Advanced Breast Care

Abstract Background: The risk of distant recurrence gene signature, MammaPrint (MP), together with the molecular subtyping gene signature, BluePrint (BP), stratifies breast tumors into Luminal A, Luminal B, HER2, and Basal subtypes, independent of immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) expression. In the Neoadjuvant Breast Registry Symphony Trial (NBRST), MP and BP identified patients likely to respond to neoadjuvant treatment with higher accuracy compared to conventional methods. Here, we report 5-year follow up (FU) data in breast cancer (BC) patients from the NBRST registry with discordant clinical and genomic subtyping.Methods: This prospective study enrolled 1072 early-stage BC patients from 2009-2014 who received MP and BP testing. Patients received neoadjuvant therapy following standard of care and consented to 5 years post-surgery FU. IHC determined hormone receptor (HR) status, including ER and PR, and IHC and/or FISH determined HER2 status. Median FU for distant metastasis free survival (DMFS) and overall survival (OS) was 4.6 and 5 years, respectively. Differences in DMFS and OS was assessed by Kaplan Meier analysis and log-rank test.Results: Overall, BP reclassified 22% of tumors into different molecular subtypes compared to IHC/FISH (Table). BP reclassified 17% of ER+HER2- tumors as BP Basal, with higher pathological complete response (pCR) rates compared to ER+/BP Luminal tumors (36% vs. 4%). ER+/BP Basal patients had similar pCR rates as triple negative BC (TNBC)/BP Basal patients (36% vs. 37%) following neoadjuvant treatment, and pCR correlated with improved survival outcomes. The 5-year DMFS and OS probabilities were lower in ER+/BP Basal patients compared to TNBC/BP Basal patients and were substantially lower compared to ER+/BP Luminal patients (P < 0.001). There were 106 HR-HER2+ patients, of whom BP reclassified 23.6% to Basal and 2.8% as Luminal B; the remaining 73.6% were confirmed HER2 by BP. The 5-year DMFS and OS probabilities were worse in HER2+/BP Basal patients compared to HER2+/BP HER2 patients. Of 142 triple positive (TP, ER+PR+HER2+) patients, BP classified 55% as Luminal, 39% as HER2, and 6% as Basal, with higher pCR rates observed in BP Basal and BP HER2 tumors compared to BP Luminal. The 5-year DMFS and OS probabilities were substantially lower in TP/BP Basal patients compared to TP/BP HER2 and TP/BP Luminal patients (P < 0.05 and P < 0.04). Of clinical HER2+ patients (HR+ or HR-) that received pertuzumab, patients that reclassified as BP Basal had worse OS compared to BP HER2 patients (P < 0.04).Conclusion: ER+HER2- and HER2+ patients that reclassified as BP Basal are more likely to achieve pCR and have improved survival, demonstrating the clinical utility of BP in the neoadjuvant setting. These patients may benefit from optimized chemotherapy used for TNBC, including novel emerging treatments such as PD-1 and PARP1 inhibitors, in addition to HER2-targeted therapy. Furthermore, HER2+ tumors that were confirmed HER2 by BP may have high response rates to regimens containing TDM-1. Lastly, BP identified a subgroup of triple positive BC patients, who reclassified as BP Luminal, that may avoid overtreatment. Overall, molecular subtyping using MP and BP is more accurate in stratifying patients and predicting treatment responses and 5-year disease outcomes than conventional methods and thus, facilitates successful treatment decisions. Clinical subtypeFrequency of BP classificationBluePrint subtypepCR%5-yr DMFS (95% CI)5-yr OS (95% CI)TNBC (n=236)0.42% (1/236)Luminal A100% (1/1)N/AN/A2.54% (6/236)Luminal B16.67% (1/6)N/AN/A1.27% (3/236)HER233.33% (1/3)N/AN/A95.76% (226/236)Basal36.73% (83/226)100% (pCR)100% (pCR)60.5% (50.5-69.1)(non-PCR)64.3%(52.1-71.2) (non-PCR)ER+HER2- (n=520)28.84% (152/520)Luminal A1.97% (3/152)91.1% (84.0-95.2)94.6% (88.3-97.6)52.37% (276/520)Luminal B5.43% (15/276)75.2% (69.0-80.4)84.5% (79.0-88.7)1.33% (7/520)HER214.29% (1/7)N/AN/A17.46% (92/520)Basal35.9%(33/92)84.1% (67.8-92.5) (pCR)86.3% (70.1-94.1) (pCR)54.6% (42.0-65.5) (non-pCR)57% (43.7-68.2) (non-pCR)HR-HER2+ (n=106)2.83% (3/106)Luminal B66.67% (2/3)100%100%73.59% (78/106)HER269% (54/78)82.8% (69.9-90.5)88.6% (76.0-94.8)23.58% (25/106)Basal40% (10/25)79.0% (52.5-91.7)79.0% (52.5-91.7)Triple Positive (n=142)12.68% (18/142)Luminal A22.22% (4/18)88.8% (76.5-94.8)94.5% (83.8-98.2)42.25% (60/142)Luminal B11.67%(7/60)38.73% (55/142)HER244.44% (24/55)87.5% (72.0-94.7)97.9% (83.8-98.2)6.34% (9/142)Basal55.56%(5/9)62.5% (22.9-86.1)70.0% (22.5-91.8)HER2+ (HR+ or HR-)treated with pertuzumab (n=105)28.6%(30/105)Luminal37% (11/30)84.7% (63.8-94.1)92.2%(71.8-98.0)57%(60/105)HER282% (49/60)91.4% (78.3-96.8)92.9%(79.2-97.7)14%(15/105)Basal40% (6/15)66.0%(31.1-86.3)64.0% (29.1-85.1) Citation Format: Pat Whitworth, James Pellicane, Jr, Paul Baron, Peter Beitsch, Laura Lee, Michael Rotkis, Angela Mislowsky, Carrie Dul, Charles Nash, Bichlien Nguyen, Mary Murray, Paul Richards, Mark Gittleman, Stephanie Akbari, Shiyu Wang, Andrea Menicucci, Erin B Yoder, Lisa Blumencranz, William Audeh. Molecular subtyping by BluePrint improves prediction of treatment responses and survival outcomes in patients with discordant clinical and genomic classification [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 PS4-04.

The fetus has always been an enigma to artists and scientists alike, enthralled by the mysteries of developing human life. Prior to the availability of fetal imaging, they were relentless in their pursuit to get a glimpse of, and a better understanding of, the developing fetus. From Da Vinci's sketches, depicting the fetus within a cadaver in the 1510s, to Hunter's Anatomia Uteri Humani in 1774, where he resorted to fetal etchings from pregnant human cadavers, we have humanity's earliest documented preserved fetal images. In 1794, two decades after Hunter, Lazzaro Spallanzani discovered that bats use ‘echolocation’ to travel in the dark, thereby laying the foundations for the physics of ultrasound. It took another 148 years for Dussik to pioneer diagnostic ultrasound, in 1942, by transmitting ultrasonic beams through the head in order to diagnose brain tumours. In 1952, the American Institute of Ultrasound in Medicine was founded (see the History of Ultrasound at http://ultrasoundschoolsguide.com/history-of-ultrasound/). In fetal medicine, the earliest forms of ‘modern’ imaging were roentograms, first used in the early 20th century. Although the risks were well noted, the utility in diagnosing pregnancy, determining the number of fetuses and uterine lie, and in diagnosing skeletal dysplasias were recognised and reported on. Four decades later, the revolution of obstetrical sonography, a safe modality, commenced with the pioneering work of Ian Donald (BJOG 1965;72:907–19; 1968;75:993–1006) and Stuart Campbell (BJOG 1965;75:568–76), with the first reports on cephalometry and placentography. Obstetrical practice was never to be the same; over the past 50 years, it has witnessed unfathomable progress facilitated by the technological advances. From Benacerraf's nuchal fold to Nicolaides’ nuchal translucency and the first-trimester scan, sonography is our primary modality for screening and diagnosing major fetal and maternal conditions. The International Society of Ultrasound in Obstetrics & Gynecology was consequently founded in 1991. Most recently, with the introduction of 3D sonography in the 1980s, and Abuhamad's automated multiplanar imaging, standardised automated scanning of the most complex of organs, the fetal heart, is now a reality. In addition, with the availability of electronic transducers, the drastic improvement in the resolution of our images is clearly visible (Figure 1). Despite other emerging technologies for imaging the fetus, with magnetic resonance imaging at the forefront, ultrasound remains the primary modality because of its safety, affordability, and portability: hand-held devices have taken our diagnostic capabilities out into any field, and as far out as outer space. Where to next? The future has unlimited potential as the technology continues to evolve. Its role in the study of fetal anatomy, in the era of cfDNA testing, shall critically move into the first trimester, and our pendulum shall shift from the study of structure to the study of function. With vision, leaders in the field are now consecrating all efforts towards the standardisation of training (Abuhamad, JUM 2018;37:19–50), in order to ensure quality and to maximise the diagnostic capabilities before the point of full automation is reached. The future is most promising and exciting – if only one were to be given the life to be able to bear witness to the unravelling of this journey of marvel… None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The majority of invasive breast cancer patients will develop axillary lymph node metastases prior to developing distant metastases. The management of the axilla in the treatment of invasive breast cancer thus remains a critical component of therapy. It influences the AJCC staging of invasive breast cancer. This chapter deals with the evaluation of the axilla. Preoperatively, it includes clinical exam, ultrasound evaluation and fine needle aspiration biopsy (FNA) or core needle biopsy (CNB) of abnormal axillary lymph nodes. Intraoperatively, this includes sentinel lymph node biopsy (SLNB) and completion axillary lymph node dissection (CALND). This review addresses some of the changing philosophy with management of the axilla in invasive breast cancer and the controversies and paradigm shifts that accompany the same. The role of axillary evaluation of breast cancer in certain special situations is discussed.

PurposeThe purpose of the NBRST study is to compare a multigene classifier to conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping to predict chemosensitivity as defined by pathological complete response (pCR) or endocrine sensitivity as defined by partial response.MethodsThe study includes women with histologically proven breast cancer, who will receive neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2, and Basal.ResultsA total of 426 patients had definitive surgery. Thirty-seven of 211 (18 %) IHC/FISH hormone receptor (HR)+/HER2− patients were reclassified by Blueprint as Basal (n = 35) or HER2 (n = 2). Fifty-three of 123 (43 %) IHC/FISH HER2+ patients were reclassified as Luminal (n = 36) or Basal (n = 17). Four of 92 (4 %) IHC/FISH triple-negative (TN) patients were reclassified as Luminal (n = 2) or HER2 (n = 2). NCT pCR rates were 2 % in Luminal A and 7 % Luminal B patients versus 10 % pCR in IHC/FISH HR+/HER2− patients. The NCT pCR rate was 53 % in BluePrint HER2 patients. This is significantly superior (p = 0.047) to the pCR rate in IHC/FISH HER2+ patients (38 %). The pCR rate of 36 of 75 IHC/FISH HER2+/HR+ patients reclassified as BPLuminal is 3 %. NCT pCR for BluePrint Basal patients was 49 of 140 (35 %), comparable to the 34 of 92 pCR rate (37 %) in IHC/FISH TN patients.ConclusionsBluePrint molecular subtyping reclassifies 22 % (94/426) of tumors, reassigning more responsive patients to the HER2 and Basal categories while reassigning less responsive patients to the Luminal category. These findings suggest that compared with IHC/FISH, BluePrint more accurately identifies patients likely to respond (or not respond) to NCT.

1078 Background: Classification into molecular subtypes is important for the selection of therapy for patients with breast cancer. Previous analyses demonstrated that breast cancer subtypes have distinct clinical outcome (Gluck, BCRT 2013). The aim of the prospective NBRST study is to measure chemosensitivity as defined by pathological Complete Response (pCR), or endocrine sensitivity as defined by partial response (PR) and metastasis-free survival in molecular subgroups. Methods: The study includes women aged 18-90 with histologically proven breast cancer, who are scheduled to start neo-adjuvant chemotherapy (NCT) or neo-adjuvant endocrine therapy (NET), and who provide written informed consent. Additional inclusion criteria include no excision biopsy or axillary dissection, no confirmed distant metastatic disease, and no prior therapy for breast cancer. Treatment is at the discretion of the physician adhering to NCCN approved regimens. Results: 336 Patients, T1-4 N0-3, had definitive surgery and the overall pCR rate was 24%. 32/167 (19%) IHC/FISH ERPR+/HER2- patients were re-classified by BluePrint (31 Basal). 43/95 (45%) IHC/FISH HER2+ patients were re-classified by BluePrint (25 Luminal and 18 Basal). 3/74 (3%) IHC/FISH triple negative patients were not Basal by BluePrint. Of 45 (13%) patients classified as Luminal A 32 received NCT; 1 patient (3%) had a pCR; 13 patients received NET and 9 (70%) had a PR. Of 116 (35%) patients classified as Luminal B 111 received NCT and 7 (6%) had a pCR. The pCR rate (17/149 (11%)) in IHC/FISH ERPR+/HER2- patients was higher. 55 (16%) are BluePrint HER2 and received NCT (51 plus trastuzumab); 27 (49%) had a pCR compared to 35/95 (37%) in IHC/FISH HER2+ patients. 120 (36%) are BluePrint Basal and received NCT; 46 (38%) had a pCR, similar to the pCR percentage seen in the 74 patients designated triple-negative by IHC/FISH. Conclusions: Molecular subtyping using MammaPrint and BluePrint leads to a reclassification of 23% (78/336) of tumors. BluePrint reclassification resulted in better grouping of patients into expected response groups compared to local surrogate subtyping with immunostains. Clinical trial information: NCT014799101.

149 Background: Accelerated partial breast irradiation (APBI) is commonly used in early-stage breast cancer. The SAVI Collaborative Research Group is a multi-institutional group created to study outcomes in patients who received APBI utilizing strut-based brachytherapy. This analysis reports the acute and late toxicities for patients with greater than 2-year follow-up (F/U) from this study. Methods: 904 APBI patients (ductal carcinoma in situ [n=267] or invasive breast cancer [n=637]), received HDR brachytherapy (34 Gy in 10 fractions) using the SAVI device (Cianna Medical). Patients with dosimetry and documented follow-up were evaluated within 6 weeks of treatment for early adverse events (AEs), and at 1 year, 2 years, and beyond for late AEs. Dosimetric parameters were evaluated with respect to toxicity and will be presented. Results: In 212 patients (median age 62.9 years, range 40-88) all with follow-up greater than 24 months, the median tumor size was 12mm. As of last follow-up (>24 months) cumulative rates of erythema and hyperpigmentation of grade 2 or higher were 1.4% and 0.5%. The incidence of grade 2 or higher telangiectasia, seroma and fat necrosis were 2.8%, 2.8%, and 0.5% respectively. Conclusions: Adverse events for APBI with SAVI are low in incidence, low in grade and compare favorably to other HDR APBI methods.

The frontomaxillary facial angle (FMFA) is a first trimester (FT) marker for trisomy. Recently, its role as a FT marker for spina bifida (SB) has been evaluated. Our objective was to determine the normogram for the FMFA in an unselected low risk Lebanese population and to compare our results to the established normogram of Borenstein et al to assess for any ethnic variations precluding its application in our population as an early FT marker of trisomy and SB. Prospective study on 361 fetuses with confirmed dating undergoing a FT scan at 11 to 14 weeks. All scans were performed by a single sonologist certified by the Fetal Medicine Foundation. The FMFA was measured in all fetuses in a mid sagittal plane according to the guidelines of the Fetal Medicine Foundation. Regression analysis was used to establish the relationship between fetal crown rump length (CRL) and FMFA. ANOVA test of means was employed to compare the mean FMFA in relation to the CRL. All fetuses were healthy term live births. A total of 361 patients were included in the analysis. Mean CRL was 72.48 mm. Mean FMFA was 77.29°. Regression analysis was employed to establish the relationship of FMFA to CRL and it revealed no significant decrease in the FMFA with advancing gestation (P = 0.609) as has previously been described by Borenstein et al. Statistical analysis using ANOVA test of means comparing the mean FMFA with CRL indicated that the mean FMFA is significantly unchanged as CRL increases or decreases. For a CRL of 50–59, 60–69, 70–79 and 80–89 mm, the mean FMFA was 79.3°, 77°, 77°, 78.1° and 77.3° respectively (P = 0.421). The FMFA was > 85° in 7.8% of our patients. Our study demonstrates that in an unselected low risk Lebanese population, there is no statistically significant decrease in the FMFA with advancing gestation as has been previously reported by Borenstein et al. In 7.8% of our population, the FMFA is > 85°. This ethnic variation calls for employing caution when using the FMFA in our FT screening for trisomy and when screening fetuses who may be at risk for SB.

With radiation therapy now a routine addition to breast conservation surgery during breast cancer therapy, newer irradiation application methods are evolving, including accelerated, partial breast irradiation (APBI) using balloon catheter brachytherapy. Typical treatment planning with balloon brachytherapy involves BID dosing over 5 days rather than the typical 6 to 6 ½ weeks needed for whole breast radiotherapy. This chapter provides an overview of APBI using balloon brachytherapy.