Utility of Breast Magnetic Resonance Imaging in Determining Candidacy for Partial Breast Irradiation

In this retrospective study, the authors hypothesized that magnetic resonance imaging (MRI) would alter partial breast irradiation (PBI) eligibility by identifying cancers outside the PBI volume compared with mammography alone. Since 2002, MRI was used nonselectively at the authors' institution for the staging of patients with nonmetastatic breast cancer. Of 450 consecutive patients with invasive breast cancer, 110 patients who were eligible for PBI were identified by using criteria outlined by National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Oncology Group trial 0413 based on mammography, ultrasonography, and initial pathology. In that trial, patients were randomized (stage I/II invasive cancers that measured <or=3 cm and <or=3 positive lymph nodes) to receive either whole-breast radiotherapy or PBI. MRI reports were reviewed to determine whether MRI identified secondary lesions 1) within the same quadrant (multifocal), 2) in a different quadrant (multicentric), or 3) in the contralateral breast. These lesions were pathologically proven carcinoma and would have rendered the patient ineligible for PBI. MRI identified secondary lesions in 10% of patients (95% confidence interval [CI], 4.4%-15.6%). Multifocal disease was identified in 3.6% (95% CI, 1.4%-9%), multicentric disease was identified in 4.5% (95% CI, 2%-10.2%), and contralateral disease was identified in 1.8% (95% CI, 0.5%-6.4%). The proportion of patients with false-positive MRI findings was 4.5% (95% CI, 2%-10.2%). The positive predictive value of MRI was 72.2% (95% CI, 46.4%-89.3%). MRI identified frequent secondary cancers that would not be removed routinely by surgery or targeted in the radiation field if treated with PBI. The current data suggest that MRI should be considered to assess PBI eligibility to minimize potential local failures.

A sufficient body of knowledge has developed about ductal carcinoma in situ of the breast to warrant a separate report on standards of care for women with this disease. This consensus report by these four organizations discusses evaluation of the patient, selection of treatment, technical aspects of diagnostic biopsy and definitive local excision, pathologic evaluation, radiation therapy considerations, follow-up care recommendations, and questions for future research.

Salvage treatment for local recurrence after breast-conserving surgery followed by radiation as initial treatment for mammographically-detected ductal carcinoma in situ of the breast

This study is to explore the role of the minimum apparent diffusion coefficient (ADC-min) value in the diagnosis of invasive breast cancer and ductal carcinoma in situ (DCIS). A total of 196 breast cancer patients with pathologically verified lesions were included. They received diffusion-weighted imaging and dynamic breast magnetic resonance imaging before the pathological confirmation. The ADC-min value and its relationship with invasive ductal carcinoma (IDC), IDC-DCIS, and DCIS were analyzed. Of the 196 breast cancer patients, there were 115 (58.67%) cases of IDC, 53 (27.04%) cases of IDC-DCIS, and 28 (14.29%) cases of DCIS. The mean ADC-min values for IDC, IDC-DCIS, and DCIS were (0.96 ± 0.16) × 10-3, (1.10 ± 0.13) × 10-3, and (1.24 ± 0.17) × 10-3 mm 2/s, respectively. The mean ADC-min value of IDC was significantly lower than that of IDC-DCIS and that of IDC-DCIS was significantly lower than that of DCIS (P < 0.01). The mean ADC-min value was also significantly different between invasive cancer and DCIS (P < 0.01). The mean ADC-min value can be used in the differential diagnosis of DCIS, with a cutoff point of 1.02 × 10-3 mm 2/s (sensitivity of 92.9% and specificity of 57.7%). The ADC-min values are significantly different among IDC, IDC-DCIS, and DCIS, with the lowest ADC-min values in IDC, followed by IDC-DCIS and DCIS. The ADC-min maybe used as a promising parameter to differentiate DCIS and invasive cancer.

Because knowledge has advanced in several fields related to the treatment of early breast cancer, revising the landmark 1992 standards for breast-conservation treatment by these four organizations is appropriate. The current report reviews and summarizes the literature and describes the selection and evaluation of patients, the technical aspects of surgical treatment and irradiation, follow-up care, and areas for further research.

We previously studied synchronous Ductal Carcinomas in Situ (DCIS) and Invasive Ductal Carcinomas (IDC) using a novel approach of multiplexing FISH probes that allows us to simultaneously assess the copy numbers of up to 20 loci within intact nuclei providing new insights into tumor clonality and heterogeneity. A high degree of chromosomal instability already in DCIS, and frequently, but not always, a direct clonal evolution from DCIS to IDC was detected. We now ask whether this degree of instability is also present in DCIS that did not progress to IDC and are therefore analyzing FFPE material from 20 patients with either low-grade and high-grade DCIS who did not present with invasive breast carcinoma during their follow-up (5-10 years), in addition to 10 patients who presented with synchronous IDC. The multiplex FISH assay used targets five oncogenes (COX2, MYC, CCND1, HER2, ZNF217) and three tumor suppressor genes (DBC2, CDH1, TP53) frequently altered in breast carcinomas. To date, we have analyzed two paired cases of synchronous DCIS and IDC, DCIS-IDC 3 and 4, and three cases of DCIS without IDC, OP-DCIS 1, 4 and 5. The paired cases exhibited very similar aberration patterns for synchronous DCIS and IDC indicating the invasive carcinoma is closely related to the DCIS lesion. Specifically, the major clones in DCIS 3 (low-grade) and IDC 3 showed a diploid tumor cell population with a gain of COX2, and losses of DBC2, MYC, TP53, and HER2. Of note, the only difference observed was a gain of ZNF217 in the DCIS which was not seen in the major clone of the invasive carcinoma. The other paired case, DCIS 4 (high-grade) and IDC 4, showed major clones of triploid tumor cell populations with gains of COX2, CCND1 and MYC and losses of DBC2, CDH1, TP53 and ZNF217. The three DCIS cases without synchronous or subsequent IDC exhibited varying degrees of aberration and complexity patterns in their clonal populations. Case OP-DCIS 1, a high-grade DCIS, revealed a tetraploid cell population which showed a major clone with an amplification of CCND1 and a MYC gain combined with losses of DBC2, CDH1, TP53 and HER2. A low-grade DCIS, OP-DCIS 4, exhibited a diploid cell population with a major clone showing loss of CDH1 as the only aberration. The third case OP-DCIS 5 (low-grade DCIS) exhibited a diploid cell population with one major clone showing losses of CDH1, MYC, DBC2, TP53, HER2 and CCND1. Our preliminary observations show a tendency of diploid lesions with a predominance of loss patterns for low-grade DCIS, while high-grade DCIS seem to reveal higher ploidy with more complex gain and loss patterns. However, also low-grade DCIS with mainly loss patterns progress to invasive cancers as seen in case DCIS-IDC3. We expect that the analysis of the remaining cases will further elucidate the dynamics of DCIS lesions which will hopefully help to assess and stratify progression risk in patients with DCIS. Citation Format: Irianna Marie Torres, Leanora Hernandez, Jausheng Tzeng, Russell Schwartz, Alejandro Schaffer, Edward Gertz, Stephen Brower, Miguel Sanchez, Gert Auer, Kerstin Heselmeyer-Haddad, Ried Thomas. Single-cell genetic analysis of ductal carcinoma in situ with and without synchronous invasive breast cancer by multiplex FISH delineates specific patterns of tumor clonality and heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2908. doi:10.1158/1538-7445.AM2017-2908

Background: Young women in the US are experiencing rising rates of breast cancer, necessitating effective treatment strategies. Neoadjuvant chemotherapy (NACT) is widely used in clinical practice, yet research on post-NACT outcomes among young women is limited, especially for those with less common histology, e.g., invasive lobular carcinoma (ILC) or invasive ductal and lobular carcinoma (IDLC). In this study, we examined differential pathologic complete response (pCR) and overall survival (OS) between invasive ductal carcinoma (IDC), ILC, or IDLC among female patients (pts) aged ≤40 years with stage I-III disease who received NACT, stratified by molecular subtype. Methods: This hospital-based, retrospective study analyzed data from the 2010-2020 National Cancer Database. We assessed 4 molecular subtypes: HR+/HER2–, HR+/HER2+, HR–/HER2+, and TNBC. pCR, defined as ypT0/Tis ypN0, was modeled using logistic regression, and adjusted odds ratios (aOR) were calculated. OS was event or censored at the time of death from any cause or last known contact, with 5-/10-year OS rates estimated using the Kaplan-Meier method and compared using log-rank tests. We performed Cox regression to generate adjusted hazard ratios (aHR). All models were stratified by molecular subtype, adjusting for clinical T/N stage, tumor grade, PR status (HR+ only), race/ethnicity, year of diagnosis, and comorbidity score. Results: Of 26,480 young women (median follow-up 52.9 [IQR 32.9, 79.2] months), 95.8% had IDC, 2.1% ILC, and 2.1% IDLC. In the HR+/HER2– cohort, 14.9% of IDC pts achieved pCR compared to 3.3% of ILC and 4.1% of IDLC pts (p&amp;lt;.001). After covariate adjustment, pts with ILC (aOR 0.45, 95% CI: 0.23-0.86) or IDLC (aOR 0.49, 95% CI: 0.27-0.89) had lower odds of pCR than IDC pts. In the HR+/HER2+ cohort, a higher pCR rate was observed among IDC pts (33.8%) than ILC (24.3%) or IDLC (27.5%) pts (p=.033). However, the odds of pCR were not significantly different between IDC and ILC (aOR 0.90, 95% CI: 0.56-1.43) or IDLC (aOR 0.77, 95% CI: 0.52-1.13). In the HR–/HER2+ cohort, pCR rates were similar across histologic types (IDLC: 70.6%; ILC: 58.8%; IDC: 49.9%; p=.180). On multivariable regression, pts with ILC (aOR 1.68, 95% CI: 0.60-4.70) or IDLC (aOR 1.96, 95% CI: 0.67-5.73) had similar odds of pCR as those with IDC. In the TNBC cohort, IDC pts achieved a higher rate of pCR than ILC or IDLC pts (36.0%, 21.3% vs. 18.0%; p=.003). Compared to IDC pts, IDLC pts had lower odds of pCR (aOR 0.40, 95% CI: 0.18-0.9) while ILC pts had similar odds of pCR (aOR 0.70, 95% CI: 0.34-1.42). IDC was associated with significantly longer 5-/10-year OS rates (compared to ILC or IDLC) among pts with HR+/HER2– (p=.012) or TNBC (p&amp;lt;.001). In the adjusted models, pts with HR+/HER2– ILC (aHR 1.55, 95% CI: 1.15-2.10) or IDLC (aHR 1.52, 95% CI: 1.15-2.03) had a greater mortality risk than IDC pts. HR–/HER2+ ILC pts also had a higher risk of death than IDC pts (aHR 3.51, 95% CI: 1.10-11.15). In the TNBC cohort, ILC was associated with an increased mortality risk compared to IDC (aHR 2.28, 95% CI: 1.41-3.69). Conclusions: In this US national registry of young women with early-stage breast cancer who received NACT, pts with ILC or IDLC consistently exhibited lower pCR rates and poorer OS than those with IDC across molecular subtypes. These disparities underscore the need for tailored treatment interventions that account for histologic type, particularly for ILC, among young women. Our findings not only highlight the importance of informed NACT counseling, but also underscore the necessity for oncology programs to optimize therapeutic approaches and continue multidisciplinary efforts to reduce disparities specifically for young women with ILC. Citation Format: Jincong Freeman, Jared H. Hara, Olasubomi J. Omoleye, Ted O. Akhiwu, Shreyas Kalantri, Heather J. Hoffman. Early Invasive Lobular or Ductal Carcinoma with Differential Clinical Outcomes Across Molecular Subtypes among Young Women Who Received Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-10-14.

Introduction: Standard treatment for ductal carcinoma in situ (DCIS) involves surgical excision with radiation and often endocrine therapy. However, not all DCIS progresses to invasive ductal carcinoma (IDC); thus, surgical intervention may constitute overtreatment for DCIS that has low risk for progressing to IDC. A period of active surveillance (AS) with magnetic resonance imaging (MRI) monitoring may offer the opportunity to stratify lesions with high and low risk for invasion and to avoid overtreatment of DCIS. The purpose of this study was to characterize the outcomes of a cohort of women who elected to go on AS to avoid surgical intervention and to identify whether clinical and imaging features would identify patients who should convert to operative management. Methods: The clinicopathologic variables and outcomes of patients with DCIS who prospectively enrolled in MRI monitoring studies between 2002 and 2019 were retrospectively analyzed with IRB approval. We included 64 cases among 63 women who declined standard operative management for DCIS and had at least two breast MRIs. Clinicopathologic data and physician recommendations regarding continuing surveillance versus converting to operative management were recorded from the medical record. Those who had surgical excision showing IDC were considered to have progressed; those with only DCIS at excision or no operative intervention were considered to have stable disease. Results: Women in the cohort were an average of 53.6 years (29.8 - 78.9) old, and nearly all cases of DCIS with estrogen receptor (ER) status were ER+ (98.3%). Of the 64 cases in the cohort, 57 received endocrine therapy (89.1%). Average length of time on AS was 2.7 years (.2 – 11.9) with a median of 3 (2 – 18) MRIs performed and mean follow-up time 5.6 years (0.9 – 15.3). A total of 31 cases (48.4%) eventually had surgical excision while 33 (51.6%) remained on AS. There were 17 cases with IDC at surgery (26.6%). The IDC was an average of 1.5 cm (0.1 – 9.0) and most commonly ER + (88.2%), HER2 + (53.3%), grade 2 (58.9%), and node negative (82.4%). Only 7 women did not take endocrine therapy, but 3 of those women had IDC (42.9%). In 15 of the 17 cases with IDC (88.2%), the physician noted concern for progression in their clinic note and recommended surgical excision. This occurred a mean of 1.9 years (0.2 – 6.5) from the start of AS, with 47%, 67%, and 87% of cases identified within 1, 2 and 3 years from the start of AS. Suspicion of progression was based on an increase in lesion size or prominence on MRI and/or increase in calcifications on mammography. Of those that were identified as good candidates to continue AS with no concern for progression (n = 49), 16 chose to undergo surgical excision (32.7%) and 2 had IDC (4.1%). Conclusion: After over a decade of following women who seek alternatives to surgery for DCIS, we have identified clinicopathologic and imaging features that discriminate good candidates for AS and endocrine risk reducing therapy from those best treated with surgical excision. In our cohort of mostly ER+ patients receiving endocrine therapy on AS, over half of the cohort (51.6%) avoided surgical intervention. Her2 status, Oncotype DCIS, and Mammaprint scores of IDC is in process and will be presented. Our data support the study of AS as a method to stratify the risk of IDC and avoid overtreatment. We will present a personalized AS algorithm (based on biology and imaging) that we intend to prospectively test in the ATHENA network and NCI funded MCL consortium. Table 1: Cohort CharacteristicsFull Cohort (n=64)No evidence of IDC (n=47)IDC at surgery (n=17)Age at Diagnosis (years)53.6 (29.8 - 78.9)52.9 (29.8 - 74.5)55.5 (41.9 - 78.9)Time on AS (years)2.7 (.2 - 11.9)2.8 (.2 - 11.9)2.2 (.3 -5.9)Follow-Up (years)5.6 (0.9 - 15.3)Menopausal StatusPremenopausal26 (40.6%)22 (46.8%)4 (23.5%)Postmenopausal35 (54.7%)24 (51.1%)11 (64.7%)Unknown3 (4.7%)1 (2.1%)2 (11.8%)Breast CompositionFatty4 (6.3%)3 (6.4%)1 (5.9%)Scattered14 (21.9%)9 (19.1%)5 (29.4%)Heterogeneous27 (42.2%)19 (40.4%)8 (47.1%)Extreme17 (26.5%)14 (29.8%)3 (17.6%)Unknown2 (3.1%)2 (4.3%)0 (0.0%)ER StatusPositive57 (89.1%)41 (87.2%)16 (94.1%)Negative1 (1.6%)0 (0.0%)1 (5.9%)Unknown6 (9.3%)6 (12.8%)0 (0.0%)PR StatusPositive50 (78.1%)36 (76.6%)14 (82.3%)Negative5 (7.8%)3 (6.4%)2 (11.8%)Unknown9 (14.1%)8 (17.0%)1 (5.9%)GradeHigh20 (31.3%)15 (31.8%)5 (29.4%)Intermediate32 (50.0%)21 (44.6%)11 (64.7%)Low10 (15.6%)9 (19.1%)1 (5.9%)Unknown2 (3.1%)2 (28.5%)0 (0.0%Hormone TherapyYes57 (89.1%)43 (91.5%)14 (82.4%)No7 (10.9%)4 (8.5%)3 (17.6%) Citation Format: Case Brabham, Rita Mukhtar, April Liang, Paul Kim, Gillian Hirst, Amrita Basu, Heather Greenwood, Rita Freimanis, Alexander Borowsky, Shelley Hwang, Rick Baehner, Gregor Krings, Nola Hylton, Laura Esserman. Active surveillance for DCIS: Clinical outcomes at 5.6 years mean follow-up [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 PS1-03.

The overexpression of heat shock protein 27 (hsp-27) in early-stage breast cancer is associated with histopathologic features of poor prognosis and clinically with an increased probability of disease recurrence. Hsp-27 is overexpressed in 25% of invasive ductal carcinomas (IDC); however, its distribution in ductal carcinoma in situ (DCIS) and DCIS associated with IDC has not been investigated. We postulated that hsp-27 might be detected and variably expressed in DCIS and, like HER-2/neu oncoprotein expression, might be a tumor-specific marker worthy of future clinical investigation. To test these hypotheses, the distribution of hsp-27 in noncomedo and comedo DCIS, and DCIS associated with IDC, was evaluated by immunohistochemistry and compared with HER-2/neu expression within the same cancers. Hsp-27 was overexpressed in 28 of 47 (approximately 60%) cases of DCIS; expression in pure DCIS was 16 of 24 (67%), and 12 of 23 (approximately 50%) in DCIS associated with IDC. Hsp-27 expression by in situ and invasive components of the same neoplasm were concordant in 22 of 23 (approximately 95%) cases tested. Comedo variants appeared to have somewhat higher hsp-27 expression than noncomedo DCIS, whether or not there was an associated IDC. These results are reminiscent of HER-2/neu oncoprotein expression in DCIS and DCIS associated with IDC observed by others. However, although 4 of 22 (18%) cancers containing DCIS + IDC expressed HER-2/neu, no relationship with hsp-27 expression in the same cancers was observed. We found a high incidence of hsp-27 overexpression in DCIS and in DCIS associated with IDC. This rate is twice that previously observed in IDC alone. Hsp-27 expression is independent of HER-2/neu expression.

Potential Impact of Preoperative Magnetic Resonance Imaging of the Breast on Patient Selection for Accelerated Partial Breast Irradiation

Introduction: Ductal carcinoma in situ (DCIS) is a bona fide non-obligate precursor of invasive carcinoma. Single cell sequencing studies have revealed intra-lesion genetic heterogeneity in DCIS and shown that progression to invasive ductal carcinoma (IDC) may occur through different mechanisms, including the selection of a subpopulation of tumor cells, acquisition of new genetic alterations or multi-clonal invasion. Here, we sought to investigate the genetic heterogeneity of DCIS, and to document further the clonal selection process accompanying progression to IDC. Materials and methods: Synchronous DCIS (n=16) and IDC (n=15) samples from 14 patients were microdissected separately, and DNA samples of tumor and matched normal tissues were subjected to whole-exome sequencing (WES; n=27) or massively parallel targeted sequencing of all coding regions of ≥410 cancer-related genes (n=4). Somatic genetic alterations and mutational signatures were identified using state-of-the-art bioinformatics algorithms. PyClone was employed to define the clonal architecture of each DCIS and IDC and infer the clonal shifts accompanying progression from DCIS to IDC. Results: DCIS were found to harbor recurrent somatic mutations affecting PIK3CA (50%), GATA3 (44%), TP53 (38%), CBFB (19%), PTEN (13%), and AKT1 (13%), which are genes known to be significantly mutated in invasive breast cancers. Despite the genomic similarities between matched DCIS and IDCs, NOTCH2 and MYC were found to be amplified solely in the IDC component of two cases, and PPM1D amplification was restricted to the DCIS component of another case. The mutational signature ascribed to aging (i.e. signature 1) was the predominant mutational signature in the DCIS and IDCs analyzed. PyClone analysis revealed that all synchronous DCIS and IDC studied here were clonally related and confirmed the previous observation that DCIS displays intra-lesion genetic heterogeneity. Evidence of clonal selection in the progression from DCIS to IDC was observed in three cases, whereby a minor DCIS subclone likely constituted the substrate for the development of IDC. In one of these cases, from a patient with a BRCA1 germline pathogenic mutation, we observed a shift from the mutational signature associated with defective homologous recombination DNA repair (i.e. signature 3) to the APOBEC-related mutational signatures (i.e. signatures 2 and 13) in the progression from DCIS to IDC. Conclusion: Intra-lesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC. Our findings corroborate the notion that DCIS is a direct non-obligate precursor of IDC, and that clonal selection in the progression of DCIS to IDC may be present in a subset of cases, but is unlikely to constitute the most frequent mechanism of progression. Citation Format: Lee JY, Bi R, Pareja F, Geyer FC, Brown D, Wen HY, Norton L, Hicks J, Weigelt B, Reis-Filho JS. Whole exome sequencing analysis of the progression from ductal carcinoma in situ to invasive ductal carcinoma [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-02.

Background The incidence of margin re-excision following breast conserving surgery (BCS) is a quality measure in the National Health Service. The threshold is less than 20% of all BCS procedures. Despite three decades of studies and a wealth of literature identifying multiple factors associated with increased risk for margin involvement, an accepted threshold rate affecting one in five procedures remains high. Aim The aim of the study was to identify adverse features that continue to compromise successful margin clearance despite the recognition of risk factors and the implementation of strategies designed to minimise those risks. Methods All margin re-excisions following BCS for invasive breast carcinoma and ductal carcinoma in situ (DCIS) performed from October 2013 to September 2018 were retrieved from the database of a single institution. A total of 1379 patients underwent BCS during the period considered, 194 of which needed margin re-excision. Radiological investigations and histopathology reports for each patient were retrieved. Lesion size and focality on mammogram, ultrasound (US) scan, and magnetic resonance imaging (MRI), and histopathologic tumour characteristics were recorded and analysed. Results The overall re-excision rate was 14.06% (194/1379 patients). Margin re-excisions cleared 69% (134/194) of wide local excision cavities that had at least one involved margin.53% (103/194) of patients had no further disease after one attempt at re-excision and 15.9% (31/of 194) had further disease, which was cleared after re-excision. Another 15.9% (31/194) had disease within the shave with involved margins. In this sub-group the presence of DCIS at the new resection margin accounted for 90.3% (28/31) of cases, 3% (1/31) were invasive ductal carcinoma (IDC) and 6% (2/31) were unrecorded. In the sub-group of patients who had an excised margin with pathology and a new clear margin (15.9% of all re-excisions), DCIS was found in 61% (19/31) of cases, IDC in 12.9% (4/31), invasive lobular carcinoma (ILC) in 6% (2/31)of cases, lobular neoplasia (LN) in 12.9% (4/31), mixed IDC and DCIS in 6% (2/31)of cases. The correlation between imaging size and actual histopathological size has shown a statistically significant discrepancy in this cohort. The median size on histology was 22 mm, compared to a median size of 16 mm on mammography, 14 mm on ultrasound, and 17 mm on MRI. Conclusion According to our cohort of patients, the most consistent factor associated with a re-excision was the presence of DCIS at the resection margin, whether pure DCIS or IDC admixed with DCIS. The comparison between tumour size on imaging and final histopathological size revealed the best correlation with mammogramfollowed by US. The weakest correlation was with MRI.

Tamoxifen for intraductal cancer

In 1973, the European Institute of Oncology performed the first prospective neoadjuvant chemotherapy study in locally advanced, inoperable breast cancer. The original purpose was to downstage the primary tumor in order to achieve surgical resection. This approach has subsequently increased in popularity, and in the last 10 years, randomized controlled trials of neoadjuvant chemotherapy have been performed with a view to further downstage the primary tumor and lymph nodes in order to achieve greater rates of breast-conserving surgery and to test whether systemic therapy given earlier would confer a survival benefit. Although the net result of these trials did demonstrate a higher rate of breast conservation, no overall survival benefit was seen. However, in subgroup analysis, there was a significant survival benefit in patients in whom a complete pathologic response (pCR) was achieved. In the National Surgical Adjuvant Breast and Bowel Project B-18 trial of neoadjuvant chemotherapy, at 9 years median follow-up, the overall survival rate for patients achieving a pCR was 85% compared with 73% in those in whom residual cancer was detected on histopathologic examination. For disease-free survival, the respective rates were 75% and 58%. After adjustment for other prognostic factors, achievement of a pCR was associated with a 50% reduction in deaths compared with the group as a whole. Mauri et al evaluated nine randomized studies, with a total of 3,946 patients with breast cancer in whom neoadjuvant therapy was compared with adjuvant systemic therapy. They found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms with regard to overall survival, disease progression, or distant disease recurrence. However, they observed that neoadjuvant therapy was associated with an increased risk of locoregional disease recurrence compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant arm received radiation therapy without surgery. In several retrospective studies, the pCR rates in invasive ductal breast carcinoma (no special type) have been shown to be approximately 15% or less, whereas the pCR rates in invasive lobular carcinoma have been shown to be 2% or less. Katz et al reviewed randomized trials of neoadjuvant chemotherapy and noted that the pCR rate was 1.7% in invasive lobular carcinoma and 11.6% in invasive ductal breast carcinoma (no special type). Regarding invasive lobular carcinoma, they concluded: “the benefit from systemic chemotherapy for individuals with this form of breast disease is unclear.” Similarly, two retrospective studies have demonstrated low rates of successful breast conservation for patients with lobular carcinoma who underwent neoadjuvant chemotherapy. In patients who received breast-conserving surgery after neoadjuvant therapy, Soucy et al found surgical margin involvement in 43% of patients with lobular carcinoma compared with 16% of patients with invasive ductal carcinoma (no special type). Another study, from the M. D. Anderson Cancer Center, of 284 consecutive patients diagnosed with pure invasive lobular carcinoma between 1998 and 2006 compared patients who received neoadjuvant chemotherapy with those who received primary surgery as first-line treatment and concluded that neoadjuvant chemotherapy did not increase the rates of breast conservation in this morphologic subtype. It should be noted that the above studies are retrospective, not randomized, trials. In the three randomized trials of neoadjuvant endocrine therapy (P024 conducted by the Letrozole Neoadjuvant Breast Cancer Study Group, IMPACT [Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen], and PROACT [Pre-Operative “Arimidex” Compared to Tamoxifen]) for women with estrogen receptor (ER) –positive disease, none of which carried out analysis of histological tumor type (ie, lobular v ductal [no special type]), a higher rate of breast conservation was observed in women who received preoperative endocrine treatment. The lack of subgroup analysis in these three studies does not allow one to draw conclusions regarding histologic type-specific effectiveness of neoadjuvant endocrine treatment, although classical lobular carcinoma is well recognized as more often being ER positive than ductal tumors (no special type). JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 22 AUGUST 1 2010

Does the Presence of Ductal Carcinoma in situ Affect Prognostic Outcomes After Neoadjuvant Therapy in Invasive Ductal Carcinoma of the Breast?