi Kumar, Karen Clements, Andrew Futreal, Sarah Pinder, Alastair Thompson, Elinor Jane Sawyer, Sloane Steering Committee, CRUK Grand Challenge PRECISION Team. Genomic analysis of paired DCIS and subsequent recurrence to assess clonal relatedness in screen detected DCIS [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 P4-07-04.

Higher density of stromal M2 macrophages in breast ductal carcinoma in situ predicts recurrence.

Immune response can affect tumour progression and treatment outcome. This study investigated the potential of stromal macrophages around ductal carcinoma in situ (DCIS) in predicting recurrence and progression. CD68 and CD163 expression of macrophages in DCIS from 198 patients was determined by immunohistochemistry. Disease free survival (DFS), clinicopathological parameters and biomarker expression were correlated with the densities of both CD68+ and CD163+ macrophages. High CD68+ macrophage density was associated with high nuclear grade (p < 0.001), oestrogen receptor (ER) negativity (p = 0.029), progesterone receptor (PR) negativity (p = 0.008) and human epidermal growth factor receptor 2 (HER2) positivity (p < 0.001). High CD163+ macrophage density was associated with high nuclear grade (p = 0.003), microinvasion (p = 0.01), ER negativity (p < 0.001), PR negativity (p = 0.001), HER2 positivity (p = 0.001) and triple negativity (p = 0.022). DCIS with higher CD68+ macrophage density disclosed significantly worse DFS for ipsilateral invasive recurrence (p = 0.004) and is affirmed by multivariate Cox regression analysis (95% CI 1.126-5.102, HR = 2.397, p = 0.023). DCIS with higher CD163+ macrophage density showed significantly worse DFS for both recurrence (p = 0.001) and ipsilateral invasive recurrence (p = 0.001). These findings, for CD163+ macrophage density, were affirmed by multivariate Cox regression analysis respectively for both recurrence (95% CI 1.210-2.293, HR = 1.880, p = 0.005) and ipsilateral invasive recurrence (95% CI 1.122-5.176, HR = 2.410, p = 0.024). This study demonstrated that DCIS with higher macrophage density was associated with poorer prognostic parameters, while DCIS with higher CD163+ macrophage density predicted both recurrence and ipsilateral invasive recurrence.

Ductal Carcinoma In Situ Management: All or Nothing, or Something in between?

Standard treatment for ductal carcinoma in situ (DCIS) is similar to that of invasive carcinoma. However, there is significant controversy regarding the true clinical implications of DCIS, and thus, the best management strategy. The aim of this review is to highlight relevant biology, diagnostic considerations, treatment options, and recent clinical trials. Outcomes are generally excellent with low recurrence rates and exceptional disease-specific survival. Outcomes can be predicted using various prognostic indicators and/or nomograms to guide treatment decisions. Ongoing clinical trials of active surveillance are based upon the argument that ipsilateral invasive recurrence is the most clinically meaningful endpoint. These trials seek to compare ipsilateral invasive cancer diagnoses between standard of care and close monitoring. Recent trials have revealed the marked heterogeneity in the biology of DCIS, offering an opportunity to de-escalate therapy for women at lowest risk for progression. DCIS also presents an ideal setting in which to test novel prevention agents. Future care of patients with DCIS will include biomarker-based risk assessment in order to better individualize treatment to biologic risk of invasive progression.

Endocrine Therapy for Ductal Carcinoma In Situ (DCIS) of the Breast with Breast Conserving Surgery (BCS) and Radiotherapy (RT): a Meta-Analysis.

The management of ductal carcinoma in situ (DCIS) with endocrine therapy remains controversial. A meta-analysis was conducted to evaluate the role of endocrine therapy for DCIS with breast conserving surgery (BCS) and radiotherapy (RT). A total of 7 articles with randomized controlled trials were included. Five articles compared the effects of BCS and RT followed by tamoxifen (TAM) or not (BCS + RT + TAM vs BCS + RT) and 2 compared the effects of TAM and anastrozole (ANA). TAM obviously reduced the rates of recurrence of ipsilateral breast cancer (IBCR), recurrence of contralateral breast cancer (CBCR), recurrence of ipsilateral invasive breast cancer (IBCR-INV) and recurrence of contralateral DCIS (CBCR-DCIS), and increased the rate of event-free survival (EFS). While ANA reduced the rates of CBCR and recurrence of contralateral invasive breast cancer (CBCR-INV). Patients with ANA had higher incidence of arthralgia, osteoporosis, hypercholesteremia, headache and vaginal dryness, but lower incidence of deep-vein thrombosis, pulmonary embolism, vasomotor or gynaecological, hot flushes, vaginal haemorrhage, vaginal discharge and vaginal candidiasis than TAM. In conclusion, DCIS patients with positive hormone receptors should be recommended to receive endocrine therapy. Selection of TAM or ANA is based on clinical characteristics and underlying disease of patients, as well as the side-effects of drugs.

Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project

BackgroundManagement of screen-detected ductal carcinoma in situ (DCIS) remains controversial. MethodsA prospective cohort of patients with DCIS diagnosed through the UK National Health Service Breast Screening Programme (1st April 2003 to 31st March 2012) was linked to national databases and case note review to analyse patterns of care, recurrence and mortality. ResultsScreen-detected DCIS in 9938 women, with mean age of 60 years (range 46–87), was treated by mastectomy (2931) or breast conserving surgery (BCS) (7007; 70%). At 64 months median follow-up, 697 (6.8%) had further DCIS or invasive breast cancer after BCS (7.8%) or mastectomy (4.5%) (p < 0.001). Breast radiotherapy (RT) after BCS (4363/7007; 62.3%) was associated with a 3.1% absolute reduction in ipsilateral recurrent DCIS or invasive breast cancer (no RT: 7.2% versus RT: 4.1% [p < 0.001]) and a 1.9% absolute reduction for ipsilateral invasive breast recurrence (no RT: 3.8% versus RT: 1.9% [p < 0.001]), independent of the excision margin width or size of DCIS. Women without RT after BCS had more ipsilateral breast recurrences (p < 0.001) when the radial excision margin was <2 mm. Adjuvant endocrine therapy (1208/9938; 12%) was associated with a reduction in any ipsilateral recurrence, whether RT was received (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41–0.80) or not (HR 0.68; 95% CI 0.51–0.91) after BCS. Women who developed invasive breast recurrence had a worse survival than those with recurrent DCIS (p < 0.001). Among 321 (3.2%) who died, only 46 deaths were attributed to invasive breast cancer. ConclusionRecurrent DCIS or invasive cancer is uncommon after screen-detected DCIS. Both RT and endocrine therapy were associated with a reduction in further events but not with breast cancer mortality within 5 years of diagnosis. Further research to identify biomarkers of recurrence risk, particularly as invasive disease, is indicated.