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Background: High circulating tumor cell (CTC) count (CTChigh) is a strong adverse prognostic factor in patients with metastatic breast cancer (mBC). In the STIC CTC trial (NCT01710605), run before the introduction of CDK4/6 inhibitors for ER+/HER2- mBC, we showed that CTC count (CTC arm) was non inferior to clinician’s choice (standard arm) on progression-free survival (PFS) to guide first line treatment selection between chemotherapy (CT) and endocrine therapy (ET) (Bidard et al., JAMA Oncol 2021). Of note, patients who had treatment escalated from ET (a priori clinician choice) to CT in the CTC arm, had a significantly longer PFS. We report here overall survival (OS) results of this multicenter CTC clinical utility trial. Methods: In the CTC arm, N=377 patients had their treatment determined by baseline CTC count: CT if CTChigh (≥5 CTCs/7.5 mL, CellSearch®), ET if CTClow. In the standard arm (N=378 patients), the choice was left to the investigator: CT if clinical high risk (Clinhigh), ET if clinical low risk (Clinlow). Therefore, patients with discordant Clinlow/CTChigh or Clinhigh/CTClow profiles had their first line treatment escalated from ET (standard arm) to CT (CTC arm) or de-escalated from CT (standard arm) to ET (CTC arm), respectively. Patients with concordant Clinlow/CTClow and Clinhigh/CTChigh profiles received ET and CT in both arms, respectively. Results: Among 755 randomized patients, N=189 (25.0%) had a Clinlow/CTChigh profile, N=103 (13.6%) Clinhigh/CTClow, N=363 (48.2%) Clinlow/CTClow and N=100 (13.2%) Clinhigh/CTChigh. OS was analyzed after a median follow-up of 57 months and 382 events (50.6%). In the Clinlow/CTChigh subgroup, CT in the CTC arm led a longer OS (mOS: 51.8 months [43.3-NR]) than ET in the standard arm (35.4 months [30.4-45.4]; HR=0.53 [0.36-0.78], p=0.001). In patients Clinhigh/CTClow, no significant difference was observed whether they received CT (standard arm) or ET (CTC arm) (45.9 months [36.3-59.8] vs 49.4 months [35.4-65.4]; HR=0.88 [0.51-1.51], p=0.63). Pooling the two discordant groups (Clinlow/CTChigh or Clinhigh/CTClow), the CTC-driven strategy was superior to the clinician-driven treatment decision (HR=0.63 [0.46-0.86], p=0.02). Pooling all concordant and discordant groups together, a median OS of 45.5 (95%CI=[40.9-51.1]) and 51.3 months [46.8-55.1] was observed in the standard and CTC arms, respectively (HR=0.84 [0.69-1.03], p=0.10). Conclusions: Prognostic information brought by CTC or standard factors is discordant in 40% of patients with ER+ HER2- mBC. In case of a discordant estimate, the STIC CTC trial shows the superiority on OS of the CTC-driven treatment decision strategy. These results also suggest a possible clinical utility of CTC to adjust systemic treatment for mBC in second and later lines, after progression on CDK4/6 inhibitors. Funding:The study was funded by Institut Curie; the French National Cancer Institute (INCa), as part of the Programme de Soutien aux Techniques Innovantes Coûteuses 2011 (STIC 2011); and Menarini Silicon Biosystems (Castel Maggiore, Italy). Citation Format: Francois-Clement Bidard, Nicolas Kiavue, Catherine Alix-Panabières, Sylvain Dureau, Thomas Bachelot, Hugues Bourgeois, Anthony Gonçalves, Etienne Brain, Sylvain Ladoire, Florence Dalenc, Joseph Gligorov, Luis Teixeira, George Emile, Jean-Marc Ferrero, Delphine Loirat, Luc Cabel, Véronique Diéras, Frédérique Berger, William Jacot, Jean-Yves Pierga. GS3-09 Circulating Tumor Cells-driven choice of first line therapy for ER+ HER2- metastatic breast cancer: overall survival analysis of the randomized STIC CTC trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-09.

Background: In contrast to the IMpassion130 trial evaluating atezo + nab-pac [Schmid, NEJM 2018], the randomized phase 3 IMpassion131 trial (NCT03125902) did not demonstrate significantly improved progression-free survival (PFS; primary endpoint) and showed no improvement in overall survival (OS; secondary endpoint) with the addition of atezo to pac as first-line therapy for mTNBC in either the PD-L1+ or the intention-to-treat (ITT) population [Miles, Ann Oncol 2021]. In IMpassion130, enhanced PFS and OS improvement with atezo + nab-pac were seen in the basal-like immune-activated (BLIA) subtype, whereas potential resistance to atezo + nab-pac was observed in the luminal androgen receptor (LAR) subtype [Emens, ASCO 2021]. LAR may be more prevalent in Asian populations [Ding, Oncotarget 2019], which represented one-third of patients enrolled in IMpassion131 and could have influenced the overall result. PFS outcomes were numerically worse in Asian vs non-Asian subgroups in IMpassion131 [Miles, Ann Oncol 2021]. To investigate potential reasons for observing different effects in IMpassion130 and IMpassion131, we explored the prevalence and impact on clinical outcomes of TNBC molecular subtypes and race in IMpassion131. Patients and Methods: Patients with mTNBC (no prior systemic therapy or ≥12 months since [neo]adjuvant chemotherapy) were randomized 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity, stratified by tumor PD-L1 status, prior taxane, liver metastases, and geographic region. Molecular subtypes according to Burstein classification were determined by RNA sequencing (Illumina TruSeq RNA Access) of baseline tumor samples. Prevalence of Burstein molecular subtypes [Burstein, Clin Cancer Res 2015] was assessed in Asian (of whom 69% were enrolled in China) and non-Asian populations; clinical outcomes were assessed according to molecular subtype and race using Cox proportional hazards analysis. All analyses were performed using the final data cut-off (Sep 4, 2020; median follow-up duration: 14.4 months). Results: The biomarker-evaluable population (BEP; n=471) was representative of the ITT population (n=651) with respect to baseline characteristics and PFS hazard ratio (HR; 0.75 [95% CI 0.61-0.92] vs 0.81 [95% CI 0.68-0.96], respectively). Distribution of molecular subtypes in the BEP was: 30% BLIA, 41% basal-like immune suppressed (BLIS), 24% LAR, 5% mesenchymal (MES), similar to IMpassion130. Among the BLIA samples, 82% were PD-L1+ and 18% PD-L1-; corresponding percentages were 41% vs 59% for BLIS, 31% vs 69% for LAR, and 32% vs 68% for MES. Compared with non-Asian patients, the Asian subgroup (n=117) included more LAR (31% vs 22%) and fewer MES (1% vs 6%) samples; this was particularly pronounced in the cohort enrolled in China (n=79; 37% LAR, 0% MES). PFS was improved with atezo + pac in the BLIA subtype (HR 0.66, 95% CI 0.45-0.97). None of the Burstein subgroups derived OS benefit from atezo + pac. Findings were similar irrespective of PD-L1 status. Direction of effect for PFS and OS favored the placebo + pac arm in the LAR Asian subgroup (n=30). Conclusion: In these exploratory analyses, the distribution of molecular subtypes and enhanced effect of atezo + pac in the BLIA subtype are consistent with findings from IMpassion130. The lack of improved efficacy with the combination of atezo + pac in the IMpassion131 trial cannot be explained by overrepresentation of a Burstein subtype less sensitive to atezo in the trial population. Citation Format: Fabrice André, Regula Deurloo, Aditi Qamra, David Cameron, Joseph Gligorov, Andreas Schneeweiss, Carlos Barrios, Binghe Xu, Ching-Wei Chang, Luciana Molinero, Shilpen Patel, Andrea Liptrot, Leilani Morales, David Miles, Joyce O’Shaughnessy. Activity of atezolizumab (atezo) plus paclitaxel (pac) in metastatic triple-negative breast cancer (mTNBC) according to Burstein molecular subtype: Analysis of the IMpassion131 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-05.

Resume Introduction L’Association d’enseignement et de recherche des internes en oncologie (AERIO) a mene une enquete nationale aupres des internes en « phase socle » de la promotion 2020 du diplome d’etudes specialisees d’oncologie. L’objectif etait de recueillir et decrire leurs motivations, ainsi que les objectifs et les obstacles de vie et de carriere de ces internes, lors de cette premiere annee de leur cursus. Methodes Un questionnaire comprenait 45 questions fermees reparties en six sections permettant de decrire : les caracteristiques demographiques de la population interrogee, l’engagement et les attentes cliniques et liees a la recherche des etudiants, leur formation, leurs objectifs de vie et de carriere, ainsi que leur engagement associatif. Resultats Soixante-dix-huit internes sur 119 ont participe (66 %), dont 68 (87 %) ayant complete le questionnaire dans son integralite. La population etait constituee en majorite de femmes (60 %) avec un âge median de 24 ans. Le choix entre oncologie option medicale ou option radiotherapie etait le plus souvent indetermine (87 %), 15 % des internes ont songe au droit au remord. Le temps de travail hospitalier moyen declare etait majoritairement situe entre 45 et 65 heures par semaine (83 %). Soixante-neuf pour cent souhaitaient s’investir dans la recherche clinique. Environ un interne sur deux (52 %) n’avait pas acces a la demi-journee de formation en autonomie. Conclusion Cette etude nationale a permis de decrire la perception des internes en phase socle d’oncologie vis a vis de leur formation, ainsi que leurs aspirations de carriere et leur rapport a la recherche.

Background Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. Materials and Methods Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (n = 486) were randomly assigned 1:1 to receive fulvestrant–palbociclib (FP) or letrozole–palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. Results A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (P Conclusion The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy. ClinicalTrials.gov Identifier NCT02491983; https://clinicaltrials.gov/ct2/show/NCT02491983).

Immunotherapy; PARP inhibitors; Pembrolizumab Immunoteràpia; Inhibidors de PARP; Pembrolizumab Inmunoterapia; Inhibidores de PARP; Pembrolizumab Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS).

Background SOLAR-1 and BYLIEVE trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA-mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP). Patients and methods: The French EAP was opened to PIK3CA-mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant, managed per standard of care. Primary endpoint was PFS by local investigators using RECIST1.1. Results Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1–16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95%CI, 4.7-6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95%CI, 37.8–52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age 5 lines of prior treatments (HR = 1.4, 95%CI = 1.0–2.0) and the C420R PI3KCA mutation (HR = 4.1, 95%CI = 1.3–13.6). Most frequent grade 3/4 adverse events (AEs) were hyperglycemia, rash, fatigue and diarrhea occurring in 11.6, 9.9, 4.3 and 3% of patients, respectively. N = 91 (39.1%) patients discontinued alpelisib due to AEs. Discussion To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant. PFS was not overtly impaired by a prior use of either everolimus or fulvestrant. No new safety signal was found.

Introduction Les patients ayant un cancer solide ou hématologique ont été considérés comme étant plus susceptibles de contracter une infection à SARS-COV-2, et de développer plus fréquemment des complications graves. Nous avons voulu comparer les caractéristiques cliniques et le pronostic des patients atteints de COVID-19 avec ou sans cancer. Méthodes Il s’agit d’une étude observationnelle de cohorte prospective, de tous les patients hospitalisés consécutivement dans une unité dédiée aux patients atteints de COVID-19 à l’hôpital de la Pitié-Salpêtrière à Paris, entre le 16 mars et le 26 avril 2020. Résultats Parmi les 262 patients hospitalisés pour un diagnostic de COVID-19 dans cette unité lors de la première vague de la pandémie, 62 étaient également suivis pour un cancer solide ou hématologique actif. Il n’y avait pas de différence significative entre les deux groupes en ce qui concerne leurs caractéristiques cliniques, les comorbidités, ou leur pronostic entre ces deux groupes. On retrouvait cependant significativement plus de patients qui avaient une lymphopénie (médiane (IQ) : 0,7 (0,5–1,1) versus 0,9 (0,7–1,3)), et qui avaient été contaminés en milieu hospitalier (35,5 % versus 18 %, p = 0,008). Conclusions Les patients oncologiques et non oncologiques hospitalisés pour COVID-19 présentaient des résultats similaires en termes de décès, d’admission en soins intensifs ou de thrombose/hémorragie. Ils devraient bénéficier de la même stratégie thérapeutique que la population générale pendant la pandémie de COVID-19.

The treatment of breast cancer has improved dramatically over the past century, from a strictly surgical approach to a coordinated one, including local and systemic therapies. Systemic therapies for early-stage disease were initially tested against observation or placebo only in adjuvant trials. Subsequent clinical trials focusing on treatment 'fine-tuning' had a marked increase in cohort size, duration and costs, leading to a growing interest in the neoadjuvant setting in the past decade. Neoadjuvant trial designs have the advantages of enabling the direct evaluation of treatment effects on tumour diameter and offer unique translational research opportunities through the comparative analysis of tumour biology before, during and after treatment. Current technologies enabling the identification of better predictive biomarkers are shaping the new era of (neo)adjuvant trials. An urgent need exists to reinforce collaboration between the pharmaceutical industry and academia to share data and thus establish large databases of biomarker data coupled with patient outcomes that are easily accessible to the scientific community. In this Review, we summarize the evolution of (neo)adjuvant trials from the pre-genomic to the post-genomic era and provide critical insights into how neoadjuvant studies are currently designed, discussing the need for better end points and treatment strategies that are more personalized, including in the post-neoadjuvant setting.

Most clinical texts including breast cancer patient summaries (BCPSs) are elaborated as narrative documents difficult to process by decision support systems. Annotators have been developed to extract the relevant content of such documents, e.g., MetaMap and cTAKES, that work with the English language and perform concept mapping using UMLS, SIFR and ECMT, that work for the French language and provide concepts using various terminologies. We compared the four annotators on a sample of 25 French BCPSs, pre-processed to manage acronyms and translated in English. We observed that MetaMap extracted the largest number of UMLS concepts (15,458), followed by SIFR (3,784), ECMT (1,962), and cTAKES (1,769). Each annotator extracted specific valuable information, not proposed by the other annotators. Considered as complementary, all annotators should be used in sequence to optimize the results.

International audience; Most clinical texts including breast cancer patient summaries (BCPSs) are elaborated as narrative documents difficult to process by decision support systems. Annotators have been developed to extract the relevant content of such documents, e.g., MetaMap and cTAKES, that work with the English language and perform concept mapping using UMLS, SIFR and ECMT, that work for the French language and provide concepts using various terminologies. We compared the four annotators on a sample of 25 French BCPSs, pre-processed to manage acronyms and translated in English. We observed that MetaMap extracted the largest number of UMLS concepts (15,458), followed by SIFR (3,784), ECMT (1,962), and cTAKES (1,769). Each annotator extracted specific valuable information, not proposed by the other annotators. Considered as complementary, all annotators should be used in sequence to optimize the results.

Resume La reforme du troisieme cycle des etudes de medecine mise en place en 2017 a cree le statut de « Docteur Junior » pour la derniere phase, appelee phase de consolidation. Elle a pour principe la mise en autonomie croissante et supervisee de l’etudiant de troisieme cycle, afin de mieux l’accompagner vers son statut de praticien senior. Des recommandations pour definir les missions specifiques a l’oncologie medicale paraissent indispensables a la bonne mise en place de la reforme. Ce document, realise conjointement par l’association pour l’enseignement et la recherche des internes en oncologie (AERIO) et le College national des enseignants en cancerologie (CNEC) est une reference nationale qui vise a orienter les pratiques locales, sans s’imposer a elles, en vue de l’arrivee des premiers Docteurs Juniors en oncologie medicale en novembre 2021. Les principaux roles du Docteur Junior y sont explicites : activite de reunion de concertation pluridisciplinaire, de consultation, d’hopital de jour, d’hospitalisation complete, d’enseignement, de recherche notamment clinique et de demarche qualite. L’option oncologie-radiotherapie n’est pas abordee dans ce document.

Purpose: Over the past twenty years, anti-HER2 targeted therapies have proven to be a revolution in the management of human epidermal growth receptor 2 (HER2)-positive breast cancers. Anti-HER2 therapies administered alone or in combination with chemotherapy have been specifically studied. Unfortunately, the safety of anti-HER2 therapies in combination with radiation remains largely unknown. Thus, we propose a literature review of the risks and safety of combining radiotherapy with anti-HER2 therapies. We will focus on the benefit/risk rationale and try to understand the risk of toxicity in early-stage and advanced breast cancer. Methods: Research was carried out on the following databases: PubMed, EMBASE, ClinicalTrial.gov, Medline, and Web of Science for the terms “radiotherapy”, “radiation therapy”, “radiosurgery”, “local ablative therapy”, and “stereotactic”, combined with “trastuzumab”, “pertuzumab”, “trastuzumab emtansine”, “TDM-1”, “T-Dxd”, “trastuzumab deruxtecan”, “tucatinib”, “lapatinib”, “immune checkpoint inhibitors”, “atezolizumab”, “pembrolizumab”, “nivolumab”, “E75 vaccine”, “interferon”, “anti-IL-2”, “anti-IL 12”, and “ADC”. Results: Association of radiation and monoclonal antibodies such as trastuzumab and pertuzumab (with limited data) seems to be safe, with no excess risk of toxicity. Preliminary data with radiation and of antibody–drug conjugate of trastuzumab combined cytotoxic (trastuzumab emtansine, trastuzumab deruxtecan), given the underlying mechanism of action, suggest that one must be particularly cautious with the association. The safety of the combination of a tyrosine kinase inhibitor (lapatinib, tucatinib) and radiation remains under-studied. The available evidence suggests that checkpoint inhibitors can be safely administrated with radiation. Conclusions: HER2-targeting monoclonal antibodies and checkpoint inhibitors can be combined with radiation, apparently with no excess toxicities. Caution is required when associating radiation with TKI and antibody drugs, considering the limited evidence.

Background The use of PPI among cancer patients (pts) is quite frequent. PAL is an oral, cyclin-dependent kinase 4 and 6 inhibitor recommended to be taken under fed conditions. PAL showed a reduced solubility when gastric pH is >4.5, a level commonly achieved by PPI. Observational, retrospective studies on concomitant PPI with PAL or ribociclib showed a shorter progression-free survival (PFS) among PPI users than nonusers. In the randomized, phase 2 PARSIFAL trial, PAL plus fulvestrant demonstrated no improvement in PFS and overall survival (OS) versus PAL plus letrozole as frontline treatment in HR+/HER2- ABC pts (Llombart-Cussac et al, JAMA Oncol 2021). Here we assessed the impact of PPI on PAL efficacy and safety in pts included in the PARSIFAL study. Methods Pts with endocrine-sensitive HR+/HER2- ABC and no prior therapy in advanced setting were randomly assigned to receive PAL (hard capsule formulation) plus either fulvestrant or letrozole. Pts with ≥1 PPI received over the entire PAL-based regimen were defined as PPI users, or PPI naïve (N-PPI) if no PPI was administered over the whole study treatment. We carried out two analyses considering early PPI users (E-PPI) –composed by pts who were receiving PPI since the PAL-based regimen initiation– and long-term PPI users (LT-PPI) –composed by pts who received PPI over the entire or ≥⅔ of the PAL-based regimen. PPI users defined as neither E-PPI nor LT-PPI were excluded from the analysis to avoid biases due to the PPI limited exposition. PFS, OS, and safety were compared among groups. Landmark analysis at 3, 6, 12, 18, 24, and 30 months (mo) was used for survival estimates conditional on surviving to certain time points and adjust for immortality bias in comparison between N-PPI and PPI users. Analyses were adjusted by stratification factors and patient characteristics. Results Of 486 pts included in the study, 325 (66.9%) were N-PPI. Among 161 (33.1%) PPI users, 64 (13.2%) were E-PPI and 91 (18.7%) were LT-PPI. Omeprazole was the most prescribed PPI in 80.7% (130 of 161) of PPI users. Median exposition to PPI for PPI users, E-PPI, and LT-PPI was 13.6, 15.9, and 19.4 mo, respectively. Compared with N-PPI, E-PPI and LT-PPI were older (median age, 60.5 vs 66.5 vs 67.0 years, respectively; P< 0.001) and had a worse functional status (ECOG PS of 0, 60.0% vs 34.0% vs 43.0%, respectively; P=0.002). Median follow-up for the whole population was 32 mo. Median PFS was 28.7 mo in N-PPI compared with 23.0 mo in E-PPI (HR 1.5; 95%CI 1.1–2.2; P=0.024) and 23.0 mo in LT-PPI (HR 1.4; 95%CI 1.0–1.9; P=0.035). Both PPI groups had poorer median PFS than N-PPI by landmark analysis at 3 and 12 mo. Subgroup analysis showed a consistent trend regardless of endocrine partner. Three-year OS rate was 81.1% in N-PPI compared with 63.5% in E-PPI (HR 2.2; 95%CI 1.3–3.7; P=0.003) and 62.0% in LT-PPI (HR 2.1; 95%CI 1.4–3.4; P=0.001). Both PPI groups had poorer 3-year OS rate than N-PPI by landmark analysis at 3, 6, 12, and 18 mo. Grade ≥3 hematological adverse events (AEs) occurred in 71.7% (233 of 325 pts) of N-PPI compared with 57.8% (37 of 64 pts; P=0.021) of E-PPI and 54.9% (50 of 91 pts; P=0.003) of LT-PPI. Dose reductions and delays due to hematological AEs were reported in 70.8% (230 of 325 pts) of N-PPI compared with 56.3% (36 of 64 pts; P=0.018) of E-PPI and 52.7% (48 of 91 pts; P=0.002) of LT-PPI. At 3 mo, 45.8% (149 of 325 pts) of N-PPI required a dose reduction or delay due to hematological AEs compared with 39.1% (25 of 64 pts; P=0.42) of E-PPI. Conclusions Early and sustained coadministration of PPI with PAL and endocrine therapy were associated with lower efficacy, hematological toxicities, and dose modifications. Despite the post-hoc nature of the study, these findings suggest pharmacokinetic interactions between PPI and PAL capsules. Further confirmatory studies including the tablet formulation of PAL, which is expected to assure its optimal absorption, are needed. Citation Format: Serena Di Cosimo, José Manuel Pérez-García, Meritxell Bellet Ezquerra, Florence Dalenc, Miguel Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-10.

The virtual forum on the diagnosis and treatment of PIK3CA-mutated metastatic breast cancer was held on 16th October 2020. The French and Russian oncology experts shared information and exchanged experience concerning the application of the first PI3K inhibitor alpelisib.

Background: P led to a meaningful improvement in clinical outcomes when used in combination with endocrine therapy for first- or later-line regimen in HR[+]/HER2[-] MBC. Grade 3-4 neutropenia was the most common adverse event (AE) in the P-containing regimens. Although venous thromboembolic events (VTE) have been rarely reported in registrational trials, a systematic review and meta-analysis of randomized controlled trials demonstrated a higher rate of these AEs. Moreover, rare but severe cases of interstitial lung disease (ILD)/pneumonitis have been observed during post-approval use of P. Here, we present a comprehensive toxicity profile of pts included in the PARSIFAL study, with particular emphasis given to AEs of special interest of the overall safety population. Methods: A total of 486 pts with HR[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse >12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with de novo metastatic disease) were randomly assigned 1:1 to receive P (oral 125 mg/day [d]; 3 weeks on/1 week off) plus either F (intramuscular injection 500 mg/d; d 0, 14, 28, and then every 28 ds) or L (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (de novo/recurrent). Safety assessments included blood analysis and collection of vital signs at screening, d1 of each cycle, and end of treatment/withdrawal. Severity was graded as per the NCI Common Terminology Criteria for Adverse Events v.4.03. Results: The incidence rate of any grade, grade 3-4, and serious AEs was 99.6%, 80.9%, and 29.9%, respectively, in the FP arm, and 99.2%, 78.5%, and 21.1% in the LP arm. Discontinuations due to AEs were 5.4% in the FP arm and 2.1% in the LP arm. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both arms. Febrile neutropenia was reported in 1.2% (3 pts) and 0.4% (1 patient) in the FP and LP arms, respectively. The rate of VTE of any grade was 5.8% (14 pts) in the FP arm and 4.5% (11 pts) in the LP arm (p = 0.531). Among 18 pts who had grade ≥ 3 pulmonary embolism (PE), the incidence reported in the FP and LP arms was 5% (12 pts) vs 2.5% (6 pts), respectively, and many of them (n=16, 88.9%) were unrelated PE. Asymptomatic grade 3 PE was reported in 10 pts of the entire study population on every 3-mo CT scan. Further, in 5 pts PE was detected in the context of progressive disease. Median time from the first dose of study drugs to occurrence of PE was 4.1 mo (range 1.4-32.0 mo) in the FP arm and 7 mo (range 1.8-19.3 mo) in the LP arm. Analysis of baseline characteristics in the whole population revealed that older pts had a significantly increased risk for developing PE (69.5 years [range 47-84 years]; p < 0.01). ECOG performance status, menopausal status, metastatic disease, visceral involvement, number of disease sites, and prior therapies including antithrombotic agents did not significantly increase the risk for developing PE. Grade 3 ILD/pneumonitis was rarely observed in the FP and LP arms (0.8% vs 1.2%, respectively) with no grade 4 AE. Conclusions: First-line treatment with FP and LP for HR[+]/HER2[-] MBC in the PARSIFAL study confirmed the favorable safety profile, with neutropenia representing the most common AE. Although rare, ILD/pneumonitis can be a side effect of P-based regimens. VTE and PE incidence rates were low and consistent with age-specific analyses from PALOMA trials and breast cancer population. Early detection of these AEs may assist in optimizing their management. Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Meritxell Bellet, Florence Dalenc, Miguel J. Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Serena Di Cosimo, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés. Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL) [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 PS10-17.

Aim: To report on the management strategies in patients with cancer of unknown primary (CUP) in middle-income countries. Methods: We conceived a survey of 20 items concerning the management of patients with CUP in daily clinical practice. Only participants from lower- and higher-middle-income countries, as per the World Bank Classification, were eligible for this study. Results: The indications for the first-line treatment did not differ between the two economic regions, whereas those for second-line treatment were more prevalent in higher-middle-income countries. The use of targeted therapy based on immunohistochemistry alone was higher in lower-middle-income countries, although the access to CUP classifiers was similar between the two regions. Conclusions: Proper recommendations must ensure that the economic burden is minimized and that other benefits outweigh the limited survival benefit achieved in patients with CUP.

In many countries, the management of cancer patients must be discussed in multidisciplinary tumor boards (MTBs). These meetings have been introduced to provide a collaborative and multidisciplinary approach to cancer care. However, the benefits of MTBs are now being challenged because there are a lot of cases and not enough time to discuss all the of them. During the evaluation of the guideline-based clinical decision support system (CDSS) of the DESIREE project, we found that for some clinical cases, the system did not produce recommendations. We assumed that these cases were complex clinical cases and needed deeper MTB discussions. In this work, we trained and tested several machine learning and deep learning algorithms on a labelled sample of 298 breast cancer patient summaries, to predict the complexity of a breast cancer clinical case. XGboost and multi-layer perceptron were the models with the best result, with an F1 score of 83%.

International audience; IntroductionIn France, participation in the organized breast cancer screening program remains insufficient. A personalized approach adapted to the risk factors for breast cancer (RBC) should make screening more efficient. A RBC evaluation consultation would therefore make it possible to personalize this screening. Here we report our initial experience.Material and methodThis is a prospective study on women who were seen at the RBC evaluation consultation and analyzing: their profile, their risk assessed according to Tyrer Cuzick model (TC) ± Mammorisk© (MMR), the existence of an indication of oncogenetic consultation (Eisinger and Manchester score), their satisfaction and the recommended monitoring.ResultsAmong the women who had had a TCS and/or MMR evaluation of SCR (n = 153), 76 (50%) had a high risk (n = 67) or a very high risk (n = 9). Almost half (47%) had a possible (15%) or certain (32%) indication to an oncogenetic consultation. Regarding this consultation, 98% of women were satisfied or very satisfied. In total, 60% of women had a change in screening methods.ConclusionThis RBC evaluation consultation satisfies women and for a majority of them, modifies their methods of breast cancer screening.; IntroductionL’adhésion en France au programme de dépistage organisé du cancer du sein demeure insuffisante. Une approche personnalisée adaptée aux facteurs de risque de cancer du sein (RCS) permettrait une meilleure efficience du dépistage. Une consultation d’évaluation du RCS permettrait donc de personnaliser ce dépistage. Nous rapportons ici notre expérience initiale.Matériel et méthodeIl s’agit d’une étude prospective portant sur les femmes ayant été vues à la consultation d’évaluation du RCS et analysant : leur profil, leur risque évalué selon les modèles de Tyrer Cuzick (TC) ± Mammorisk© (MMR), l’existence d’une indication de consultation d’oncogénétique (scores d’Eisinger et de Manchester), leur satisfaction et la surveillance préconisée.RésultatsParmi les femmes ayant eu une évaluation du RCS par le modèle TC et/ou MMR (n = 153), 76 (50 %) avaient un risque élevé (n = 67) ou très élevé (n = 9). Près de la moitié (47 %) avait une indication possible (15 %) ou certaine (32 %) à une consultation d’oncogénétique. Concernant cette consultation, 98 % des femmes étaient satisfaites ou très satisfaites. Au total, 60 % des femmes ont eu un changement des modalités de surveillance.ConclusionCette consultation d’évaluation du RCS satisfait les femmes et pour une majorité d’entre elles, modifie les modalités de leur surveillance mammaire.

BACKGROUND: Palbociclib in combination with endocrine therapy (ET) is the first- or second-line standard of care for patients (pts) with hormone receptor (HR)-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) metastatic breast cancer (MBC). No clinically validated markers of long-term benefit from palbociclib have been established and the clinically relevant resistance mechanisms to cyclin-dependent kinases 4 and 6 inhibitors remain undefined. In the present study, we explored candidate circulating exosomal microRNAs (miRNAs) as putative predictors of benefit and/or resistance to palbociclib in combination with ET in pts included in the PARSIFAL-1 trial (ClinicalTrials.gov identifier: NCT02491983). MATERIALS AND METHODS: PARSIFAL-1 was a randomized, open-label, phase II trial aimed at evaluating the efficacy and safety of palbociclib plus either fulvestrant or letrozole in HR+/HER2- MBC pts. For the study of exosomal miRNAs, forty-five consenting pts were selected based on primary endocrine resistance according to the ABC-4 criteria. Nine pts who progressed within the first six months after treatment initiation in the absence of an objective response were considered Resistant and thirty-six pts who progressed more than six months after starting therapy were classified as Sensitive. Exosomes were isolated from plasma samples collected at study entry (baseline) and after 12 weeks of treatment initiation. Differences in miRNA expression between Resistant and Sensitive pts as well as miRNA pharmacodynamic changes between baseline and 12-week samples were assessed. Ribonucleic acid (RNA) was isolated using the miRNeasy plasma kit and the library preparation was done using the QIAseq miRNA library kit according to manufacturer’s instructions. All experiments were conducted at QIAGEN Genomic Services in Germany. Differential expression of miRNA between different conditions was studied using EdgeR statistical software package from Bioconductor. Estimated p-values for significantly differentially expressed miRNAs were adjusted using Benjamini-Hochberg’s False Discovery Rate (FDR). Differences in expression of miRNA with an FDR below 0.05 were considered significant. RESULTS: Sequencing of exosomal RNA and preparation of miRNA libraries were successful for all included samples, with good technical performance. On average, 2.8 million Unique Molecular Index-corrected reads were obtained for each sample and the average percentage of mappable reads was 34.5%. Overall, expression of miRNAs was higher in Resistant compared with Sensitive pts. Eight miRNAs were called as differentially expressed between the two groups. Four miRNAs (miR-1246; miR-375; miR-193a-5p; miR-181d-5p) were differentially expressed at baseline, three (miR-196a-5p, miR-200a-3p, miR-320d) were differentially expressed at 12 weeks, and expression of one miRNA (miR-141-3p) was consistently higher across both time points in Resistant pts. Significant pharmacodynamic changes in miRNA expression were observed both in Resistant and Sensitive pts. Seven miRNAs (miR-224-5p, miR-16-5p, let-7a-5p, miR-381-3p, miR-200c-3p, miR-493-3p, let-7b-5p) in Sensitive pts and three miRNAs (miR-223-3p, miR-126-3p, miR-320b) in Resistant pts were differentially expressed between baseline and 12-week samples. CONCLUSIONS: Circulating exosomal miRNA profiling is feasible in liquid biopsies from MBC pts. Differential expression of selected miRNAs at baseline or their pharmacodynamic modulation may predict benefit from palbociclib combined with ET in pts with HR+/HER2- MBC. Validation of the most promising miRNAs by custom quantitative PCR is warranted. Citation Format: David Casadevall, Joan Albanell Mestres, Federico Rojo, Beatríz Bellosillo, Abel González, Violeta Serra, Meritxell Bellet, Miguel Angel Gil, Miquel Angel Pujana, Angelo Gámez, Enrique Espinosa, Peter Schmid, Joseph Gligorov, Frederik Marmé, Carlos L. Arteaga, Leonardo Mina, Andrea Malfettone, Miguel Sampayo, José Manuel Pérez-García, Javier Cortés, Antonio Llombart-Cussac. Baseline and pharmacodynamic changes of circulating exosomal microRNAs predict early versus late progression to palbociclib plus endocrine therapy in patients with metastatic breast cancer. A sub-analysis of the PARSIFAL-1 trial [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 P4-10-17.

Introduction: Invasive lobular carcinoma (ILC) differs from invasive ductal carcinoma (IDC) in a number of biological features with possible implication in treatment choice particularly for adjuvant chemotherapy. Multigene assay are being used increasingly to guide therapy for endocrine responsive breast cancer without HER2 overexpression or amplification at early stage. But if their interest is well defined for IDC, there are few data for ILC. Our study examine the impact of a multigene assay, Oncotype Dx (ODx), for the population of lobular breast cancer. Patients and methods: It was a retrospectively analysis of a French prospective cohort of patients (PONDx), with use of ODx (n= 882 patients). We studied and compared the specifics aspects of the use and the results of ODx for the ILC ( n= 125 (14,2%)) and IDC patients (n= 691 (78.3%)). We took account of the clinicopathological features, the Recurrence Score (RS), resulting of ODx and its impact on decision making. Results: In our cohort ILC were more frequently grade 2 tumours, had a significantly larger size, and lower Ki67 than IDC. RS distribution was lower for ILC (p30 ; whereas for IDC RS30 for 11%. But there was a similar overall rate of change in treatment decision for ILC (46,4%) and IDC (43%) and a de-escalation of treatment (for no adjuvant chemotherapy) for 67,7% of ILC and 57,1% of IDC with initial indication of adjuvant chemotherapy. On the other hand, about 10% of patients with no initial indication of chemotherapy had an escalation of treatment after ODx for adjuvant chemotherapy. The analysis of the whole population shows a correlation of the lobular histologic type with low RS in univariate or multivariate analysis. Conclusion: RS is clearly prognostic for ILC and IDC. The predictive value of chemotherapy benefit was prospectively demonstrated for IDC, but not so clearly for ILC. In the PONDx cohort, despite a larger size of tumors, the RS of ILC was lower showing different biological features among the gene studied by ODx. The impact on decision making of ODx was similar for ILC and IDC, showing the interest of genomic assay in decision making independently from histologic subtypes (between ILC and IDC). Citation Format: Gaëlle Douchet, Elsa Curtit, Hugues Bourgeois, Sandrine Richard, Sonia Zilberman, Younes Mahi, Joseph Gligorov. Specific aspect of utilization of the prognostic multigene assay for invasive lobular carcinoma at early stage: Oncotype Dx in the prospective French cohort PONDx [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 P2-11-13.

Purpose To test the hypothesis that a simple machine learning algorithm could improve pathological complete response (pCR) prediction in breast cancer patients treated with neoadjuvant chemotherapy (NAC) using an integrative approach based on clinico-pathological and metabolic factors. Methods A total of 311 patients with non-metastatic breast cancer were included. Baseline clinico-pathologic features were evaluated before NAC and tumor uptake of FDG was evaluated before and after one course of NAC. The predictive value of clinico-pathologic and metabolic parameters on pCR was calculated by means of logistic regression analysis and a simple machine learning algorithm generating a hierarchical predictive model using a classification and regression tree (CART). Results: The CART model performed better than all the clinico-pathological and metabolic parameters that were predictive of pCR after univariate analysis. The CART model identified five different groups (G): G1 (luminal cancer with Ki67≤30%), G2 (luminal cancer with Ki67>30% and baseline SUVmax≤10.1), G3 (luminal cancer with Ki67 10.1), G4 (Her2 positive or triple negative cancer with ΔSUVmax ≤50%) and G5 (Her2 positive or triple negative cancer with ΔSUVmax >50%). The pCR rates predicted by the model for each of the identified groups were G1: 7.2%, G2: 16.7%, G3: 54.6%, G4: 35% and G5: 85% Conclusion This study showed that CART, a simple machine learning algorithm, integrating clinico-pathological and metabolic parameters easily obtainable in routine clinical practice, can improve pCR prediction in early breast cancer and identify subgroups that will not benefit from NAC Baseline patient characteristics of the entire cohort and according to the tumor subtypeCharacteristicsGlobalLumALumBHER2THN311321198476Age (median)4950.249.351.143.3Histological type NST/Other290/2127/5107/1281/375/1Grade 14%22%4%1%0%Grade 237%56%46%32%19%Grade 357%22%47%62%80%Grade missing2%0%3%5%1%ER+58%100%89%45%0%PgR+48%88%75%37%0%ER and PgR neg36%0%0%43%0%HER2 positif27%0%0%100%0%Nodal status negative32%13%32%35%33%Nodal status positive64%50%63%63%61%Nodal status missing data4%37%5%2%6%Stage 11%0%0%0%1%Stage 2A25%28%24%11%28%Stage 2B26%34%24%31%17%Stage 3A16%9%17%13%18%Stage 3B21%22%23%25%17%Stage 3C7%3%7%5%11%Missing stage5%3%5%4%8%mean SUV max (PET-FDG)8.94.859.28.411.7 Univariate and multivariate analyses for pCR predictionVariablepCR (%)OR (95% CI)Univariate analysisp valueOR (95% CI)Multivariate analysisp valueMolecular subtypeLum A1 (3.1)0.15 (0.01-0.076)30%60 (41.4)3.01 (1.77-5.23)AJCC TNM Stage0.36nodal statusN033 (33)0.53N+58 (29)Body surface area1.73143 (47.2)1Baseline SUV max10.139 (47.6)3.22 (1.77-5.98)2.24 (1.04-4.67)Delta SUV max=50%22 (66.7)6.82 (2.83-17.41) Citation Format: Marc-Antoine Benderra, Martine Antoine, Sonia Zilberman, Sandrine Richard, Fatima Kebir, Sofiane Bendifallah, Jean-Pierre Lotz, Emile Darai, Joseph Gligorov, Khaldoun Kerrou. Can we improve pCR prediction in early breast cancers treated with neoadjuvant chemotherapy using a simple machine learning algorithm based on 18-FDG and clinico-pathological parameters? [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 P2-16-22.

Clinical decision support systems (CDSSs) implementing cancer clinical practice guidelines (CPGs) have the potential to improve the compliance of decisions made by multidisciplinary tumor boards (MTB) with CPGs. However, guideline-based CDSSs do not cover complex cases and need time for discussion. We propose to learn how to predict complex cancer cases prior to MTBs from breast cancer patient summaries (BCPSs) resuming clinical notes. BCPSs being unstructured natural language textual documents, we implemented four semantic annotators (ECMT, SIFR, cTAKES, and MetaMap) to assess whether complexity-related concepts could be extracted from clinical notes. On a sample of 24 BCPSs covering 35 complexity reasons, ECMT and MetaMap were the most efficient systems with a performance rate of 60% (21/35) and 49% (17/35), respectively. When using the four annotators in sequence, 69% of complexity reasons were extracted (24/35 reasons).

Background The incidence of pregnancy-associated cancers has been increasing for decades. (18F)-FDG Positron Emission Tomography (PET)/Computed Tomography (CT) imaging has become a golden standard in the staging of many malignant diseases. The aims of the current study were to evaluate the feasibility, safety and impact of (18F)-FDG PET/CT performed during pregnancy. Material and methods A retrospective analysis from the prospective database of the Cancer Associe a La Grossesse (CALG) network (Tenon Hospital, France) including patients who underwent (18F)-FDG PET/CT during their pregnancy between 2015 and 2020. Results Of the 536 patients for whom advice from the CALG network was requested during the study period, 359 were diagnosed with cancer during pregnancy. Study population was composed of 63 (17.5%) patients who underwent (18F)-FDG PET/CT. Most cancers were diagnosed during the second trimester. Seventy-five percent were diagnosed with breast cancer, mostly locally advanced invasive ductal carcinomas. Median term of pregnancy at PET/CT was 24.8 weeks of gestation. Twelve (19%), 24 (38.1%) and 22 (34.9%) patients underwent the exam during the 1st, 2nd and 3rd trimester, respectively. (18F)-FDG PET/CT resulted in stage modification for 38 (60.3%) of the patients (28 with more extensive lymph node involvement and 10 with metastatic disease) with subsequently/accordingly modified first-line medical treatment. Fifty patients gave birth to healthy newborns. Two patients had a medical termination of pregnancy, five had a medical abortion, one neonatal death occurred in a patient with severe preeclampsia (unrelated to (18F)-FDG PET/CT). The data of 46 children were available at 6 months, 29 at 12 months, and 15 at 24 months. No cases of mental retardation, childhood cancer, or malformation were reported within 2 years. Conclusion (18F)-FDG PET/CT has a major impact on the management of pregnancy-associated cancers and does not appear to cause fetal side effects suggesting that the exam is feasible during pregnancy as maternal benefits outweigh fetal risks.