Regional lymph node changes on breast MRI in patients with early-stage breast cancer receiving neoadjuvant chemo-immunotherapy.

PURPOSE: Establishing breast MRI imaging patterns associated with neoadjuvant immunotherapy is needed to monitor response. We analyzed serial breast MRIs in patients receiving neoadjuvant chemo-immunotherapy on the I-SPY2 clinical trial. METHODS: Patients with stage 2-3 HER2-negative breast cancer were randomized to weekly paclitaxel (control), weekly paclitaxel and pembrolizumab, or weekly paclitaxel, pembrolizumab and intra-tumoral injection of SD-101, a TLR9 agonist. All patients received AC. Regional lymph nodes were retrospectively evaluated on breast MRI at baseline, 3, 12 and 20 weeks by a single blinded radiologist. MRIs were assessed for development of new regional lymphadenopathy, or increase in the longest diameter or cortical thickness of the largest abnormal regional lymph node. RESULTS: Between 12/2015 and 4/2021, a total of 43 patients enrolled in the control (n = 16) and paclitaxel + pembrolizumab ± SD-101 (n = 27) arms. 12 of 27 patients (44.4%) receiving chemo-immunotherapy experienced increased lymphadenopathy within the first 12 weeks compared to 1 of 16 patients (6.3%) in the control group (p = 0.014). Most patients with increased lymphadenopathy were in the SD101/pembro arm (n = 10, p = 0.002). Increased lymphadenopathy was observed despite concomitant decrease in breast tumor size at all time points. 11 of 12 patients with increased lymphadenopathy had pathologically negative nodes at surgery. There was no association between lymphadenopathy and lower residual cancer burden or immune-related toxicity. CONCLUSIONS: The combination of neoadjuvant paclitaxel and pembrolizumab ± SD101 intratumoral injection was associated with early increases in regional lymphadenopathy on MRI despite decreased breast tumor size. Increased lymphadenopathy was not associated with node positive disease at surgery.

Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab-deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2-Immune-DNA repair deficiency- subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 .

The role of digital mammographic surveillance for detection of asymptomatic recurrence in autologous flap reconstructions.

OBJECTIVE: To evaluate the utility of digital mammography in detecting asymptomatic malignancy in autologous flap reconstructions after mastectomy. METHODS: A retrospective database review identified all mammograms performed on asymptomatic patients with flap reconstructions over a 9-year period (1/1/2009 to 12/31/2017). A negative examination was defined as BI-RADS 1 or 2 and a positive examination was defined as BI-RADS 0, 4, or 5 assigned to the mastectomy side. Malignant outcomes were determined by pathology results. Interval cancers, or false negatives, were defined as locoregional malignant diagnosis within one year of a negative mammogram. Sensitivity, specificity, predictive values, abnormal interpretation rate, and cancer detection rate were calculated. RESULTS: 626 mammograms of asymptomatic flap reconstructions were performed in 183 patients. The most common flap type was TRAM (83.5 %, 523/626) and DIEP (13.4 %, 84/626). Most exams (98.2 %, 615/626) were negative, assessed as BI-RADS 1 or 2, with no interval cancers at follow-up. Eleven exams (1.8 %, 11/626) were positive, assessed as BI-RADS 0, 4, or 5. After diagnostic work-up of all BI-RADS 0 exams, 9 cases had a final recommendation for biopsy of which 3 were malignant. Mammography yielded a cancer detection rate of 0.5 % (3/626), abnormal interpretation rate of 1.8 % (11/626), NPV of 100 % (615/615), overall PPV of 27.3 % (3/11), PPV2 (positive predictive value of a biopsy recommendation) of 33.3 % (3/9), sensitivity of 100 % (3/3), and specificity of 98.7 % (615/623). CONCLUSION: Digital mammography of asymptomatic autologous flap reconstructions after mastectomy demonstrated high sensitivity and low abnormal interpretation rate. Cancer detection rate was comparable to current national benchmarks for mammographic screening in the general U.S. population without mastectomy.

Effect of Longitudinal Variation in Tumor Volume Estimation for MRI-guided Personalization of Breast Cancer Neoadjuvant Treatment.

Purpose To investigate the impact of longitudinal variation in functional tumor volume (FTV) underestimation and overestimation in predicting pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC). Materials and Methods Women with breast cancer who were enrolled in the prospective I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) from May 2010 to November 2016 were eligible for this retrospective analysis. Participants underwent four MRI examinations during NAC treatment. FTV was calculated based on automated segmentation. Baseline FTV before treatment (FTV0) and the percentage of FTV change at early treatment and inter-regimen time points relative to baseline (∆FTV1 and ∆FTV2, respectively) were classified into high-standard or standard groups based on visual assessment of FTV under- and overestimation. Logistic regression models predicting pCR using single predictors (FTV0, ∆FTV1, and ∆FTV2) and multiple predictors (all three) were developed using bootstrap resampling with out-of-sample data evaluation with the area under the receiver operating characteristic curve (AUC) independently in each group. Results This study included 432 women (mean age, 49.0 years ± 10.6 [SD]). In the FTV0 model, the high-standard and standard groups showed similar AUCs (0.61 vs 0.62). The high-standard group had a higher estimated AUC compared with the standard group in the ∆FTV1 (0.74 vs 0.63), ∆FTV2 (0.79 vs 0.62), and multiple predictor models (0.85 vs 0.64), with a statistically significant difference for the latter two models (P = .03 and P = .01, respectively). Conclusion The findings in this study suggest that longitudinal variation in FTV estimation needs to be considered when using early FTV change as an MRI-based criterion for breast cancer treatment personalization. Keywords: Breast, Cancer, Dynamic Contrast-enhanced, MRI, Tumor Response ClinicalTrials.gov registration no. NCT01042379 Supplemental material is available for this article. © RSNA, 2023 See also the commentary by Ram in this issue.

Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51-52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379.

Diffusion-Weighted MRI for Predicting Pathologic Complete Response in Neoadjuvant Immunotherapy.

This study tested the hypothesis that a change in the apparent diffusion coefficient (ADC) measured in diffusion-weighted MRI (DWI) is an independent imaging marker, and ADC performs better than functional tumor volume (FTV) for assessing treatment response in patients with locally advanced breast cancer receiving neoadjuvant immunotherapy. A total of 249 patients were randomized to standard neoadjuvant chemotherapy with pembrolizumab (pembro) or without pembrolizumab (control). DCE-MRI and DWI, performed prior to and 3 weeks after the start of treatment, were analyzed. Percent changes of tumor ADC metrics (mean, 5th to 95th percentiles of ADC histogram) and FTV were evaluated for the prediction of pathologic complete response (pCR) using a logistic regression model. The area under the ROC curve (AUC) estimated for the percent change in mean ADC was higher in the pembro cohort (0.73, 95% confidence interval [CI]: 0.52 to 0.93) than in the control cohort (0.63, 95% CI: 0.43 to 0.83). In the control cohort, the percent change of the 95th percentile ADC achieved the highest AUC, 0.69 (95% CI: 0.52 to 0.85). In the pembro cohort, the percent change of the 25th percentile ADC achieved the highest AUC, 0.75 (95% CI: 0.55 to 0.95). AUCs estimated for percent change of FTV were 0.61 (95% CI: 0.39 to 0.83) and 0.66 (95% CI: 0.47 to 0.85) for the pembro and control cohorts, respectively. Tumor ADC may perform better than FTV to predict pCR at an early treatment time-point during neoadjuvant immunotherapy.

Effect of Inter-Reader Variability on Diffusion-Weighted MRI Apparent Diffusion Coefficient Measurements and Prediction of Pathologic Complete Response for Breast Cancer.

This study evaluated the inter-reader agreement of tumor apparent diffusion coefficient (ADC) measurements performed on breast diffusion-weighted imaging (DWI) for assessing treatment response in a multi-center clinical trial of neoadjuvant chemotherapy (NAC) for breast cancer. DWIs from 103 breast cancer patients (mean age: 46 ± 11 years) acquired at baseline and after 3 weeks of treatment were evaluated independently by two readers. Three types of tumor regions of interests (ROIs) were delineated: multiple-slice restricted, single-slice restricted and single-slice tumor ROIs. Compared to tumor ROIs, restricted ROIs were limited to low ADC areas of enhancing tumor only. We found excellent agreement (intraclass correlation coefficient [ICC] ranged from 0.94 to 0.98) for mean ADC. Higher ICCs were observed in multiple-slice restricted ROIs (range: 0.97 to 0.98) than in other two ROI types (both in the range of 0.94 to 0.98). Among the three ROI types, the highest area under the receiver operating characteristic curves (AUCs) were observed for mean ADC of multiple-slice restricted ROIs (0.65, 95% confidence interval [CI]: 0.52-0.79 and 0.67, 95% CI: 0.53-0.81 for Reader 1 and Reader 2, respectively). In conclusion, mean ADC values of multiple-slice restricted ROI showed excellent agreement and similar predictive performance for pathologic complete response between the two readers.

Utility and Outcomes of Preoperative Screening Breast MRI for Planned Bilateral Prophylactic Mastectomy in High-Risk Patients.

BACKGROUND. There is a paucity of data and consensus guidelines on the utility of preoperative MRI for planned bilateral prophylactic mastectomy. OBJECTIVE. The purpose of this study was to evaluate the utility of breast MRI performed in high-risk patients for the indication of planned bilateral prophylactic mastectomy, with attention given to the diagnostic performance for breast cancer detection. A secondary aim was to assess the potential impact of breast MRI findings on the decision to perform sentinel lymph node biopsy at the time of prophylactic mastectomy. METHODS. A retrospective database review identified MRI examinations performed at an academic medical center from August 2003 to January 2020 for the indication of planned bilateral prophylactic mastectomy. Patient demographics, imaging findings, operative details, and pathology were recorded. BI-RADS category 1 and 2 assessments were considered negative examinations, and BI-RADS category 3, 4, and 5 assessments were considered positive examinations. Descriptive statistics and performance metrics were calculated. RESULTS. The final cohort included 53 patients (mean age, 45 years). Most (35/53; 66.0%) studies were baseline examinations. Of the 53 patients, 31 (58.5%) had negative MRI examinations and 22 (41.5%) had positive MRI examinations. MRI detected two malignancies (one invasive lobular carcinoma and one high-grade ductal carcinoma in situ), both of which were assessed as BI-RADS category 4. The patient with invasive lobular cancer underwent sentinel lymph node biopsy at the time of mastectomy, which showed metastasis. Breast MRI had sensitivity of 100.0% and specificity of 60.8% for overall breast cancer detection and sensitivity of 100.0% and specificity of 59.6% for invasive cancer detection. CONCLUSION. Preoperative MRI for planned bilateral prophylactic mastectomy detected all cancers, indicating a potential role for MRI in impacting surgical decision making. CLINICAL IMPACT. Given the high NPV for cancer, our results suggest that lymph node biopsy may be safely avoided in patients with a negative MRI examination. This is clinically relevant because sentinel nodes cannot be identified after mastectomy.

Outcomes of screening mammography performed prior to fertility treatment in women ages 40-49.

OBJECTIVE: There are currently various conflicting recommendations for breast cancer screening with mammography in women between ages 40-49. There are no specific guidelines for breast cancer screening in women of this age group prior to assisted reproductive technology (ART) for the treatment of infertility. The purpose of our study was to evaluate outcomes of screening mammography, specifically ordered for the purpose of pre-fertility treatment clearance in women aged 40-49 years old. MATERIALS AND METHODS: This was an IRB approved retrospective study of women aged 40-49 presenting for screening mammography prior to ART between January 2010 and October 2018. Clinical history, imaging, and pathology results were gathered from the electronic medical record. Descriptive statistics were performed. RESULTS: Our study cohort consisted of 118 women with a mean age of 42 years (range 40-49). Sixteen of 118 (14%) women were recalled from screening for additional diagnostic work-up. Five of the 16 (31%) were recommended for biopsy (BI-RADS 4 or 5). One of 5 biopsies yielded a malignant result (PPV 20%). Overall cancer detection rate was 0.85% or 8.5 women per 1000 women screened. The single cancer in this cohort was an ER+ PR+ HER2- invasive ductal carcinoma. CONCLUSION: Screening mammography in women 40-49 performed prior to initiation of ART may identify asymptomatic breast malignancy. In accordance with ACR and SBI guidelines to screen women of this age group, women of this age group should undergo screening mammography prior to ART.

Breast MRI during Neoadjuvant Chemotherapy: Lack of Background Parenchymal Enhancement Suppression and Inferior Treatment Response.

Background Suppression of background parenchymal enhancement (BPE) is commonly observed after neoadjuvant chemotherapy (NAC) at contrast-enhanced breast MRI. It was hypothesized that nonsuppressed BPE may be associated with inferior response to NAC. Purpose To investigate the relationship between lack of BPE suppression and pathologic response. Materials and Methods A retrospective review was performed for women with menopausal status data who were treated for breast cancer by one of 10 drug arms (standard NAC with or without experimental agents) between May 2010 and November 2016 in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2, or I-SPY 2 TRIAL (NCT01042379). Patients underwent MRI at four points: before treatment (T0), early treatment (T1), interregimen (T2), and before surgery (T3). BPE was quantitatively measured by using automated fibroglandular tissue segmentation. To test the hypothesis effectively, a subset of examinations with BPE with high-quality segmentation was selected. BPE change from T0 was defined as suppressed or nonsuppressed for each point. The Fisher exact test and the Z tests of proportions with Yates continuity correction were used to examine the relationship between BPE suppression and pathologic complete response (pCR) in hormone receptor (HR)-positive and HR-negative cohorts. Results A total of 3528 MRI scans from 882 patients (mean age, 48 years ± 10 [standard deviation]) were reviewed and the subset of patients with high-quality BPE segmentation was determined (T1, 433 patients; T2, 396 patients; T3, 380 patients). In the HR-positive cohort, an association between lack of BPE suppression and lower pCR rate was detected at T2 (nonsuppressed vs suppressed, 11.8% [six of 51] vs 28.9% [50 of 173]; difference, 17.1% [95% CI: 4.7, 29.5]; P = .02) and T3 (nonsuppressed vs suppressed, 5.3% [two of 38] vs 27.4% [48 of 175]; difference, 22.2% [95% CI: 10.9, 33.5]; P = .003). In the HR-negative cohort, patients with nonsuppressed BPE had lower estimated pCR rate at all points, but the P values for the association were all greater than .05. Conclusions In hormone receptor-positive breast cancer, lack of background parenchymal enhancement suppression may indicate inferior treatment response. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Philpotts in this issue.