Factors affecting the value of diffusion-weighted imaging for identifying breast cancer patients with pathological complete response on neoadjuvant systemic therapy: a systematic review.

This review aims to identify factors causing heterogeneity in breast DWI-MRI and their impact on its value for identifying breast cancer patients with pathological complete response (pCR) on neoadjuvant systemic therapy (NST). A search was performed on PubMed until April 2020 for studies analyzing DWI for identifying breast cancer patients with pCR on NST. Technical and clinical study aspects were extracted and assessed for variability. Twenty studies representing 1455 patients/lesions were included. The studies differed with respect to study population, treatment type, DWI acquisition technique, post-processing (e.g., mono-exponential/intravoxel incoherent motion/stretched exponential modeling), and timing of follow-up studies. For the acquisition and generation of ADC-maps, various b-value combinations were used. Approaches for drawing regions of interest on longitudinal MRIs were highly variable. Biological variability due to various molecular subtypes was usually not taken into account. Moreover, definitions of pCR varied. The individual areas under the curve for the studies range from 0.50 to 0.92. However, overlapping ranges of mean/median ADC-values at pre- and/or during and/or post-NST were found for the pCR and non-pCR groups between studies. The technical, clinical, and epidemiological heterogeneity may be causal for the observed variability in the ability of DWI to predict pCR accurately. This makes implementation of DWI for pCR prediction and evaluation based on one absolute ADC threshold for all breast cancer types undesirable. Multidisciplinary consensus and appropriate clinical study design, taking biological and therapeutic variation into account, is required for obtaining standardized, reliable, and reproducible DWI measurements for pCR/non-pCR identification.

Prognostic value of breast MRI characteristics before and during neoadjuvant endocrine therapy in patients with ER+/HER2- breast cancer.

OBJECTIVE: To investigate whether BIRADS MRI characteristics before or during neoadjuvant endocrine therapy (NET) are associated with the preoperative endocrine prognostic index (PEPI) in ER+/HER2- breast cancer patients. METHODS: This retrospective observational cohort study included 35 ER+/HER2- patients with 38 tumors (3 bilateral cases) treated with NET. The pre- and midtreatment (after 3 months) MRIs were evaluated by two breast radiologists for BIRADS imaging characteristics, shrinkage pattern, and radiologic response. PEPI was used as end point. PEPI is based on the post-treatment surgical specimen's pT- and pN-stage, Ki67, and ER-status. Tumors were assigned PEPI-1 (good prognosis) or PEPI-2/3 (poor prognosis). We investigated whether pre- and midtreatment BIRADS characteristics were associated with PEPI. RESULTS: Median patient age was 65 years (interquartile interval [IQI]: 53, 70). 17 tumors (44.7%) were associated with good prognosis (PEPI-1), and 21 tumors (55.3%) with poor prognosis (PEPI-2/3). A larger reduction in tumor size after 3 months of NET was significantly associated with PEPI; 10 mm (IQI: 5, 13.5) in PEPI-1 tumors vs 4.5 mm (IQI: 3, 7; p = .045) in PEPI-2/3 tumors. Other BIRADS characteristics, shrinkage pattern or radiologic response were not associated with PEPI. CONCLUSION: Only a larger reduction in tumor size on MRI after 3 months of NET was associated with PEPI-1 (good prognosis) in ER+/HER2- breast cancer patients. ADVANCES IN KNOWLEDGE: MRI characteristics previously reported to be associated with prognosis during neoadjuvant chemotherapy are not necessarily associated with prognosis during NET in ER+/HER2- breast cancer patients.

Minimally Invasive Complete Response Assessment of the Breast After Neoadjuvant Systemic Therapy for Early Breast Cancer (MICRA trial): Interim Analysis of a Multicenter Observational Cohort Study.

BACKGROUND: The added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI. METHODS: We performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1-4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR). RESULTS: Between April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45-61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27-49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72-55.89; p = 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95-21.73; p = 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87-1.00; p = 0.051). CONCLUSION: The MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.

Local staging of ipsilateral breast tumor recurrence: mammography, ultrasound, or MRI?

BACKGROUND: Despite increasingly effective curative breast-conserving treatment (BCT) regimens for primary breast cancer, patients remain at risk for an ipsilateral breast tumor recurrence (IBTR). With increasing interest for repeat BCT in selected patients with IBTR, a reliable assessment of the size of IBTR is important for surgical planning. AIM: The primary aim of this study is to establish the performance in size estimation of XMG, US, and breast MRI in patients with IBTR. The secondary aim is to compare the detection of multifocality and contralateral lesions between XMG and MRI. PATIENTS AND METHODS: The sizes of IBTR on mammography (XMG), ultrasound (US), and magnetic resonance imaging (MRI) in 159 patients were compared to the sizes at final histopathology. The accuracy of the size estimates was addressed using Pearson's coefficient and Bland-Altman plots. Secondary outcomes were the detection of multifocality and contralateral lesions between XMG and MRI. RESULTS: Both XMG and US significantly underestimated the tumor size by 3.5 and 4.8 mm, respectively, while MRI provided accurate tumor size estimation with a mean underestimation of 1.1 mm. The sensitivity for the detection of multifocality was significantly higher for MRI compared to XMG (25.5% vs. 5.5%). A contralateral malignancy was found in 4.4% of patients, and in 1.9%, it was detected by MRI only. CONCLUSION: The addition of breast MRI to XMG and US in the preoperative workup of IBTR allows for more accurate size estimation. MRI provides a higher sensitivity for the detection of multifocality compared to XMG.

Feasibility of radioguided occult lesion localization of clip-marked lymph nodes for tailored axillary treatment in breast cancer patients treated with neoadjuvant systemic therapy.

BACKGROUND: Selective removal of initially tumor-positive axillary lymph nodes in breast cancer patients who underwent neoadjuvant systemic treatment (NST) improves the accuracy of nodal staging and provides the opportunity for more tailored axillary treatment. This study evaluated whether radioguided occult lesion localization (ROLL) of clip-marked lymph nodes is feasible in clinical practice. METHODS: Prior to NST, a clip marker was placed inside a proven tumor-positive lymph node in all breast cancer patients (cTis-4N1-3 M0). After NST, technetium-99m-labeled macroaggregated albumin was injected in the clip-marked lymph nodes. The next day, these ROLL-marked nodes were selectively removed at surgery to evaluate the pathological response of the axilla. RESULTS: Thirty-seven patients (38 axillae) underwent clip insertion. After NST, the clip was visible by ultrasound in 36 procedures (95%). In the other two patients, the ROLL-node injection was performed in a sonographically suspicious unclipped node (1), and near the clip under computed tomography guidance (1). Initial surgery successfully identified the ROLL-marked node with clip in 33 procedures (87%). Removed specimens in the other five procedures contained only the sonographically suspicious tumor-positive unclipped node (1), a node with signs of complete response but no clip (2), a clip without node (1), and tissue without node nor clip, and a second successful ROLL-node procedure was performed (1). Overall, 10 ROLL-marked nodes had no residual disease. CONCLUSIONS: This study demonstrates that the ROLL procedure to identify clip-marked lymph nodes is feasible. This facilitates selective removal at surgery and may tailor axillary treatment in patients treated with NST.

Reliability of preoperative breast biopsies showing ductal carcinoma in situ and implications for non-operative treatment: a cohort study.

PURPOSE: The future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen. METHODS: We studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000-2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded. RESULTS: Among 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3-18.1) were upstaged to IBC and a further 14.6% (11.3-18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, pdifference = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, pdifference < 0.001) and with use of 14G core-needle rather than 9G vacuum-assisted biopsy (22.8% vs 7.0%, pdifference < 0.001). Larger mammographic size increased the risk of both upgrading (pheterogeneity = 0.01) and upstaging (pheterogeneity = 0.004). CONCLUSIONS: The risk of upstaging of DCIS in preoperative biopsies is lower than previously estimated and justifies conducting randomized clinical trials testing the safety of active surveillance for lower grade DCIS. Selection of women with low grade DCIS for such trials, or for active surveillance, may be improved by consideration of the additional factors identified in this study.

Towards the use of diffuse reflectance spectroscopy for real-time in vivo detection of breast cancer during surgery.

BACKGROUND: Breast cancer surgeons struggle with differentiating healthy tissue from cancer at the resection margin during surgery. We report on the feasibility of using diffuse reflectance spectroscopy (DRS) for real-time in vivo tissue characterization. METHODS: Evaluating feasibility of the technology requires a setting in which measurements, imaging and pathology have the best possible correlation. For this purpose an optical biopsy needle was used that had integrated optical fibers at the tip of the needle. This approach enabled the best possible correlation between optical measurement volume and tissue histology. With this optical biopsy needle we acquired real-time DRS data of normal tissue and tumor tissue in 27 patients that underwent an ultrasound guided breast biopsy procedure. Five additional patients were measured in continuous mode in which we obtained DRS measurements along the entire biopsy needle trajectory. We developed and compared three different support vector machine based classification models to classify the DRS measurements. RESULTS: With DRS malignant tissue could be discriminated from healthy tissue. The classification model that was based on eight selected wavelengths had the highest accuracy and Matthews Correlation Coefficient (MCC) of 0.93 and 0.87, respectively. In three patients that were measured in continuous mode and had malignant tissue in their biopsy specimen, a clear transition was seen in the classified DRS measurements going from healthy tissue to tumor tissue. This transition was not seen in the other two continuously measured patients that had benign tissue in their biopsy specimen. CONCLUSIONS: It was concluded that DRS is feasible for integration in a surgical tool that could assist the breast surgeon in detecting positive resection margins during breast surgery. Trail registration NIH US National Library of Medicine-clinicaltrails.gov, NCT01730365. Registered: 10/04/2012 https://clinicaltrials.gov/ct2/show/study/NCT01730365.

Simplifying Breast Imaging Reporting and Data System classification of mammograms with pure suspicious calcifications.

Objectives To investigate the risk of malignancy following stereotactic breast biopsy of calcifications classified as Breast Imaging Reporting and Data System (BI-RADS) 3, 4, and 5. Methods The study included women with pure calcifications (not associated with masses or architectural distortions) who underwent stereotactic breast biopsy at the Dutch Cancer Institute between January 2011 and October 2013. Suspicious calcifications (Breast Imaging Reporting and Data System 3, 4, or 5) detected on mammography were biopsied. All lesions were assessed by breast radiologists and classified according to the BI-RADS lexicon. Results Overall, 473 patients underwent 497 stereotactic breast biopsies. Sixty-six percent (326/497) of calcifications were classified B4, 30% (148/497) B3, and 4% (23/497) B5. Of the 226 (45%) malignant lesions, there were 182 pure ductal carcinoma in situ, 22 mixed ductal carcinoma in situ and invasive carcinomas (ductal or lobular), 21 pure invasive carcinomas, and one angiosarcoma. Malignancy was found in 32% (95% confidence interval [CI] 0.24 to 0.39) of B3, 49% (95% CI 0.43 to 0.54) of B4, and 83% (95% CI 0.61 to 0.95) of B5 calcifications. Conclusions Considering the high predictive value for malignancy in B3 calcifications, we propose that these lesions should be classified as suspicious (B4), especially in a screening setting.

The feasibility of manual parameter tuning for deformable breast MR image registration from a multi-objective optimization perspective.

Deformable image registration is typically formulated as an optimization problem involving a linearly weighted combination of terms that correspond to objectives of interest (e.g. similarity, deformation magnitude). The weights, along with multiple other parameters, need to be manually tuned for each application, a task currently addressed mainly via trial-and-error approaches. Such approaches can only be successful if there is a sensible interplay between parameters, objectives, and desired registration outcome. This, however, is not well established. To study this interplay, we use multi-objective optimization, where multiple solutions exist that represent the optimal trade-offs between the objectives, forming a so-called Pareto front. Here, we focus on weight tuning. To study the space a user has to navigate during manual weight tuning, we randomly sample multiple linear combinations. To understand how these combinations relate to desirability of registration outcome, we associate with each outcome a mean target registration error (TRE) based on expert-defined anatomical landmarks. Further, we employ a multi-objective evolutionary algorithm that optimizes the weight combinations, yielding a Pareto front of solutions, which can be directly navigated by the user. To study how the complexity of manual weight tuning changes depending on the registration problem, we consider an easy problem, prone-to-prone breast MR image registration, and a hard problem, prone-to-supine breast MR image registration. Lastly, we investigate how guidance information as an additional objective influences the prone-to-supine registration outcome. Results show that the interplay between weights, objectives, and registration outcome makes manual weight tuning feasible for the prone-to-prone problem, but very challenging for the harder prone-to-supine problem. Here, patient-specific, multi-objective weight optimization is needed, obtaining a mean TRE of 13.6 mm without guidance information reduced to 7.3 mm with guidance information, but also providing a Pareto front that exhibits an intuitively sensible interplay between weights, objectives, and registration outcome, allowing outcome selection.

MRI predicts pathologic complete response in HER2-positive breast cancer after neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant treatment of HER2-positive breast cancer frequently leads to a pathologic complete response (pCR), which is associated with favourable long-term outcome. Treatment regimens typically consist of 6-9 cycles of trastuzumab-based chemotherapy, although many patients achieve early radiologic complete response (rCR). If rCR accurately predicts pCR, the number of chemotherapy cycles can possibly be reduced. METHODS: We performed a diagnostic accuracy study to determine the association between rCR and pCR in patients with stage II-III HER2-positive breast cancer treated with neoadjuvant trastuzumab-based chemotherapy at the Netherlands Cancer Institute. RCR was defined as the disappearance of pathologic contrast enhancement in the original tumour region on repeated magnetic resonance imaging (MRI). PCR was defined as the absence of invasive tumour cells in the resected breast specimen (ypT0/is). Diagnostic accuracy was estimated in the overall population and in subgroups based on hormone receptor (HR) status. The prognostic value of rCR for recurrence-free interval was evaluated as an exploratory analysis. RESULTS: We identified 296 eligible patients with 297 HER2-positive tumours (154 HR-negative and 143 HR-positive) treated with neoadjuvant trastuzumab-based chemotherapy between 2004 and 2016. Overall, the rCR rate was 69% (206/297) and the pCR rate was 61% (181/297). Among 206 patients with rCR, 150 also had pCR (negative predictive value [NPV] = 150/206 = 73%). Among 91 patients without rCR, 60 had residual tumour at pathology (positive predictive value [PPV] = 60/91 = 66%). The NPV was better in HR-negative compared to HR-positive tumours (88 vs. 57%), while the PPV was better in HR-positive tumours (50 vs. 78%). Achieving rCR was associated with a 5-year recurrence-free interval of 88% compared to 68% without rCR (hazard ratio 0.34, 95% confidence interval 0.17-0.65, P = 0.001). CONCLUSION: Achieving rCR corresponds well with pCR in HER2-positive breast cancer, particularly in the HR-negative subgroup. RCR is also associated with improved long-term outcome.

Supine Breast MRI Using Respiratory Triggering.

RATIONALE AND OBJECTIVES: This study aims to evaluate if navigator-echo respiratory-triggered magnetic resonance acquisition can acquire supine high-quality breast magnetic resonance imaging (MRI). MATERIALS AND METHODS: Supine respiratory-triggered magnetic resonance imaging (Trig-MRI) was compared to supine non-Trig-MRI to evaluate breathing-induced motion artifacts (group 1), and to conventional prone non-Trig-MRI (group 2, 16-channel breast coil), all at 3T. A 32-channel thorax coil was placed on top of a cover to prevent breast deformation. Ten volunteers were scanned in each group, including one patient. The acquisition time was recorded. Image quality was compared by visual examination and by calculation of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and image sharpness (IS). RESULTS: Scan time increased from 56.5 seconds (non-Trig-MRI) to an average of 306 seconds with supine Trig-MRI (range: 120-540 seconds). In group 1, the median values (interquartile range) of SNR, CNR, and IS improved from 11.5 (6.0), 7.3 (3.1), and 0.23 (0.2) cm on supine non-Trig-MRI to 38.1 (29.1), 32.8 (29.7), and 0.12 (0) cm (all P < 0.01) on supine Trig-MRI. All qualitative image parameters in group 1 improved on supine Trig-MRI (all P < 0.01). In group 2, SNR and CNR improved from 14.7 (6.8) and 12.6 (5.6) on prone non-Trig-MRI to 36.2 (12.2) and 32.7 (12.1) (both P < 0.01) on supine Trig-MRI. IS was similar: 0.10 (0) cm vs 0.11 (0) cm (P = 0.88). CONCLUSIONS: Acquisition of high-quality supine breast MRI is possible when respiratory triggering is applied, in a similar setup as during subsequent treatment. Image quality improved when compared to supine non-triggered breast MRI and prone breast MRI, but at the cost of increased acquisition time.

Should we screen BRCA1 mutation carriers only with MRI? A multicenter study.

BRCA1 mutation carriers are offered screening with MRI and mammography. Aim of the study was to investigate the additional value of digital mammography over MRI screening. BRCA1 mutation carriers, who developed breast cancer since the introduction of digital mammography between January 2003 and March 2013, were included. The images and reports were reviewed in order to assess whether the breast cancers were screen-detected or interval cancers and whether they were visible on mammography and MRI, using the breast imaging and data system classification allocated at the time of diagnosis. In 93 BRCA1 mutation carriers who underwent screening with MRI and mammography, 82 invasive breast cancers and 12 ductal carcinomas in situ (DCIS) were found. Screening sensitivity was 95.7 % (90/94). MRI detected 88 of 94 breast cancers (sensitivity 93.6 %), and mammography detected 48 breast cancers (sensitivity 51.1 %) (two-sided p < 0.001). Forty-two malignancies were detected only by MRI (42/94 = 44.7 %). Two DCIS were detected only with mammography (2/94 = 2.1 %) concerning a grade 3 in a 50-year-old patient and a grade 2 in a 67-year-old patient. Four interval cancers occurred (4/94 = 4.3 %), all grade 3 triple negative invasive ductal carcinomas. In conclusion, digital mammography added only 2 % to the breast cancer detection in BRCA1 patients. There was no benefit of additional mammography in women below age 40. Given the potential risk of radiation-induced breast cancer in young mutation carriers, we propose to screen BRCA1 mutation carriers yearly with MRI from age 25 onwards and to start with mammographic screening not earlier than age 40.