Lobular Subtype Research Articles

Invasive Ductal Carcinoma of the Breast Presenting as Small Bowel Obstruction and Ruptured Appendix: A Rare Case Report and Review

Introduction: Metastasis of breast carcinomas to the GI tract is uncommon, and when present is usually of the invasive lobular carcinoma subtype. This case report presents an even more unusual example of invasive ductal carcinoma metastasizing to the GI tract, and with the unusual presentation of a ruptured appendix and Small bowel obstruction. Case presentation: This case report describes a 52-year-old female patient who was diagnosed with metastatic invasive ductal breast carcinoma, which had an extremely unusual presentation of severe abdominal pain, nausea, and vomiting and perforation of the appendix and small bowel obstruction. Although tumors themselves are not an uncommon cause of SBO, metastatic breast cancer is extremely uncommon. Suspicion of breast carcinoma was initially considered after CT scan performed for abdominal pain revealed a previously unknown breast nodule. Subsequent worsening of symptoms, caused by rupture of an appendiceal metastasis, required laparotomy revealed mass of the appendix. Conclusion: This case report and review highlights that it is essential to keep an open mind regarding nonspecific symptoms, and always consider unusual presentations. Early diagnosis from appropriate and timely workup results in better patient outcomes and reduces morbidity and mortality. Invasive Ductal carcinomas of the breast very rarely metastasize to the GI tract, Invasive lobular carcinomas more commonly metastasize to the GI tract whereas invasive Ductal carcinoma metastasizes to lungs and liver. Throughout 23 years reviewing about 8699 appendectomy specimens only about 15 cases of secondary appendiceal tumors were identified.

Abstract P5-07-13: Causes of death among breast cancer patients and their relationship to etiology of breast cancer

Abstract Background: With improved survival among women with breast cancer, the risk of dying from causes other than breast cancer has increased. Emerging studies suggest the possibility of shared modifiable risk factors between some of the causes of death among breast cancer patients and the occurrence of breast cancer. This study is aimed at understanding the etiology of breast cancer from identifying the mortality causes of women with breast cancer. Methods: The study cohort consists of 50481 female breast cancer patients diagnosed between 1971 and 2000 and registered in the national population-based Finnish Cancer Registry. The cohort was followed up until the end of 2012 by data linkage with National Causes of Death Register. Standardized mortality rates (SMRs) for the different cause of deaths among breast cancer patients were calculated by age at diagnosis of cancer (<50 years, 50+ years), histology (ductal, lobular), and by period of follow-up after the breast cancer diagnosis (< 1 year, 1-4·99 years and 5-11·99 years, 12+ years). A Poisson regression model, with adjustment of age and calendar period, was used to further compare the difference in risk of each cause of death between breast cancer histology and between different follow-up time categories. Results: 30841 deaths were recorded during the total follow up, of which 41% was due to causes other than breast cancer (SMR 2.71, 95% CI 2.68-2.74). SMRs for other malignant neoplasms such as stomach (SMR 2.25, 95% CI 1.67- 2.96), larynx, trachea and lung (SMR 1.84, 95% CI 1.49- 2.24), and ovary (SMR 1.49, 95% CI 1.12- 1.94) was significantly high among women <50 years. For women 50+ years, SMR was significantly high only for stomach cancer (SMR 1.31, 95% CI 1.13- 1.49). Among other cancers, only stomach cancer had significantly increased SMRs for both ductal and lobular subtypes. Diseases of the circulatory system were significantly increased among women at age <50 years and 50+ years, however, increased SMR was observed only for ductal breast cancer subtype. The SMR for the diseases of the respiratory system significantly increased only for women 50+ years of age and did not show any significant difference in the risk by histology. The risk of age-adjusted mortality due to other causes excluding breast cancer increased with follow up time for women <50 years, however, for women 50+ years, the highest risk of all-cause excluding breast cancer was observed in <1 year follow up (HR 19.7 95% CI 18.8-20.6) as compared to 5-11.99 years. Conclusion: This study concludes that the causes of death among breast cancer patients vary by age at diagnosis, histology and follow up time and indicates that there might be shared genetic and environmental risk factors between breast cancer and mortality outcomes among breast cancer patients. The mortality patterns provide indirect information on what risk factors might have played on the development of breast cancer. Citation Format: Sushmita Katuwal, Eero Pukkala. Causes of death among breast cancer patients and their relationship to etiology of breast cancer [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 P5-07-13.

Abstract P4-05-04: Advanced breast cancer (ABC) in young women (YW): A comprehensive genomic profiling (CGP) study

Abstract Background: ABC in YW is an aggressive disease with a higher mortality rate than that seen in older women (OW). Pre-menopausal women face challenges in balancing treatment with reproductive health and are often excluded from promising clinical trials. Studies from NCI SEER suggest that the rate of YW breast cancer has nearly doubled in the last 40 years from 1.5 to 2.9 cases per 100,000. In this study, we compare the genomic alterations (GA) in ABC in YW vs OW across ancestry groups. Methods: Hybrid-capture based CGP of at least 315 cancer-related genes was performed on 21,440 clinically advanced breast cancers in 4,303 YW (<45) and 17,137 OW (≥45). Predominant ancestry was assessed using a SNP-based approach (Connelly et al, 2018). Subgroups were analyzed on histological (Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC) and molecular subtypes (ER-positive (ER+), HER2-amplified (HER2+), TNBC). Results: Our cohort of young women (YW) exhibit different frequencies of genetic driver events compared to older women (OW) (25 genes with a corrected p < 0.01) including a lower frequency of alterations in PIK3CA (23% in YW v 36% in OW, p = 8E-63), TBX3 (1.1% v 3.9%, p = 1E-16), and RUNX1 (1.2% v 2.4%, p = 6E-08) and a higher frequency of BRCA1 (8.5% in YW vs 3.2% in OW; p = 1E-32), BRCA2 (6.3% v 4.3%, p = 9E-08), and GATA3 (12.5% v 8.4%, p = 5E-16). When accounting for histological and molecular subtype, many of the same trends hold (Table 1). For example, PIK3CA alterations were observed at a significantly reduced rate in YW in ER+, HER2+, and TNBC disease. Although BRCA1 mutations are generally associated with TNBC, we observed a significantly higher frequency of alterations in YW with ILC (4.7% v 0.8%, p = 0.01) and ER+ disease (5.9% v 2.2%; p = 0.003). ESR1 point mutations were lower in YW v OW (6% v 13%, p = 3E-38), possibly reflecting differences in therapy. Unexpectedly, the distribution of ESR1 LBD alterations differed between the cohorts, with Y537S as the most common alteration in YW (40% v 24% in OW; p = 1E-06). YW with ILC showed a significantly higher rate of biopsy from the female reproductive tract (40% v 7.5% in OW, p =0.0001). TNBC tumors exhibited a higher rate of brain metastasis rate in YW (23% v 6% in OW, p = 0.003). HER2 tumors exhibited a lower rate of metastases to the skin in YW (8% v 14%, p = 0.02). No significant differences were observed in sites of distant metastasis in the ER+ subtype (all p >0.08). YW ABC was depleted in European ancestry (OR = 0.56, p = 2e-56) and strongly enriched in Asian and American ancestry (OR = 1.7 and 1.9, respectively, p < 6E-15) relative to the cohort of OW. No genes exhibited significant differences in frequency across ancestry groups (p >0.05). Across ancestry groups, BRCA1/2, ESR1, GATA3, and TBX3 show similar patterns between YW and OW. Patterns of metastatic tissue tropism were also largely similar across ancestry groups. significance YW v OW in groupGenefreq YWfreq OWoverallILCIDCER+HER2+TNBCPIK3CA23.1%36.3%P<0.0001nsP<0.0001P<0.0001P<0.001P<0.01TBX31.1%3.9%P<0.0001p<0.05P<0.0001P<0.01P<0.01nsRUNX11.2%2.4%P<0.0001nsP<0.01nsP<0.001nsBRCA18.5%3.2%P<0.0001P<0.01P<0.0001P<0.01nsP<0.01BRCA26.3%4.3%P<0.0001p<0.05nsnsnsnsGATA312.5%8.4%P<0.0001nsP<0.0001P<0.0001nsnsESR16.0%12.6%P<0.0001P<0.01P<0.0001P<0.0001P<0.01ns Conclusions: CGP of ABC in YW vs OW revealed consistent genetic differences across molecular and histological subtypes, which may impact targeted therapies. YW have a lower frequency of alterations in PIK3CA across all molecular subtypes, potentially limiting the utility of PI3K-alpha inhibitors, such as alpelisib. The high frequency of BRCA1/2 alterations across subtypes may predict sensitivity to PARP inhibitors. While there are differences in the relative prevalence of ancestry groups in our population, we did not observe significant differences in driver alterations or tissue tropism across these groups. Citation Format: Ethan S Sokol. Advanced breast cancer (ABC) in young women (YW): A comprehensive genomic profiling (CGP) study [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 P4-05-04.

368P - Clinicopathological characteristics, survival and prognostic factors of breast cancer-related microangiopathic haemolytic anemia: A multicenter study

BackgroundCancer-related microangiopathic haemolytic anemia (MAHA) is a rare but life-threatening paraneoplastic syndrome. Only case reports or very small series (<5-10 cases) with mixed cancer types have been been reported so far. We conducted the first retrospective multicenter study focusing on breast cancer related-MAHA (BC-MAHA). Methods13 centers in France were contacted for this retrospective study in patients treated for BC over the past 20 years. Presence of schistocyte and either low haptoglobin or cytopenia was mandatory to retain the diagnosis of MAHA. MAHA from other causes than BC were excluded, as well as patients treated with gemcitabine or bevacizumab prior to MAHA diagnosis. Patient characteristics, treatments and outcome were retrieved from digital medical records. ResultsIndividual data from 54 patients with BC-MAHA were obtained from 7 centers. 23 (44%) patients had a lobular BC and most BC were of low grade (grade I/II, N=39, 75%). 33 (69%) primary BC were ER+/HER2- whereas 7 (15%) were HER2+ and 8 (17%) triple negative. At MAHA diagnosis, all 54 patients had a stage IV cancer, 32 (59%) had ≥3 metastatic sites. Median overall survival (OS) was 28 days (range: 0-1035; Q1:10, Q3:186). In univariate logistic regression analysis performed after imputation of missing data with MICE procedure, PS >2 (OR=6.0, CI95% [1.8; 19.8]), one or more prior lines of treatment (OR=2.9, [0.9; 8.7]), elevated bilirubin (OR=5.5, [1.5; 20.6]), haemoglobin <80g/L (OR=4.0, [1.35; 12.0]), and prothrombin ratio <50% (OR=7.1, [0.9; 50.0]) were associated with a higher risk of death within 4 weeks of MAHA diagnosis. In multivariate analysis, PS >2 (OR=6.1, [1.4; 25.9]), elevated bilirubin (OR 4.7, [1.0; 24.0]), haemoglobin <80g/L (OR=4.0, [0.9; 16.7]) and prothrombin ratio <50% (OR=11.1, [1.06; 100.0]) remained associated with a higher risk of death within 4 weeks of MAHA diagnosis. ConclusionsThis study is the first attempt at characterizing BC-MAHA, which appears to be more frequent in the lobular subtype. In spite of a dismal median OS, a few patients experienced long-term survival and we document, for the first-time, prognostic factors that may guide therapeutic decision making. Legal entity responsible for the studyFrançois-Clément Bidard (Institut Curie, Paris, France). FundingHas not received any funding. DisclosureF.C. Bidard: Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: Menarini Silicon Biosystems; Speaker Bureau / Expert testimony: Amgen. P. Heudel: Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Sandoz; Travel / Accommodation / Expenses: Roche. J. Pierga: Honoraria (institution), Research grant / Funding (self): Amgen; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (self): illumina; Honoraria (self), Research grant / Funding (self): Genomic Health; Honoraria (self), Research grant / Funding (self): puma; Honoraria (self), Research grant / Funding (self): Celltrion; Honoraria (self), Research grant / Funding (self): sandoz; Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Ipsen; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): jansen diagnostics; Research grant / Funding (institution): menarini silicon biosystems; Research grant / Funding (institution): bms; Research grant / Funding (institution): MSD; Research grant / Funding (institution): daiichi senkyo; Research grant / Funding (institution): Servier. S. Delaloge: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: astrazeneca; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): puma; Advisory / Consultancy, Research grant / Funding (institution): orion; Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Amgen. J. Frenel: Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: bio cad; Advisory / Consultancy: astrazeneca; Advisory / Consultancy: Lilly; Honoraria (institution): Novartis. C. Levy: Advisory / Consultancy, Travel / Accommodation / Expenses: astrazeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: biogaran; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

Risk of breast cancer among women with benign ovarian tumors: a Danish nationwide cohort study.

To assess the association between benign ovarian tumors and subsequent risk of breast cancer, and to examine this association according to type of benign ovarian tumors. This nationwide cohort study comprised all Danish women diagnosed with a benign ovarian tumor during 1978-2016 (n = 158,221) identified through the Danish National Patient Register. The cohort was linked to the Danish Cancer Registry to identify all cases of breast cancer, and standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated. Overall, women with a benign ovarian tumor were at significantly increased risk of breast cancer. The risk was confined to women with a solid ovarian tumor (SIR 1.09; 95% CI 1.05-1.13), particularly in women ≥ 50years at benign tumor diagnosis (SIR 1.19; 95% CI 1.12-1.26). The risk remained increased up to 20years or more after the diagnosis of a solid ovarian tumor (SIR 1.11; 95% CI 1.04-1.18), and women with a solid tumor were at increased risk of ductal, lobular, and other types of breast cancer, although most consistent for the lobular subtype. For cystic tumors, this association was confined to ductal breast cancer in women with the tumor diagnosed at age ≥ 50years. Women with a benign ovarian tumor were at increased risk of breast cancer. This association was largely confined to women with a solid ovarian tumor, and the excess risk was present 20years or more after the ovarian tumor diagnosis. The underlying mechanism is unknown and should be investigated further.

FGFR4 overexpression and hotspot mutations in metastatic ER+ breast cancer are enriched in the lobular subtype

Invasive lobular carcinoma (ILC) is an understudied subtype of breast cancer that requires novel therapies in the advanced setting. To study acquired resistance to endocrine therapy in ILC, we have recently performed RNA-Sequencing on long-term estrogen deprived cell lines and identified FGFR4 overexpression as a top druggable target. Here, we show that FGFR4 expression also increases dramatically in endocrine-treated distant metastases, with an average fold change of 4.8 relative to the paired primary breast tumor for ILC, and 2.4-fold for invasive ductal carcinoma (IDC). In addition, we now report that FGFR4 hotspot mutations are enriched in metastatic breast cancer, with an additional enrichment for ILC, suggesting a multimodal selection of FGFR4 activation. These data collectively support the notion that FGFR4 is an important mediator of endocrine resistance in ILC, warranting future mechanistic studies on downstream signaling of overexpressed wild-type and mutant FGFR4.

Validation of a panel of risk factors for predicting breast cancer reappearance.

e12004 Background: The aim of this clinical study was to assess a panel of risk factors for ipsilateral breast tumor recurrence (IBTR) and de novo contralateral breast cancer (BC) after primary BC treatment. Methods: Retrospectively, 15,168 consecutive patients with primary monolateral BC were enrolled in this monocentric study (1994-2006). Clinicopathological features, follow-up and survival at 15 years were considered for statistical analysis. Results: Significant increased risk for IBTR were verified with younger age ( &lt; 50 years) [HR = 1.31 (1.15-1.49), p &lt; 0.0001], lobular subtype [HR 1.40 (1.15-1.70), p = 0.0007)], pT3 [HR 1.90 (1.42-2.54), p &lt; 0.0001] or pT4 [HR 2.70 (1.47-4.97), p = 0.001], metastatic axillary lymph nodes [HR 1.50 (1.29-1.73), p &lt; 0.0001], peritumoral vascular invasion (PVI) [HR = 1.27 (1.10-1.46), p = 0.001], luminal B [HR 1.57 (1.33-1.87), p &lt; 0.0001], HER2-positivity [HR 1.85 (1.32-2.59), p = 0.0004] and triple-negative subtype [HR 1.76 (1.28-2.43), p = 0.0005]. Older age ( &gt; 70 years) [HR 1.50 (1.05-2.15), p = 0.03] and positive family history [HR 1.86 (1.48-2.34), p &lt; 0.0001] were risk factors for contralateral BC. Significant protective factors for IBTR were mucinous subtype [HR 0.45 (0.27-0.77), p = 0.003], total mastectomy [HR = 0.37 (0.30-0.46), p &lt; 0.0001], hormonotherapy [HR 0.56 (0.45-0.69), p &lt; 0.0001], chemotherapy [HR 0.77 (0.66-0.90), p = 0.001] and external radiotherapy [HR 0.39 (0.31-0.50), p &lt; 0.0001]. Hormonotherapy was also confirmed as a protective factor for contralateral second BC [HR 0.51 (0.38-0.69), p &lt; 0.0001]. Cumulative incidence for IBTR at 5, 10, and 15 years was higher than for than for contralateral BC. Conversely, overall survival for IBTR was lower than for contralateral BC. Conclusions: We classified factors influencing IBTR and contralateral BC into high- and low-risk groups. The high-risk group for IBTR included: age &lt; 50 years, positive axillary nodes, PVI positivity, luminal B, HER2-positive, lobular and triple-negative subtypes. The low-risk group included: adjuvant treatments (hormone-chemotherapy, external radiotherapy) and mucinous histotype. We hypothesize that in the low-risk group, adjuvant treatments exert a strong impact in the prevention of IBTR risk (HER2-positive and triple negative BC should be considered also for neo-adjuvant therapies); this was not confirmed in the high-risk group, in which a more aggressive surgery is still theoretically justified. The proposed panel represents the basis for a nomogram to predict BC reappearance.

The effect of length of birth interval on the risk of breast cancer by subtype in grand multiparous women

BackgroundThe length of interval between successive childbirths (birth interval) might influence the incidence of breast cancer, either by stimulating or by inhibiting the factors that are responsible for the initiation of breast cancer or its early development.MethodsThis is a case-control study nested in a cohort of 47,479 Finnish grand-multiparous (GM) women born after 1934, and registered as having had at least five births before 2013. The 1354 women with breast cancer diagnosis were compared with controls (1:5) matched by parity and date of birth of the mother. Conditional logistic regression was used to estimate odds ratios of the risk of ductal and lobular breast cancer subtypes associated with each of the intervals between the 1st and 5th birth, stratified by age at diagnosis. Age at first and last birth before index date were used as covariates.ResultsIncreased intervals between the 1st and 5th births were associated with an increased risk of lobular breast cancer. In contrast, regarding ductal cancer, premenopausal women with shorter length of interval (< 2 years) between the 1st and 2nd birth had greater risk and longer intervals (3+ years) were associated with reduced risk. Spacing between the 2nd and 5th birth did not influence the risk of ductal breast cancer.ConclusionThe findings of our study suggest that the effect of the length of birth interval on breast cancer depends on the age and histology. The protective effect of shorter birth intervals on lobular breast among postmenopausal women and the opposite effect on ductal cancer in premenopausal women may reflect distinct differentiation and functional roles of lobular and ductal cells, and possibly also different response to hormonal exposure.

Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer.

SummaryBackgroundTriple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC.MethodsFGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays.Results50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed.ConclusionsWe identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.

Abstract P2-08-01: Factors predicting relapse in early breast cancer patients with a pathological complete response after neoadjuvant therapy – Results of a pooled analysis based on the GBG meta-database

Abstract Background Even though patients with a pCR following neoadjuvant chemotherapy have an excellent prognosis still some of these patients will eventually relapse. A better identification of pts with an increased risk of relapse despite a pCR would be helpful to select these patients for additional post-neoadjuvant treatment strategies. Thus, the rationale of this retrospective analysis was to identify factors predicting relapse despite a pCR. Methods This pooled retrospective analysis based on the GBG meta-database includes the neoadjuvant trials GeparTrio, GeparQuattro, GeparQuinto, GeparSixto and GeparSepto. In these trials 2188 (27%) of 7933 pts had a pCR according to ypT0/ypTis ypN0 Definition and were included. The primary endpoint was disease-free survival (DFS), secondary endpoints were distant DFS (DDFS) and overall survival (OS). A multivariate Cox proportional hazards model was used to report hazard ratios with 95% confidence interval (CI). The two-sided significance level was set to α=0.05. Endpoints were analysed for all pts and in subgroups defined by intrinsic subtypes. The potential risk factors intrinsic subtype (HER2 negative/hormone receptor (HR) positive, triple negative, HER2 positive/HR positive, HER2 positive/HR negative), histological tumor type (lobular vs other), grade (G1/G2 vs G3), KI67 (≤20% vs higher), initial cT and cN stadium (cT1 vs cT2 vs cT3/4; cN0 vs cN+), age (≤40 vs 41-59 vs ≥60), BMI (&amp;lt; 25 vs 25-29 vs ≥ 30), planned number of cycles of chemotherapy (≤6 vs &amp;gt; 6), menopausal status (pre- vs postmenopausal) and clinical response after 2-4 cycles (SD vs PR vs CR vs PD) were included as covariates in multivariate Cox regression models as well as study identification. Results From 2188 evaluable patients DFS, DDFS and OS events were observed in 290/197/130 pts respectively; the median follow-up over all studies was 59 months. In multivariate analysis including study and all potential risk factors DFS was significantly different with regard to the initial cN status (cN+ vs cN0, hazard ratio (HR) 1.70; 95% CI [1.2, 2.4], p=0.002). Of borderline significance was histological type (non-lobular vs lobular, HR 0.52 95% CI [0.3, 1.1]; p=0.076) and initial tumor stage (cT3/4 vs cT1, HR 1.61 95% CI [1.0, 2.7]; p=0.064). In terms of DDFS significant differences were seen for the initial cN status (cN+ vs cN0, HR 2.34; 95% CI [1.5, 3.6], p&amp;lt;0.001) and initial tumor stage (cT3/4 vs cT1, HR 1.83 95% CI [1.0, 3.3]; p=0.044); histological type was again close to significance (non-lobular vs lobular, HR 0.46 95% CI [0.2, 1.1]; p=0.067). Multivariate analysis showed significantly worse OS with initial cT3/4 tumors (cT3/4 vs cT1, HR 2.48 95%CI [1.1, 5.7]; p=0.030), and the lobular type (non-lobular vs lobular, HR 0.35 95% CI [0.1, 0.9]; p=0.026) and a trend for worse OS in pts with cN+ (cN+ vs cN0, HR 1.67 95% CI [1.0, 2.9]; p=0.067). Conclusions Initial tumor load before start of neoadjuvant chemotherapy (tumor stage and nodal status) and lobular subtype were predictors of long term outcome after a pCR following neoadjuvant chemotherapy. Intrinsic subtype, KI67, grade and planned number of cycles were not predictive for a relapse. Citation Format: Huober J, Schneeweiss A, Blohmer J-U, Denkert C, Tesch H, Hanusch CA, Salat C, Rhiem K, Rezai M, Solbach C, Fasching PA, Jackisch C, Mehta K, Nekljudova V, Seither F, von Minckwitz G, Loibl S, Untch M. Factors predicting relapse in early breast cancer patients with a pathological complete response after neoadjuvant therapy – Results of a pooled analysis based on the GBG meta-database [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 P2-08-01.

Abstract P1-15-14: Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of triple negative breast cancer

Abstract Background: The use of neoadjuvant platinum with taxane for triple negative breast cancer (TNBC) has gained increased attention for improving rates of pathologic complete response (pCR). Our prior trial combining carboplatin (CAR) with liposomal doxorubicin (DOX) for metastatic TNBC showed good response rates with minimal side effects while allowing for greater platinum dosing compared to a taxane combination. We hypothesized that the doublet of DOX+CAR is effective and tolerable in the neoadjuvant setting for TNBC and that tumor genomics may aid in determining those patients most likely to benefit. Methods: A phase II single arm trial was conducted for patients (pts) diagnosed with stage II-III TNBC. Patients received 4 cycles of neoadjuvant carboplatin (AUC 5) and liposomal doxorubicin (30mg/m2) administered every 28 days, then underwent definitive breast surgery followed by 12 weeks of adjuvant paclitaxel 80 mg/m2 administered weekly. Primary and secondary clinical endpoints were rate of pCR and two year recurrence free survival (RFS) and overall survival (OS), respectively. Cardiac safety of the combination was assessed. Fresh residual tumor samples were obtained at time of surgery for generation of patient derived xenografts (PDX). Tumor genomic profiling was done to determine the mutational spectrum, association of this spectrum in primary tumors with achieving pCR, and identifying alternative treatment strategies for PDX evaluation for patients with resistant disease. Results: From 2/2015 to 5/2018, 36 pts were enrolled and 32 completed treatment; 4 pts await definitive surgery; 12 (33%) are two years from diagnosis. Median age of the cohort was 53 years. There was high participation by under-represented groups: 23% African American, 20% Asian, 14% Hispanic. Most histologies were invasive ductal but included apocrine, pleomorphic lobular, and metaplastic subtypes. Of the 32 pts who completed surgery, 34% (11) achieved pCR and 64% (23) had clinical response on serial physical exam. At 2 years, there were 2 distant and 1 local recurrence. The most common toxicities during DOX+CAR were grade 1 nausea in 19 pts (53%), grade 3/4 neutropenia occurred in 10 pts (28%); these pts received GCSF support with subsequent cycles; febrile neutropenia occurred in 1 pt (3%) in this group. Grade 3 thrombocytopenia (2 pts), pruritis (1 pt), and mucositis (1 pt) were observed. Only 6 pts (17%) had grade 1 alopecia. There were no delays in treatment due to cardiotoxicity or complications from surgical healing. TP53 (93%), PI3K/PTEN (26.6%), and NOTCH (20%) were the most commonly altered pathways. Structural variants, such as amplifications, rearrangements, and frameshifts were the most frequent alterations detected. Of the 25 pts who had residual disease, PDX was attempted from 14 pts, and 10 (71%) PDX were established, including those for all 3 patients experiencing recurrence. Conclusion: Neoadjuvant DOX+CAR demonstrated good efficacy and tolerability. Post-chemotherapy PDX is feasible and may help identify targeted approaches for patients with resistant disease. These results warrant further evaluation of this combination for early stage TNBC. Citation Format: Chan N, Riedlinger GM, Lu S-e, Pham KT, Kirstein LJ, Eladoumikdachi FG, George MA, Potdevin LB, Kowzun MJ, Desai SA, Tang DM, Omene CO, Wong ST, Rodriguez-Rust L, Kumar S, Kearney TJ, Liu C, Ganesan S, Toppmeyer DL, Hirshfield KM. Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of triple negative breast cancer [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 P1-15-14.

Metastases to extraocular muscles from breast cancer: case report and up-to-date review of the literature

BackgroundUnilateral or bilateral metastases to extraocular muscles are very rare in breast cancer.Case presentationWe describe a case of inferior rectus extraocular muscle involved by ductal luminal B/Her-2 neu negative breast cancer, observed in a cohort of 580 patients. Our patient had received chemotherapy and hormonal therapy (tamoxifen for 3 years and letrozole in the following 3 years) for her primary cancer and developed an orbital metastasis while she was under aromatase inhibitor-based therapy. Diagnosis was confirmed by MRI and biopsy. Orbital radiotherapy, combined with fulvestrant, resulted in shrinking of the secondary mass. A third line hormonal therapy using palbociclib was then started. Twelve-months later, MRI showed no residual tumor mass. Currently, the patient is alive and in good general conditions after 20 months.ConclusionsLiterature review yielded 57 patients with extraocular muscle metastases from breast cancer, mostly due to the invasive lobular subtype of carcinoma. In addition to the present case, only 4 other extraocular muscles metastases from invasive ductal carcinoma has been reported, pointing out to the rarity of ductal type spread to the orbit in the natural history of breast cancer. Surgery may be used as a single treatment, despite no improvement of symptoms. Radiotherapy alone or combined with chemotherapy, or with chemotherapy plus hormonal therapy are available options. Results are, however, missing or poor. The present case is the first one with complete and stable response after 20 months to radiotherapy, antiestrogen drug fulvestrant and selective inhibitor of CDK4 /CDK6 palbociclib. In this subset of patients, with unusual metastatic sites and frequent multi-organ metastatic impairment, a multidisciplinary approach is indicated in order to achieve the best therapeutic management and long-term surveillance.

Trends on Axillary Surgery in Nondistant Metastatic Breast Cancer Patients Treated Between 2011 and 2015: A Dutch Population-based Study in the ACOSOG-Z0011 and AMAROS Era.

To evaluate patterns of care in axillary surgery for Dutch clinical T1-4N0M0 (cT1-4N0M0) breast cancer patients and to assess the effect of the American College for Surgeons Oncology Group (ACOSOG)-Z0011 and After Mapping of the Axilla: Radiotherapy Or Surgery (AMAROS) trial on axillary surgery patterns in Dutch cT1-2N0M0 sentinel node positive breast cancer patients. Since publication of the ACOSOG-Z0011 and AMAROS trial, omitting a completion axillary lymph node dissection (cALND) in sentinel node positive breast cancer patients is proposed in selected patients. Data were obtained from the nationwide Nationaal Borstkanker Overleg Nederland breast cancer audit. Descriptive analyses were used to demonstrate trends in axillary surgery. Multivariable logistic regression analyses were used to identify factors associated with the omission of cALND in cT1-2N0M0 sentinel node-positive breast cancer patients. Between 2011 and 2015 in cT1-4N0M0 breast cancer patients, the use of sentinel lymph node biopsy as definitive axillary staging increased from 72% to 93%, and (c)ALND as definitive axillary staging decreased from 24% to 6% (P < 0.001). The use of cALND decreased from 75% to 17% in cT1-2N0 sentinel node-positive patients (P < 0.001). Earlier year of diagnosis, lower age, primary mastectomy, invasive lobular subtype, increasing tumor grade, and treatment in a nonteaching hospital were associated with a lower probability of omitting cALND (P < 0.001). This study shows a trend towards less extensive axillary surgery in Dutch cT1-T4N0M0 breast cancer patients; illustrated by an overall increase of sentinel lymph node biopsy and decrease in cALND. Despite this trend, particularly noticed in cT1-2N0 sentinel node-positive patients after publication of the ACOSOG-Z0011 and AMAROS trial, variations in patterns of care in axillary surgery are still present.

Discrepancy in risk assessment of hormone receptor positive early-stage breast cancer patients using breast cancer index and recurrence score.

A recent comparison of the prognostic accuracy of Breast Cancer Index (BCI) and the Recurrence Score (RS) showed that BCI was more precise than RS. BCI identified a subset of RS low and intermediate risk patients with clinically relevant elevated rates of distant recurrences (DR). The current study analyzed the correlation of BCI and RS risk classification to clinical and pathological parameters and further examined the re-categorization between the two risk group indices in a multi-institutional cohort of hormone receptor positive (HR+) breast cancer patients. 560 women with HR+, lymph node-negative breast cancer who underwent testing with RS as part of their routine clinical care were included in the final analysis. Individual risk was assessed using predefined categories of RS and BCI (Low, Intermediate and High, respectively). Correlations between BCI, RS, and standard clinical-pathological prognostic factors were examined, and re-categorization of risk groups between BCI and RS was analyzed. An overall significant association between histological tumor grade and RS or BCI was observed with high-grade tumors more prevalent among RS and BCI high-risk patients. The invasive ductal carcinoma histologic subtype was associated with 98% and 93% of high-risk RS and BCI cases, respectively. The invasive lobular subtype accounted for 0% and 6% of high-risk RS and BCI cases, respectively. A poor agreement between the two biomarker risk group indices was demonstrated with more than 51% of the total cohort stratified differently between BCI and RS. As compared with RS, BCI stratified fewer patients into the intermediate-risk group (29% vs. 39%, BCI and RS, respectively) and more patients into the high-risk group (19% vs. 7%, BCI and RS, respectively). Subsets of both RS low- and intermediate-risk patients were identified by BCI as high risk. In this clinical series, BCI and RS risk groups demonstrated a significant association with histological tumor grade. BCI showed a modest correlation with tumor size and no correlation with age, while RS showed no correlation with tumor size or age. Compared with RS, BCI classifies fewer intermediate risk patients, identifies subsets of low and intermediate RS risk patients as high-risk, and provides distinct individualized risk assessment for patients with early-stage breast cancer.

Tumour characteristics of bilateral screen-detected cancers and bilateral interval cancers in women participating at biennial screening mammography

BackgroundUnilateral interval breast cancers show less favourable prognostic features than unilateral screen-detected cancers, but data on tumour characteristics of bilateral interval cancers in a systematically screened population are sparse. Therefore, we compared tumour characteristics of bilateral interval cancers with those of bilateral screen-detected cancers. MethodsWe included all 468,720 screening mammograms of women who underwent biennial screening mammography in the South of the Netherlands between January 2005 and January 2015. We collected breast imaging reports, biopsy results and surgical reports of all recalled women and of all women who presented with interval breast cancer. In women with synchronous bilateral breast cancer, the tumour with the highest tumour stage was defined as the index cancer. For comparison of data between both groups Fisher exact test and Chi-square test were used. ResultsSynchronous bilateral cancer was diagnosed in 2.2% of screen-detected cancers (64/2947) and in 3.2% of interval cancers (24/753) (P = 0.1). Index tumours of bilateral screen-detected cancers and interval cancers showed similar characteristics, except for a larger proportion of T-stage 2 or worse (T2+) cancers among interval cancers (16/24 (66.7%) versus 23/58 (39.7%) (P = 0.03). Index cancers, compared to contralateral cancers, were less frequently stage T1 in both bilateral screen-detected cancers and bilateral interval cancers (35/64 (60.3%) versus 40/64 (88.9%) (P = 0.001) and 8/24 (33.3%) versus 18/24 (85.7%) (P < 0.001), respectively). In bilateral screen-detected cancers, contralateral cancers were more often stage 1a-c (P < 0.001) compared to index cancers. In bilateral index cancers, index cancers were more often of the lobular subtype (P < 0.001). ConclusionIndex cancers of bilateral screen-detected cancers and bilateral interval cancers show significant differences in tumour size, whereas nodal status, receptor status and final surgical treatment are comparable. In bilateral screen-detected cancer, index cancers had a significantly higher tumour stage. In bilateral screen-detected cancer, index cancers were more often the ductal invasive subtype compared to contralateral cancers.

Dynamic Contrast-enhanced Breast MRI for Evaluating Residual Tumor Size after Neoadjuvant Chemotherapy.

Purpose To investigate the accuracy of dynamic contrast material-enhanced (DCE) breast MRI for determining residual tumor size after neoadjuvant chemotherapy (NAC). Materials and Methods For this retrospective study, 487 consecutive women (mean age, 47.0 years ± 10.3 [standard deviation]; range, 24-78 years) underwent preoperative DCE MRI following NAC and subsequent surgeries between 2008 and 2011. Tumor size was measured at early-phase, conventional delayed-phase, and late delayed-phase MRI (90, 360, and 590 seconds after contrast material injection, respectively). At histopathologic examination, total tumor size (both invasive and in situ) and the size of invasive tumor alone were separately recorded. Absolute agreement between tumor size at MRI and histopathologic examination was assessed by using intraclass correlation coefficient (ICC) analysis. Factors affecting size discrepancy were assessed by using multiple linear regression analysis. Results Compared with tumor size at histopathologic examination, total tumor sizes showed higher agreement at conventional delayed-phase MRI than at early-phase MRI (ICC, 0.76 vs 0.56; P ˂ .001) and comparable agreement at conventional and late delayed-phase MRI (ICC, 0.76 vs 0.74; P = .55). Lobular histologic features and tumor subtype were independently associated with greater size discrepancy (P ˂ .001). Lobular cancers were underestimated in size compared with ductal cancers (mean size discrepancy, -2.8 cm ± 3.2 vs -0.3 cm ± 1.8; P = .004). Estrogen receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative cancers were underestimated compared with HER2-positive cancers (-0.8 cm ± 2.0 vs -0.3 cm ± 1.7, P = .006) and triple-negative cancers (-0.8 cm ± 2.0 vs 0.3 cm ± 1.7, P ˂ .001). Conclusion Delayed-phase MRI is more accurate than early-phase MRI for evaluating residual breast tumor size after neoadjuvant chemotherapy. Lobular or estrogen receptor-positive/human epidermal growth factor receptor 2-negative cancers are underestimated in size at MRI compared with ductal or other subtypes. © RSNA, 2018 Online supplemental material is available for this article.

Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer

Summary Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.

Abstract MS2-3: Tailoring systemic therapy for patients with lobular breast cancer

Abstract Recent developments in breast cancer treatment include an increasing awareness of the role of systemic therapies in selected subgroups of patients. A consequence of this strategy is the importance of accurate and reliable histopathological assessment. Through the identification of lobular breast cancer, that account for up to 15% of all invasive breast carcinomas, it is possible to select patients with correlates of responsiveness to therapy other than important indicators of outcome. It was in fact demonstrated that the response to neoadjuvant chemotherapy is significantly lower in lobular breast carcinomas, if compared with the ductal histotype. Also the value of adjuvant chemotherapy in lobular carcinomas was recently questioned, while the magnitude of the effect of adjuvant trastuzumab is similar in lobular and ductal breast cancer. The diagnosis of lobular breast cancer might be relevant also for the selection of endocrine agents in the adjuvant treatment. In particular the relative effectiveness of letrozole compared with tamoxifen was shown to be greater for patients diagnosed with lobular breast cancer. Nevertheless, the use of available information has been limited in tailoring therapy on patients with the lobular subtype, due to the relative rarity of the disease, the absence of prospective studies and the limited number and size of retrospective analysis. The development of effective therapies for these patients should not rely on information mainly contributed from small retrospective analyses. Prospective tailored research through international cooperation is key to make progress and reach consensus on how to treat individual patients with lobular breast carcinomas. Citation Format: Colleoni MA. Tailoring systemic therapy for patients with lobular breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr MS2-3.

UDP-sugar accumulation drives hyaluronan synthesis in breast cancer

Increased uptake of glucose, a general hallmark of malignant tumors, leads to an accumulation of intermediate metabolites of glycolysis. We investigated whether the high supply of these intermediates promotes their flow into UDP-sugars, and consequently into hyaluronan, a tumor-promoting matrix molecule. We quantified UDP-N-Acetylglucosamine (UDP-GlcNAc) and UDP-glucuronic acid (UDP-GlcUA) in human breast cancer biopsies, the levels of enzymes contributing to their synthesis, and their association with the hyaluronan accumulation in the tumor. The content of UDP-GlcUA was 4 times, and that of UDP-GlcNAc 12 times higher in the tumors as compared to normal glandular tissue obtained from breast reductions. The surge of UDP-GlcNAc correlated with an elevated mRNA expression of glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), one of the key enzymes in the biosynthesis of UDP-GlcNAc, and the expression of GFAT1 was also elevated. The contents of both UDP-sugars strongly correlated with tumor hyaluronan levels. Interestingly, hyaluronan content did not correlate with the mRNA levels of the hyaluronan synthases (HAS1–3), thus emphasizing the role of the UDP-sugar substrates of these enzymes. The UDP-sugars showed a trend to higher levels in ductal vs. lobular cancer subtypes. The results reveal for the first time a dramatic increase of UDP-sugars in breast cancer, and suggest that their high supply drives the accumulation of hyaluronan, a known promoter of breast cancer and other malignancies. In general, the study shows how the disturbed glucose metabolism typical for malignant tumors can influence cancer microenvironment through UDP-sugars and hyaluronan.

Lobular carcinoma in situ and invasive lobular breast cancer are characterized by enhanced expression of transcription factor AP-2β

Transcription factor AP-2β (TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated AP-2β in breast cancer (BC). This study characterizes AP-2β expression in the mammary gland and in BC. AP-2β protein expression was assessed in the normal mammary gland epithelium, in various reactive, metaplastic and pre-invasive neoplastic lesions and in two clinical BC cohorts comprising >2000 patients. BCs from various genetically engineered mouse (GEM) models were also evaluated. Human BC cell lines served as functional models to study siRNA-mediated inhibition of AP-2β. The normal mammary gland epithelium showed scattered AP-2β-positive cells in the luminal cell layer. Various reactive and pre-invasive neoplastic lesions, including apocrine metaplasia, usual ductal hyperplasia and lobular carcinoma in situ (LCIS) showed enhanced AP-2β expression. Cases of ductal carcinoma in situ (DCIS) were more often AP-2β-negative (P<0.001). In invasive BC cohorts, AP-2β-positivity was associated with the lobular BC subtype (P<0.001), loss of E-cadherin (P<0.001), a positive estrogen receptor (ER) status (P<0.001), low Ki67 (P<0.001), low/intermediate Oncotype DX recurrence scores (P<0.001), and prolonged event-free survival (P=0.003). BCs from GEM models were all AP-2β-negative. In human BC cell lines, AP-2β expression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2β diminished proliferation of lobular BC cell lines in vitro. In summary, AP-2β is a new mammary epithelial differentiation marker. Its expression is preferentially retained and enhanced in LCIS and invasive lobular BC and has prognostic implications. Our findings indicate that AP-2β controls tumor cell proliferation in this slow-growing BC subtype.