Invasive Breast Cancer Recurrence Research Articles

Invasive disease-free survival and brain metastasis rates in patients treated with neoadjuvant chemotherapy with trastuzumab and pertuzumab

Patients with HER2(+) early breast cancer (EBC) receiving neoadjuvant systemic therapy (NAST) have poorer outcomes if they have residual disease (RD). We analyzed IDFS and brain metastasis (BM) rates in patients with HER2(+) EBC treated with NAST and report the outcomes of patients with HER2(−) RD. Patients with HER2(+) EBC who received NAST between 1 Jan 2019 and 31 Jan 2022 were reviewed. IDFS was defined as the time from surgery until first occurrence of invasive breast cancer recurrence, distant recurrence, or death from any cause. The total cohort was 594 patients. pCR (ypT0/isN0) was achieved in 325(55%) and RD was seen in 269(45%) patients. In 269 patients with RD, 45(17%) did not have HER2 retesting and were excluded. In the remaining 224 patients, 143(64%) were HER2(+) and 81(36%) were HER2(−). With a median follow up of 24 months, 8 patients developed BM at initial recurrence, 4/325(1.2%) with pCR and 4/143(2.8%) with HER2(+) RD. IDFS events occurred in 22/594(3%) patients; 14/269(5%) in RD and 8/325(2%) in pCR (p = 0.04). There was no difference in IDFS between 9/143(6%) patients with HER2(+) RD or 5/81(6%) with HER2(−) RD (p = 0.10). Patients with RD had higher IDFS events than those with pCR. In those with RD, 36% lost HER2(+) status; IDFS events appeared similar in those with HER2(+) RD versus those with HER2(−) RD. The BM events seen in those with RD and pCR highlights the need for more effective therapy in NAST and adjuvant setting to minimize BM risk.

Recurrence in lobular carcinoma of the breast: A 14-year review.

The two most common types of breast cancer are invasive or infiltrating ductal carcinoma (IDC) and invasive or infiltrating lobular carcinoma (ILC) (Pestalozzi etal., J. Clin. Oncol., 26, 2008, 3006). Between 5% and 15% of invasive breast carcinomas are lobular carcinomas (Pestalozzi etal., J. Clin. Oncol., 26, 2008, 3006; Dossus and Benusiglio, Breast Cancer Res., 17, 2015, 37; Braunstein etal., Breast Cancer Res. Treat., 149, 2015, 555). The paucity of data relating to recurrence rates of lobular cancers prompted this study. A retrospective cohort study of all cases of lobular breast carcinoma reported to the Western Australia Cancer Registry with the clinical and pathological details between 2000 and 2014. Overall, 2463 subjects with a total of 2526 events of invasive lobular carcinoma of the breast. 11/2463 (0.45%) subjects met criteria for local recurrence of invasive lobular breast cancer, with an incidence of 1 in 224. There are clinical implications for the management and follow-up for patients with a diagnosis of lobular cancer of the breast. Due to the low recurrence rate, now, the standard practice in our institution does not offer magnetic resonance imaging (MRI) as part of the follow-up for ILC patients. Other centres should establish local recurrence rates to aid development of appropriate management protocols.

Use of beta-blockers in patients with ductal carcinoma in situ and risk of invasive breast cancer recurrence: a Swedish retrospective cohort study

BackgroundRetrospective observational studies suggest a potential role of beta-blockers as a protective strategy against progression and metastasis in invasive breast cancer. In this context, we investigated the impact of beta-blocker exposure on risk for progression to invasive breast cancer after diagnosis of ductal cancer in situ (DCIS).MethodsThe retrospective study population included 2535 women diagnosed with pure DCIS between 2006 and2012 in three healthcare regions in SwedenExposure to beta-blocker was quantified using a time-varying percentage of days with medication available. The absolute risk was quantified using cumulative incidence functions and cox models were applied to quantify the association between beta-blocker exposure and time from DCIS diagnosis to invasive breast cancer, accounting for delayed effects, competing risks and pre-specified confounders.ResultsThe median follow-up was 8.7 years. One third of the patients in our cohort were exposed to beta-blockers post DCIS diagnosis. During the study period, 48 patients experienced an invasive recurrence, giving a cumulative incidence of invasive breast cancer progression of 1.8% at five years. The cumulative exposure to beta-blocker was associated with a reduced risk in a dose-dependent manner, though the effect was not statistically significant.ConclusionOur observational study is suggestive of a protective effect of beta-blockers against invasive breast cancer after primary DCIS diagnosis. These results provide rationales for experimental and clinical follow-up studies in carefully selected DCIS groups.

Abstract PO2-11-03: A long-term follow-up of patients who interrupted endocrine therapy to become pregnant following breast cancer surgery

Abstract Introduction: Regarding discontinue adjuvant endocrine therapy to attempt pregnancy, Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer (POSITIVE) clinical trials have revealed temporary interruption of endocrine therapy to attempt pregnancy did not confer short-term risk of breast cancer events. However, that report involved a short observation period, longer-term follow-up is required. This study was aimed to evaluate the safety of endocrine therapy interruption with long-term followed-up data base. Methods: This was a retrospective study using surveying of medical chart data between June 2007 and November 2015 at St. Luke’s International Hospital. The subjects were 65 patients with estrogen-receptor positive primary breast cancer (clinical stage I-III) who had been performed fertility preservation prior to starting breast cancer treatment. Adjuvant endocrine therapy completion was defined as 120 months (10 years) and discontinuation was defined as < 120 months. Using the definition, we classified the patients into an endocrine therapy interruption-group and a continuation-group. The primary outcome was the breast cancer free interval (BCFI). We defined breast cancer events as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer during follow-up. Results: Median follow-up period was 110 (range, 36–181) months. The number of adjuvant endocrine therapy interruption-group was 30 and continuation-group was 35. Among 65 patient, the mean patient age in the interruption vs. continuation groups were as follows: 38(range, 26-48) years vs. 36.5 (range, 26–45) years at breast cancer diagnosis and HER2 positive breast cancer was identified in 4 (11.4%) vs 4 (13.3%) patients. Clinical stages were Stage I, 9 (30%) vs. 11 (31.4%) patients; Stage II, 18 (60%) vs. 18 (51.4%) patients; and Stage III, 3 (10%) vs. 6 (17.1%) patients. Chemotherapy was administered in 17 (56.7%) and 23 (65.7%) patients, respectively. The median duration of endocrine therapy before interruption was 25.5 months: 3 (10%) patients received endocrine therapy for 0–18 months, 16 (53.3%) for 18–30 months, and 11 (36.7%) for >30 months. The BCFI was 124 and 119 months in the interruption and continuation groups, respectively (p = 0.16). There were 6 (20%) and 9 (25.7%) breast cancer events in the interruption-group and continuation-group, respectively (p = 0.4). All the pregnancies were in the endocrine therapy interruption group (17 pregnancies, 16 deliveries), with one pregnancy involving the delivery of twins. Three pregnancies were spontaneous. Endocrine therapy was resumed in 16 (59.3%) patients in the interruption-group (median time to resumption, 20.5 months). One patient developed distant metastasis during endocrine therapy interruption period. Conclusion: Among patients who performed fertility preservation prior to starting breast cancer treatment, our long-term follow-up data, almost 9 years, suggested that the BCFI was not statistically different between endocrine therapy interruption-group and continuation-group. A limitation of this study is that only three cases of Stage III breast cancer were included in the interruption group. Therefore, we consider that careful decisions should be made regarding interruption of endocrine therapy. Citation Format: Risa Kasahara, Atsuko Kitano, Fumi Akitani, Kyoko Shiota, Kumiko Kida, Junko Takei, Atsushi Yoshida. A long-term follow-up of patients who interrupted endocrine therapy to become pregnant following breast cancer surgery [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-03.

Abstract PO4-22-05: Changes in Treatment Recommendation for Patients with Ductal Carcinoma In Situ Using a 7-Gene Predictive Biosignature: Analysis of the PREDICT Australia Study

Abstract Background: The role of adjuvant radiotherapy (RT) following breast-conserving surgery (BCS) for women with ductal carcinoma in situ (DCIS) remains controversial. Although there is Level 1 evidence supporting the use of RT to reduce the risk of local recurrence, prognostic and predictive tools are needed to better stratify the individual risks and benefits of RT. The 7-gene predictive DCIS biosignature provides a validated score (DS) for women receiving BCS that assesses 10-year risk of DCIS recurrence and development of invasive breast cancer with and without adjuvant RT. We established a registry to evaluate the decision impact of the 7-gene predictive biosignature on DCIS treatment recommendations in an Australian setting. Methods: The PREDICT study is a prospective, multi-institutional registry for patients who received DCISionRT testing as part of their routine care. The registry includes females 26 and older who are diagnosed with DCIS and are candidates for BCS and eligible for RT. Treating physicians completed treatment recommendation forms before and after receiving test reports to capture surgical, radiation and hormonal treatment (HT) recommendations and patient preferences. Results: This planned interim analysis was performed in 483 patients with complete data treated at 43 clinical sites in Australia. The median age of patients was 61 years, 19% were 50 or younger, nuclear grade was high in 51%, and tumor size was 2.5 cm or greater in 15%. Overall, RT recommendation (yes/no) was changed for 41% of women and HT recommendation was changed for 9% after testing with a net reduction in recommended RT of 14% (66% pre-assay to 52% post-assay p< 0.001). Of patients recommended to receive RT pre-test, 42% were recommended to not receive RT post-test and of the patients recommended to not receive RT pre-test, 40% were recommended to receive RT post-test. The post-test RT recommendation rate increased with increasing DS score (< 2, 2-4, >4), with 9% of patients recommended RT for DS< 2, 62% for DS 2-4, and 100% for DS 4-10. The use of the test resulted in different RT recommendations than with clinicopathology alone, where RT recommendations were changed for 49%, 37%, and 34% for women of age< 50 yrs, with Grade 3 DCIS, or with DCIS > 2.5 cm, respectively. Collectively, this suggests that physicians had a high confidence in the test results when making their final treatment recommendations with the test results. Conclusions: This analysis demonstrates that the use of the 7-gene predictive biosignature resulted in significant changes in recommendations to add or omit RT in this study of 483 women. The integration of DCISionRT into the clinical decision-making processes has a substantial impact on recommendations to personalize care and prevent over- or under-treatment. Table 1: Impact of DCISionRT on Adjuvant Radiation Recommendations by Clinicopathologic Features Citation Format: Yvonne Zissiadis, Bruce Mann, David Speakman, Christobel Saunders, Marcus Dreosti, Christopher Pyke, Daniel De Viana, Melissa Bochner, James French, Sally Baron-Hay, Karuna Mittal, Steven Shivers, Troy Bremer. Changes in Treatment Recommendation for Patients with Ductal Carcinoma In Situ Using a 7-Gene Predictive Biosignature: Analysis of the PREDICT Australia Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-22-05.

A tricky singular papular peri‐cicatricial mammarian lesion

AbstractBreast cancer represents the most common malignancy in women worldwide. In most cases, metastasis is the leading cause of mortality. Early diagnosis is still challenging despite standardised, government‐led screening programs, but is crucial in achieving improved survival rates. Additionally, a deeper understanding of the metastatic potential of breast cancer is critical for developing therapeutic interventions to combat widespread disease. Cutaneous metastasis from underlying breast carcinoma is uncommon as the first manifestation of visceral malignancies and is commonly observed in advanced‐stage malignancies, often associated with poor prognosis, and a prompt, precise tissue diagnosis is mandatory. A high index of suspicion in oncologic patients is required to diagnose these lesions, as they can mimic benign skin manifestations and clinical findings may be subtle and going unnoticed. We report on a case of a 76‐year‐old female patient presenting to our non‐invasive diagnostic outpatient clinic with an unusual cutaneous presentation, as an early sign of locally advanced invasive ductal carcinoma breast cancer recurrence. The aim of our article is to underline the importance of the dermatologist in the multi‐disciplinary oncologic diagnostic process, including non‐invasive imaging evaluation of cutaneous lesions, especially insidious breast carcinomas. Dynamic optical coherence tomography (D‐OCT) is not routinely used due to its cost, therefore lesion's aspect has not been completely described, consequently, the correct evaluation of skin architecture appearance can add important information, especially in cutaneous oncology where it can help in early diagnosis or cancer recurrency. OCT may contribute to the detection of subclinical cutaneous manifestations of cancer or recurrence, in particular, when they are difficult to differentiate clinically from benign lesion. In the case we described, OCT of suspected lesion showed the loss of the DEJ with solid nests and irregular vessels.

265 (PB-081) Poster - Clinical validation of an Artificial-intelligent (AI) enabled digital test using the patients diagnostic breast biopsy to predict invasive breast cancer recurrence within 6-years

265 (PB-081) Poster - Clinical validation of an Artificial-intelligent (AI) enabled digital test using the patients diagnostic breast biopsy to predict invasive breast cancer recurrence within 6-years

Microcalcification crystallography as a potential marker of DCIS recurrence

Ductal carcinoma in-situ (DCIS) accounts for 20–25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer

BackgroundProspective data on the risk of recurrence among women with hormone receptor–positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking.MethodsWe conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial.ResultsAmong 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort.ConclusionsAmong select women with previous hormone receptor–positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.)

Abstract 3354: Isolation and characterization of circulating tumor cells from ductal carcinoma in situ patients using label free technology

Abstract Ductal carcinoma in situ (DCIS) is an early form of breast cancer that has traditionally been characterized by neoplastic cells that are still confined to the mammary ducts. The 20-year breast cancer mortality rate following a DCIS diagnosis, with or without treatment, remains at 3.3%. Despite the overall success in DCIS treatments preventing local invasive breast cancer recurrence, there are still a substantial number of women who, after a DCIS diagnosis, die from metastatic breast cancer. We currently lack predictive tools to identify the high-risk patients who would benefit most from treatment. Emerging clinical and experimental evidence suggest that breast cancer cells may disseminate throughout the body very early in carcinogenesis. These circulating tumor cells (CTCs), rare cancer cells that are shed from the primary tumor into blood, may offer insights into early cancer progression and help identify high-risk patients. Because CTCs can extravasate from blood into tissue and form secondary tumor sites or dormant niches, they are potential biomarkers of metastasis and recurrence. The labyrinth, a high-throughput inertial microfluidic device, has previously demonstrated success in isolating CTCs through inertial separation due to their larger size when compared to white blood cells. Compared to antigen-based isolation technology, inertial microfluidic devices can isolate heterogeneous CTCs with a variety of surface proteins. Using this technology, we isolated and identified CTCs (DAPI+/Pan cytokeratin+/CD45- cells) in 63.2% (12/19) of DCIS patients with an average of 1.27 CTCs per five mls of blood compared to 0.259 CTCs per five mls of blood found in healthy controls (p =0.0078, unpaired t-test). The majority of healthy controls (15/19) had no detectable CTCs. Additionally, immunofluorescence staining showed that 10.5% of CTCs were EpCAM (Epithelial cell adhesion molecule) positive and 26.3% were positive for vimentin, a mesenchymal marker. Single-cell qPCR revealed potential CTCs with no gene expression of traditional white blood cell markers such as CD45, CD20, CD11B, and CD3D. The majority of these cells expressed proliferation (PKM2, TIMP1) and mesenchymal (SPARC, TGFβ1) markers, which can contribute to the cells’ ability to migrate and metastasize. Preliminary targeted DNA sequencing of eight CTC-enriched blood samples identified copy number variations previously associated with higher grade and poorly differentiated DCIS, and single nucleotide variations previously found in DCIS samples (NOTCH1 c.7541_7542del). Ultimately, this study suggests that DCIS generates CTCs prior to microinvasion. CTC isolation and detection may serve as a biomarker for high-risk DCIS and may also be used to explore mechanisms of early cancer dissemination. Citation Format: Brittany Rupp, Brooke Thanasiu, Neha Nagpal, Yan Hong, Dean E. Brenner, Kirsten Tuck, Kirk Herman, Fariba Behbod, Justin Colacino, Max Wicha, Sunitha Nagrath. Isolation and characterization of circulating tumor cells from ductal carcinoma in situ patients using label free technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3354.

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

Abstract GS4-08: 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer

Abstract We have previously shown in a phase 3 trial that tamoxifen 5 mg/day for 3 years decreased by 52% the incidence of recurrence of invasive breast cancer or DCIS after a median follow-up of 5.1 years in women with excised non invasive breast disease, including atypical ductal hyperplasia, DCIS or LCIS (DeCensi et al. JCO 2019; 37:1629). Toxicity was negligible with only an extra hot flash per day in the tamoxifen arm compared with the placebo arm. These findings were incorporated into the ASCO clinical practice guidelines for breast cancer risk reduction as an alternative option to standard doses and duration of tamoxifen or aromatase inhibitors in women with non-invasive disease (Visvanathan et al. JCO 2019; 37:3152). In the present study we update the findings on breast cancer recurrence after a median of 9.14 years (interquartile range, IQR, 7.16-10.73) and a total of 10.57 person years of follow up to see if the treatment effect is retained with more events and after a median of approximately 6 years from treatment cessation. We conducted a national multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. Between November 1, 2008, and March 31, 2015, 1,160 women were screened and 500 aged 75 years of age or younger were included in the study. Women with high-grade or comedo/necrotic DCIS received adjuvant radiotherapy of 50 Gy in 25 courses. The mean age was 54 years (standard deviation, 9 years), and 55% of participants were postmenopausal. The mean (SD) body mass index, kg/m2, was 25.7 (4.8) on tamoxifen and 25.3 (4.2) on placebo. Twenty percent had ADH, 11% had LCIS, and the remaining 69% had DCIS. After a median follow-up of 9.14 years, there were 22 neoplastic events (invasive breast cancer or DCIS) with tamoxifen and 37 with placebo (annual rate 11.09, 95% CI, 7-30-16.84 on T vs 19.71, 95% CI, 14.28-27.21 on P per 1,000 person-years; hazard ratio, 0.56; 95% CI, 0.33 to 0.95; P = .03), which resulted in a 5-year number needed to treat of 18. Overall, 71% of the recurrences were invasive breast cancer. The follow-up was updated with the most recent visit within 12 months in two thirds of the participants, so an update of all participants will be performed by Sept 30th with full analysis of neoplastic events, annual risk rate ratio, serious adverse events and deaths. Moreover, an updated analysis of potential effect modifiers will be conducted, including menopausal status, baseline estradiol levels, menopausal symptoms, BMI, smoking status and Ki-67 of the primary lesion. In conclusion, our findings indicate that low dose tamoxifen given for 3 years still significantly prevents recurrences from non-invasive breast cancer after a median of 6 years from treatment cessation, providing a valid prevention/interception option in this disease group. Supported by Ente Ospedaliero Ospedali Galliera, Genova, Italy, the Italian Ministry of Health (RFPS-2006-1-339898), the Italian Association for Cancer Research (IG 2008 Grant No. 5611), and the Italian League against Cancer (LILT 7-08). Citation Format: Andrea De Censi, Matteo Lazzeroni, Matteo Puntoni, Luca Boni, Aliana Guerrieri Gonzaga, Tania Buttiron Webber, Marianna Fava, Irene Maria Briata, Livia Giordano, Maria Digennaro, Laura Cortesi, Fabio Falcini, Franca Avino, Francesco Millo, Katia Cagossi, Elisa Gallerani, Alessia De Simone, Anna Cariello, Giuseppe Aprile, Maria Renne, Bernardo Bonanni. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-08.

Abstract P2-21-03: Unique Collagen Peptide Signatures between Ductal Carcinoma in Situ and Invasive Breast Cancer by Mass Spectrometry Tissue Imaging

Abstract Ductal carcinoma in situ (DCIS) is characterized by inter-tumor heterogeneity that poses a therapeutic challenge due to its unpredictable recurrence and progression to invasive breast cancer (IBC). Recent publications have implicated the crucial role of the tumor microenvironment particularly stromal differences between DCIS patients who progress to IBC (progressors) and those that do not (non-progressors). However, spatial regulation of the collagen proteome has yet to be investigated in the context of disease progression in DCIS. In this study, we hypothesized that the collagen proteome was significantly altered between DCIS and IBC and that differentiating collagen peptide signatures could be related to clinical outcomes. Our initial studies investigated collagen peptide signatures in lumpectomies (n=13) annotated as DCIS, DCIS and invasive ductal carcinoma (IDC), or IDC only. We leveraged our previously published method for spatial imaging of collagen proteomics on tissue to report collagen types and collagen post-translational modifications including 40 other extracellular matrix (ECM) proteins involved in the regulation of collagen fibers. Over 1000 peaks were found to be linked to annotated pathologies or adjacent regions. Initial comparison of DCIS to IDC lesions demonstrated 63 differentially expressed peaks between these regions by unpaired, two-tailed t-test (p< 0.001). Image segmentation of the 315,541 pixels demonstrated 16 high-level hierarchical groups designating unique spatially localized ECM proteomic groups. Notably, these groups overlaid with histopathological features and pathological annotations. Next, we investigated collagen peptide signatures in a subset of DCIS samples from the Resource of Archival Breast Tissue (RAHBT) (n=37). Samples were histologically diverse within the tissue microarrays, with cribriform, micropapillary, papillary, solid, and comedo necrosis architectural patterns. In our preliminary analysis, we found two peptide peaks that could distinguish the solid subtype (n=22) from comedo necrosis (n=4) and one peak that could discriminate between the cribriform (n=8) and solid subtype (n=22) by area under the receiver operating curve (AUROC)≥0.75 and Wilson/Brown t-test (p< 0.05). Evaluated per clinical outcome, four ECM peptides showed significantly different peak intensities in progressors with IBC recurrence (n=7) compared to non-progressors (n=26) (AUROC≥0.75; Wilson/Brown t-test p< 0.05). One peptide had significantly different peak intensities between progressors with contralateral IBC recurrence and DCIS recurrence (n=5) and non-progressors (n=26) (AUROC≥0.75; Wilson/Brown t-test p< 0.05). Overall, the data suggest that unique collagen signatures in DCIS could be useful for understanding recurrence and progression to IBC. Further investigation of the spatial distribution of the collagen proteome within DCIS pathologies and relative to clinical outcome is warranted. Citation Format: Taylor S. Hulahan, Elizabeth N. Wallace, Siri H. Strand, Graham A. Colditz, E Shelley Hwang, Robert West, Laura Spruill, Jeffrey Marks, Richard R. Drake, Peggi M. Angel. Unique Collagen Peptide Signatures between Ductal Carcinoma in Situ and Invasive Breast Cancer by Mass Spectrometry Tissue Imaging [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-21-03.

Abstract P4-02-02: Changes in treatment recommendation for patients with Ductal Carcinoma In Situ using a 7-gene predictive biosignature: Analysis of the PREDICT Study

Abstract Background: The role of adjuvant radiotherapy (RT) following breast conserving surgery (BCS) for women with ductal carcinoma in situ (DCIS) remains controversial. Although there is Level 1 evidence supporting the use of RT in reducing the risk of local recurrence, prognostic and predictive tools are needed to better stratify individual risks and benefits of RT. The DCISionRT® Test (PreludeDx, Laguna Hills, CA) is a 7-gene predictive biosignature that uses tumor biology in conjunction with clinicopathologic factors. The test provides a validated score (DS) for women receiving BCS that assesses 10-year risk of DCIS recurrence and development of invasive breast cancer with and without adjuvant RT. We established a registry to evaluate the decision impact of the 7-gene predictive biosignature on DCIS treatment recommendations. Methods: The PREDICT study is a prospective, multi-institutional registry for patients who received DCISionRT testing as part of their routine care. The registry includes females 26 and older who are diagnosed with DCIS and are candidates for BCS and eligible for RT or systemic therapy. Treating physicians completed treatment recommendation forms before and after receiving test reports to capture surgical, radiation and hormonal treatment (HT) recommendations and patient preferences. The primary endpoint is to identify the proportion of patients where testing led to a change in RT recommendation. Additional analyses include changes in recommendations in patient subgroups based on clinicopathologic factors or clinician specialty. Results: Analysis was performed in 2,308 patients treated at 63 clinical sites. The median age of patients was 62 years, 18% were 50 or younger, nuclear grade was high in 33%, and tumor size was 2.5 cm or greater in 11%. Test results were DS Low Risk (DS ≤ 3) for 63% of women and 37% were DS Elevated Risk (DS > 3). Overall, RT recommendation (yes/no) was changed for 38% of women after the 7-gene biosignature testing and HT recommendation was changed for 11%. There was a net decrease in RT recommendation from 71% pre-assay to 53% post-assay (p< 0.001), where RT recommendations decreased 53% in DS Low Risk patients but increased 25% in DS Elevated Risk patients. Surgeons were more likely to change their RT recommendation (47%) than radiation oncologists (35%). When test results indicated DS Elevated Risk, both surgeons (79%) and radiation oncologists (88%) were likely to recommended RT, but when the results were DS Low risk, surgeons were more likely than radiation oncologists to recommend omitting RT (82% vs. 60%, respectively). Compared to traditional clinicopathologic features, the factor most strongly associated with RT recommendation was the biosignature result with other factors of importance being patient preference, tumor size and grade. Conclusions: This analysis demonstrates significant changes in recommendations to add or omit RT based on the 7-gene predictive biosignature in 2,308 patients. The integration of DCISionRT into clinical decision processes has substantial impact on recommendations aimed at optimal management to prevent over- or under-treatment. Table 1. Impact of the 7-gene predictive biosignature on adjuvant radiation recommended by clinicopathologic features. Citation Format: Pat Whitworth, Steven C. Shivers, Chirag Shah, Rakesh Patel, Karuna Mittal, Troy Bremer, Charles Cox. Changes in treatment recommendation for patients with Ductal Carcinoma In Situ using a 7-gene predictive biosignature: Analysis of the PREDICT Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-02.

Cyclin A2 and Ki-67 proliferation markers could be used to identify tumors with poor prognosis in African American women with breast cancer.

Diagnosed invasive breast carcinomas in African American patients are more aggressive compared with those in Caucasian patients and diagnosed at later stages of the disease with higher grade tumors. Despite advances in breast cancer systemic treatment, new prognostic and predictive biomarkers are still needed. Therefore, potential biomarkers were chosen to correlate with different subtypes, recurrence, and survival of invasive breast cancer in a cohort of African American women. Eight protein biomarkers (ER, PR, HER2, Cyclin A2, Cytokeratin 5, Vimentin, Bcl2, and Ki-67) were evaluated using tissue microarrays (TMAs) and immunohistochemistry (IHC). The IHC results from TMAs were analyzed by both supervised and unsupervised clustering methods. The predictive clusters for the supervised and unsupervised methods were compared for agreement with the empirical classification. Kappa values were used to determine the overall percent correct clusters and agreement between specific clusters. Chi-square statistics was used to examine the association between hierarchical and multinomial logistic clustering methods. Five subtypes of breast tumors with distinct protein expression patterns were identified among the studied 166 breast tumors. Luminal B tumors have been distinguished from luminal A tumors by staining for cell cycle proteins Cyclin A2 and Ki-67, which promote cell proliferation. Forty-nine percent were stained positive for Cyclin A2, 39.2% positive for Ki-67, and 37% positive for both Cyclin A2 and Ki-67. The age of patients did not show any significant effect whether five (p-value= 0.576) or eight (p-value= 0.605) biomarkers were used, which indicating that age did not have any influence on the classification of the subtypes. Ninety percent of the thirty triple negative tumors were positive for Cyclin A2 or Ki-67 or both. Six-year overall survival was better for luminal A tumors (76%) than luminal B tumors (71%). Likewise, six-year relapse-free survival was better for luminal A tumors (76%) than luminal B tumors (29%). Discovery of molecular markers such as Cyclin A2 and Ki-67, and subtypes that are most prevalent in African Americans could lead to a better understanding of the factors contributing to higher morbidity and mortality in this group and to aid in decision-making to offer earlier treatment.

Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts.

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

Abstract B019: Discrete regulation of the collagen proteome among pathological features in DCIS and invasive breast cancer by mass spectrometry tissue imaging

Abstract Ductal carcinoma in situ (DCIS) is characterized by inter-tumor heterogeneity that poses a therapeutic challenge due to its unpredictable recurrence and progression to invasive breast cancer (IBC). In recent publications, collagen stromal differences have been reported between patients that progressed to IBC (progressors) and those that did not (non-progressors). However, details on the role spatial regulation of the collagen proteome might play in this progression have yet to be studied. Here, we investigated the pathological distribution of collagen post-translational modifications in a cohort of patients classified as progressors with ipsilateral IBC recurrence compared to non-progressors. Previously published methods for collagen proteomics by targeted tissue mass spectrometry imaging were used. The method reports collagen types and post-translational modifications within the collagen triple-helical region as well as approximately 40 other extracellular matrix (ECM) proteins involved in the regulation of collagen fibers. Initial studies investigated collagen variation in lumpectomies (n=7) with DCIS, DCIS plus invasive ductal carcinoma (IDC) or IDC only. Over 590 peptides were found to be linked to annotated pathologies. A preliminary comparison of DCIS (n=2392 spectra) to IBC (n=4696 spectra) using area under the receiver operating curve (AUROC) ≥0.85 demonstrated that 47 peptides could individually discriminate between DCIS and IBC in this limited cohort. Image segmentation of the 405,652 pixels demonstrated 11 high-level hierarchical groups designating unique spatially localized ECM proteomic groups; these groups overlaid with histopathological features and pathological annotations. A total of 87 samples from the Resource of Archival Breast Tissue (RAHBT) matched with clinical characteristics were also investigated. Cores were histologically diverse within the tissue microarrays, with cribriform, micropapillary, papillary, solid, and comedo necrosis architectural patterns. Initial results suggest certain peptides may differentiate between non-progressors and progressors with ipsilateral IBC recurrence. Our current work focuses on correlating collagen signatures to mixed pathologies and the cellular content of cores. Further investigation of the collagen proteome is warranted. Overall, the data suggest unique collagen signatures in DCIS that could be useful for understanding recurrence and progression to IBC. Citation Format: Taylor S. Hulahan, Elizabeth N. Wallace, Siri H. Strand, Robert Michael Angelo, Graham Colditz, Eun-Sil Shelley Hwang, Robert West, Laura Spruill, Jeffrey R. Marks, Richard R. Drake, Peggi M. Angel. Discrete regulation of the collagen proteome among pathological features in DCIS and invasive breast cancer by mass spectrometry tissue imaging [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 B019.

Width of excision margins after breast conserving surgery for invasive breast cancer and distant recurrence and survival

One premise of cancer treatment is that if a tumour is cut out but tumour cells remain present or close to the edges (of the cut), the risk of cancer...

Radiomics Nomogram: Prediction of 2-Year Disease-Free Survival in Young Age Breast Cancer.

Simple SummaryBreast cancer in young women under 40 years of age shows a poor prognosis, and its treatment is difficult due to premenopausal status and fertility preservation. The early prediction of prognosis of young age breast cancer would be helpful for planning treatment and postoperative surveillance. In this study, the radiomics-based nomogram for the prediction of recurrence shows good predictive ability, especially 2-year disease-free survival after surgery. Several radiomics features presumed to be unique imaging features of young age breast cancer were also observed: tumor homogeneity and tumor sphericity. As these radiomics features are quantitative parameters extracted through the texture analysis of breast MRI, they may reflect the information of tumors more objectively, such as the tumor microenvironment. Furthermore, these results will be the basis for identifying the unique biology of young age breast cancer through multi-omics studies such as radio-genomics.This study aimed to predict early breast cancer recurrence in women under 40 years of age using radiomics signature and clinicopathological information. We retrospectively investigated 155 patients under 40 years of age with invasive breast cancer who underwent MRI and surgery. Through stratified random sampling, 111 patients were assigned as the training set, and 44 were assigned as the validation set. Recurrence-associated factors were investigated based on recurrence within 5 years during the total follow-up period. A Rad-score was generated through texture analysis (3D slicer, ver. 4.8.0) of breast MRI using the least absolute shrinkage and selection operator Cox regression model. The Rad-score showed a significant association with disease-free survival (DFS) in the training set (p = 0.003) and validation set (p = 0.020) in the Kaplan–Meier analysis. The nomogram was generated through Cox proportional hazards models, and its predictive ability was validated. The nomogram included the Rad-score and estrogen receptor negativity as predictive factors and showed fair DFS predictive ability in both the training and validation sets (C-index 0.63, 95% CI 0.45–0.79). In conclusion, the Rad-score can predict the disease recurrence of invasive breast cancer in women under 40 years of age, and the Rad-score-based nomogram showed reasonably high DFS predictive ability, especially within 2 years of surgery.

Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5–10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.