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Solid-basaloid variant of adenoid cystic carcinoma of the breast with near complete response to neoadjuvant chemotherapy

Solid-basaloid variant of adenoid cystic carcinoma of the breast with near complete response to... www.nature.com/npjbcancer CASE REPORT OPEN Solid-basaloid variant of adenoid cystic carcinoma of the breast with near complete response to neoadjuvant chemotherapy 1 1 1 2 1 3 Anne Grabenstetter , Edi Brogi , Hong Zhang , Pedram Razavi , Jorge S. Reis-Filho , Kimberly J. VanZee , 2 1 Larry Norton and Hannah Y. Wen Breast adenoid cystic carcinoma (AdCC) is a rare subtype of triple negative breast cancer. Two morphologic variants are described, namely classic AdCC (C-AdCC) and solid basaloid (SB-AdCC). Recent studies have shown that the SB-AdCC variant has significantly worse prognosis than C-AdCC. Due to the rarity of SB-AdCC, no standard recommendations are available for its management. Data on the use and benefit of chemotherapy in patients with SB-AdCC are sparse and the response to neoadjuvant chemotherapy has not been reported. We present the clinical and pathologic findings of a patient with SB-AdCC treated with neoadjuvant chemotherapy who achieved a remarkable pathologic response. npj Breast Cancer (2022) 8:93 ; https://doi.org/10.1038/s41523-022-00469-z INTRODUCTION of the right axilla showed a suspicious lymph node. An ultrasound guided biopsy of the breast mass yielded an infiltrating Breast adenoid cystic carcinoma (AdCC) is a rare histologic moderately differentiated mammary carcinoma with associated subtype of breast cancer, usually of triple negative phenotype. intermediate grade intraductal carcinoma, solid and cribriform These tumors account for <1% of all breast cancers, composed of type. Subsequently, the patient presented to Memorial Sloan a dual population of epithelial and myoepithelial neoplastic cells, Kettering Cancer Center (MSK) for cancer care. arranged in cribriform, tubular and/or solid growth patterns. Physical examination revealed a palpable right breast mass AdCCs have been shown to be driven by activation of the MYB measuring approximately 10 mm immediately deep to the nipple, pathway, most commonly due to a MYB-NFIB fusion gene, focally inseparable from the skin. There was no obvious palpable followed by fusion genes involving MYBL1 or MYB gene adenopathy. Breast MRI revealed a 13 × 13 × 12 mm irregular amplification . The solid basaloid variant of AdCC (SB-AdCC) is composed of cells with scant cytoplasm, marked nuclear atypia enhancing mass with T2 hyperintensity in the retroareolar region and increased mitotic activity . In contrast to the classic form of along with an abnormal right level 1 axillary lymph node, measuring AdCC (C-AdCC), which typically follows a relatively indolent 10 mm (Fig. 1). As per protocol, the initial core biopsy was reviewed 2–4 course, the SB-AdCC variant has an aggressive clinical behavior . by the MSK Pathology Department. Microscopically, multiple tissue Vanishingly rare (there are less than 100 published cases of SB- cores were involved by an infiltrating basaloid carcinoma with solid AdCC), currently there are no standardized recommendations nests and focal cribriform architecture within a desmoplastic stroma regarding management. In the limited series available, most showing approximately 5–10% stromal tumor infiltrating lympho- patients were treated with surgical excision and post-operative cytes (Fig. 2). The neoplastic cells displayed a high nuclear to radiation but adjuvant chemotherapy was often omitted, similar to cytoplasmic ratio, moderate nuclear atypia and conspicuous mitoses. 5–7 the management of C-AdCC . At present, there is a paucity of Immunohistochemistry (IHC) demonstrated diffuse expression of data on chemotherapy benefit for SB-AdCC and its response to cytokeratin 7 (CK7), CK8/18, CK5/6 and c-kit (CD117), occasional p63 neoadjuvant treatment is unknown. Here, we describe a case of reactivity, and MYB nuclear expression (Fig. 2). A MYB translocation SB-AdCC treated with neoadjuvant chemotherapy with a near was identified by fluorescence in situ hybridization (FISH) utilizing complete pathologic response. break apart probes. The tumor lacked estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) expression. The Ki67 proliferation index was RESULTS approximately 40% (Fig. 2). The histologic, IHC and molecular Case presentation findings supported a diagnosis of SB-AdCC. Focal in situ carcinoma A 56 years old woman of Ashkenazi Jewish descent with no was also identified. Fine needle aspiration (FNA) of the suspicious significant past medical history or family history of breast or right axillary node yielded malignant cells, consistent with metastatic ovarian cancer, initially presented to an outside hospital after carcinoma. palpating a right breast mass. The patient underwent bilateral Breast conservation surgery (BCS) and mastectomy, along with mammogram that revealed a right breast 9 mm spiculated mass sentinel lymph node biopsy were discussed with the patient. Due with associated calcifications and nipple retraction, corresponding to the central location of the tumor and imaging suggesting involvement of areolar skin, a wide excision would also require to the sonographic finding of an 8 mm irregular, retroareolar mass removal of the nipple areolar complex. In this context, a medical which appeared to invade the nipple-areolar complex. Ultrasound 1 2 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. email: grabensa@mskcc.org Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A. Grabenstetter et al. oncology consultation was obtained. Given the triple negative could provide a complete pathologic response in the axilla that would obviate the need for axillary dissection. The patient elected phenotype and biopsy proven positive lymph node status, to have an attempt at BCS and thus was given pre-operative dose- neoadjuvant chemotherapy was recommended because if it dense AC-T (doxorubicin plus cyclophosphamide each two weeks with G-CSF support for four cycles followed by carboplatin each 3 weeks for four cycles plus twelve cycles of weekly paclitaxel), which was well tolerated. Because AdCC is often regarded to be a chemotherapy-resistant subtype of breast cancer the patient was monitored with monthly imaging studies to assess response and ensure there was continued shrinkage of disease. After FDA approval, she was also started on pembrolizumab. However, she developed immune-mediated nephritis after the second dose of pembrolizumab resulting in its discontinuation. An MRI was performed following completion of therapy which showed very faint, residual 7 mm linear enhancement extending towards the nipple, significantly decreased from prior study (Fig. 1). On pre- surgical physical examination, the palpable mass was no longer appreciated, the areolar skin did not feel tethered to the underlying breast tissue and there was no axillary adenopathy. The patient underwent breast conserving surgery with removal of nipple and sentinel lymph node biopsy upon completion of neoadjuvant treatment. The resection specimen obtained post-neoadjuvant treatment showed a single focus of residual invasive carcinoma, spanning <0.5 mm microscopically, along with approximately 5 mm of residual in situ carcinoma, present in a fibrotic tumor bed grossly measuring 12 × 7 mm (Fig. 3). The carcinoma harbored a MYB rearrangement as detected by in situ hybridization and lacked ER, PR and HER2 expression by IHC. Lymphovascular invasion was not identified. The margins of resection were uninvolved by carci- noma. Three sentinel lymph nodes were retrieved and showed no residual metastatic disease. Treatment related changes were not identified in the lymph nodes. The patient was referred to Fig. 1 Pre and post neoadjuvant chemotherapy imaging. a Pre- therapy MRI showing retroareolar, irregular enhancing mass, 1.3 cm; radiation oncology and received adjuvant radiation therapy to 50 b Post-therapy MRI showing faint linear enhancement, 0.7 cm. Gray in 25 fractions. The patient developed mild erythema during Fig. 2 Core needle biopsy, treatment naïve. a Core biopsy showing infiltrating basaloid carcinoma with solid and cribriform nests (H&E, 50X); b Ki67 proliferation index of approximately 40% (50X); c Diffuse nuclear expression with MYB immunohistochemistry (50X); d p63 immunohistochemistry demonstrates loss of myoepithelial cells surrounding invasive nests, inset reveals focal in situ carcinoma with rim of p63 positive myoepithelial cells (50X, inset 200X). npj Breast Cancer (2022) 93 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A. Grabenstetter et al. Fig. 3 Excision specimen, post neoadjuvant chemotherapy. a Residual carcinoma, H&E, 10X; b Residual invasive (lower right corner) and in situ carcinoma, H&E, 100X; c p63 immunohistochemistry, 10X; inset MYB in situ hybridization, 100X; d p63 immunohistochemistry, 100X. radiotherapy but otherwise tolerated it well. She is currently six achieved an excellent pathologic response, showing complete months status post operation and has recovered well from resolution of the patient’s axillary disease and less than 0.5 mm of neoadjuvant chemotherapy and radiation without major compli- residual invasive carcinoma. Published data on the effect of chemotherapy in patients with SB- cations. She was then started on adjuvant capecitabine, which she AdCC is based on small trials and more frequently involve AdCC is tolerating well. She has remained clinically disease free and is undergoing active surveillance as per guidelines. arising in organs other than the breast. Laurie et al. performed a systematic review of 34 studies, including prospective and retro- spective data, examining the systemic treatment of metastatic or DISCUSSION locally recurrent AdCC, all but one of which included only tumors of The mammary SB-AdCC variant was first described in a report by salivary gland origin. In the trials which looked at single agent Shin and Rosen , in which they detailed 9 cases collected over a cytotoxic therapy, the observation of stable disease, noted in 58% period of 11 years. While none of the patients in their series had (64/111) of patients, was more common than objective major evidence of local recurrence or distant metastases despite a follow responses which were seen in only 13% (18/141) of patients. Overall, up period of up to 7.3 years (mean 32 months), the data presented in trials utilizing combination therapy, 25% of patients responded, in that study suggested that SB-AdCC had a higher propensity for most commonly to regimens composed of cisplatin, doxorubicin lymph node metastases than C-AdCC. Subsequent studies and cyclophosphamide (CAP) . These results should be interpreted confirmed this observation, which lead to the recommendation with caution, though, as none of these multi-agent trials enrolled for routine axillary staging in these patients, and also noted more more than 12 patients. The authors also found discrepant response 3,6,8 aggressive clinical behavior . In the largest series reported to rates amongst reports, with higher rates observed in retrospective date, Schwartz et al. compared the clinicopathologic features and reviews versus clinical trials and ultimately conclude further study is follow-up data of 29 SB-AdCC and 75 C-AdCC from MSK. SB-AdCCs needed to develop a standardized management approach. The had significantly higher histologic grade, higher rates of lympho- patient reported here had a remarkable response, providing further vascular invasion and lymph node metastases, and were more support to the notion that chemotherapy may be effective in at least likely to recur locally and develop distant metastatic disease. In a subset of SB-AdCCs. contrast, C-AdCC had a favorable clinical course, with higher Additionally, novel drug therapies targeting specific molecular survival rates than invasive breast carcinoma of no special type, alterations may prove to be efficacious in the rare SB-AdCC. The and 5- and 10-year disease free survival (DFS) rates greater than 95 translocation t(6;9)(q23;p23) leading to the MYB-NFIB fusion gene 1,8 6 and 90%, respectively . In the cohort described by ref. , the is identified in up to 86% of C-AdCC and has been confirmed to be surgical approach and use of adjuvant radiotherapy were similar present in the solid-basaloid variant as well, however it is seen between the variants, however patients with SB-AdCC were much less frequently, reported in only 12.5% of cases in one significantly more likely to receive adjuvant chemotherapy than series . Additionally, MYB expression by IHC has been observed in C-AdCC (68.4% versus 17.3%, respectively). Despite this, DFS was up to 63% of other basal-like, triple negative breast cancers and is significantly reduced in patients with SB-AdCC, with a median DFS not pathognomonic for SB-AdCC . We do not recommend using of 46.5 months for SB-AdCC versus 151.8 months in those with FISH or IHC testing for MYB unless there are morphologic features C-AdCC. While the optimal chemotherapy regimen and benefitof strongly raising the differential for SB-AdCC, to avoid over- chemotherapy for SB-AdCC are unknown, the poor outcomes of diagnosis. The most definitive feature pointing to the diagnosis the solid and basaloid variant suggest systemic therapy may be is the identification of areas showing C-AdCC features, particularly warranted. We present a case of SB-AdCC treated with platinum identifying the dual cell population and pseudolumina filled with and anthracycline containing neoadjuvant chemotherapy which basement membrane material. In the core biopsy presented here Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 93 A. Grabenstetter et al. the tumor showed focal “cribriforming” areas along with typical 10. D’Alfonso, T. M. et al. MYB-NFIB gene fusion in adenoid cystic carcinoma of the breast with special focus paid to the solid variant with basaloid features. Hum. basaloid cytologic features suggesting the diagnosis. Another Pathol. 45, 2270–2280 (2014). feature of SB-AdCC is the characteristic nested growth pattern 11. Poling, J. S. et al. MYB labeling by immunohistochemistry is more sensitive and embedded in a markedly desmoplastic stroma which contrasts specific for breast adenoid cystic carcinoma than MYB labeling by FISH. Am. J. with the typically solid, dense mass seen in poorly differentiated Surg. Pathol. 41, 973–979 (2017). triple negative tumors of no special type. 12. Andersson, M. K. et al. ATR is a MYB regulated gene and potential therapeutic While there are currently no drugs available to target the MYB target in adenoid cystic carcinoma. Oncogenesis 9, 5 (2020). gene, recent analysis has revealed that ATR gene expression is significantly upregulated in MYB overexpressing cells . Andersson et al. observed a dose dependent decrease in proliferation and ACKNOWLEDGEMENTS increase in apoptosis following inhibition of ATR, a gene involved This work was partly supported by the National Institutes of Health (NIH)/National in DNA damage repair, and in vivo experimentation demonstrated Cancer Institute (NCI) Cancer Center Support Grant (P30 CA008748). J. S. Reis-Filho is significant tumor suppression and, in one case, tumor regression, funded in part by the NIH/NCI P50 CA247749 01 and Breast Cancer Research Foundation. supporting the development of therapeutic targets to ATR in the treatment of C-AdCC and possibly a subset of SB-AdCC. Furthermore, it has been reported that the mutation rate of AUTHOR CONTRIBUTIONS NOTCH genes is significantly higher in SB-AdCC compared to A.G. and H.Y.W. conceptualized manuscript. A.G. wrote original draft of manuscript. C-AdCC . Clinical trials involving Notch signaling inhibitors are 3 H.Y.W. supervised and contributed to review and editing of manuscript. E.B., H.Z. and currently ongoing and may show usefulness in this variant . L.N. analyzed data and reviewed and edited manuscript. K.J.V., P.R., and J.S.R.F. In conclusion, SB-AdCC is a rare subtype of AdCC. While scant reviewed and edited manuscript. All authors read and approved the final paper. data on optimal management are available, we demonstrate that neoadjuvant chemotherapy may induce an excellent response. Our case suggests that combination chemotherapy has a role in COMPETING INTERESTS treatment. If ongoing studies are successful, additional targeted The authors declare the following competing financial interests: A.G. is a consultant for therapies could provide desirable outcomes in this more Paige.AI. J.S.R.-F. reports receiving personal/consultancy fees from Goldman Sachs, aggressive subtype. REPARE Therapeutics, Paige.AI and Eli Lilly, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics, Paige.AI and Personalis, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientificadvisory METHODS boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech and InVicro, outside the scope of this study. P.R. reports receiving institutional grant/funding Data collection from Grail/Illumina, Novartis, AstraZeneca, Epic Sciences, Invitae/ArcherDx, Tempus, Written informed consent was obtained from the patient to publish this Inivata, Biothernostics; and Consultation/Ad board/Honoraria from Novartis, Foundation case report and associated clinical details. Clinical and radiologic data for Medicine, AstraZeneca, Pfizer, Daiichi, Epic Sciences, Inivata, Natera, Biovica, and this case were obtained from the electronic medical record. IHC was Tempus. H.Y.W. reports consultancy fees from AstraZeneca. L.N. declares no competing performed according to manufacturer’s manual. FISH was done using DNA financial interests. L.N. and J.S.R.-F. are Editors-in-chief of npj Breast Cancer. A.G., P.R., breakapart signal analysis. and H.Y. Wen declare no competing non-financial interests. E.B., H.Z., and K.J.V.Z. declare no competing financial or non-financial interests. DATA AVAILABILITY All the data supporting the findings in this case report are contained within the text. ETHICS APPROVAL IRB approval was not required per Memorial Sloan Kettering institutional policy, and Received: 11 April 2022; Accepted: 28 July 2022; all additional relevant ethical considerations were complied with. ADDITIONAL INFORMATION Correspondence and requests for materials should be addressed to Anne REFERENCES Grabenstetter. 1. Lokuhetty, D., White, V. A., Watanabe, R. & Cree, I. A. WHO Classification of Reprints and permission information is available at http://www.nature.com/ Tumours Editorial Board. Breast tumors. Lyon 2, 142–145 (2019). reprints 2. Shin, S. J. & Rosen, P. P. Solid variant of mammary adenoid cystic carcinoma with basaloid features: a study of nine cases. Am. J. Surg. Pathol. 26, 413–420 (2002). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 3. Masse, J. et al. Solid-type adenoid cystic carcinoma of the breast, a distinct in published maps and institutional affiliations. molecular entity enriched in NOTCH and CREBBP mutations. Mod. Pathol. 33, 1041–1055 (2020). 4. Schwartz, C. J. et al. The clinical behavior and genomic features of the so-called adenoid cystic carcinomas of the solid variant with basaloid features. Mod. Pathol. 35, 193–201 (2022). Open Access This article is licensed under a Creative Commons 5. Chae, Y. K. et al. Adenoid cystic carcinoma: current therapy and potential therapeutic Attribution 4.0 International License, which permits use, sharing, advances based on genomic profiling. Oncotarget 6,37117–37134 (2015). adaptation, distribution and reproduction in any medium or format, as long as you give 6. Schwartz C. J., et al. The clinical behavior and genomic features of the so-called appropriate credit to the original author(s) and the source, provide a link to the Creative adenoid cystic carcinomas of the solid variant with basaloid features. Mod. Pathol. Commons license, and indicate if changes were made. The images or other third party https://doi.org/10.1038/s41379-021-00931-6 (2021). material in this article are included in the article’s Creative Commons license, unless 7. Goldbach, M. M., Hoffman, D. I., Burkbauer, L., Nayak, A. & Tchou, J. Treatment indicated otherwise in a credit line to the material. If material is not included in the patterns and clinical outcomes of adenoid cystic breast carcinoma: a single- article’s Creative Commons license and your intended use is not permitted by statutory institution experience. Am. Surg. 86, 1684–1690 (2020). regulation or exceeds the permitted use, you will need to obtain permission directly 8. Slodkowska, E. et al. Predictors of outcome in mammary adenoid cystic carci- from the copyright holder. To view a copy of this license, visit http:// noma: a multi-institutional study. Am. J. Surg. Pathol. 44, 214–223 (2020). creativecommons.org/licenses/by/4.0/. 9. Laurie, S. A., Ho, A. L., Fury, M. G., Sherman, E. & Pfister, D. G. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol. 12, 815–824 (2011). © The Author(s) 2022 npj Breast Cancer (2022) 93 Published in partnership with the Breast Cancer Research Foundation http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

Solid-basaloid variant of adenoid cystic carcinoma of the breast with near complete response to neoadjuvant chemotherapy

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www.nature.com/npjbcancer CASE REPORT OPEN Solid-basaloid variant of adenoid cystic carcinoma of the breast with near complete response to neoadjuvant chemotherapy 1 1 1 2 1 3 Anne Grabenstetter , Edi Brogi , Hong Zhang , Pedram Razavi , Jorge S. Reis-Filho , Kimberly J. VanZee , 2 1 Larry Norton and Hannah Y. Wen Breast adenoid cystic carcinoma (AdCC) is a rare subtype of triple negative breast cancer. Two morphologic variants are described, namely classic AdCC (C-AdCC) and solid basaloid (SB-AdCC). Recent studies have shown that the SB-AdCC variant has significantly worse prognosis than C-AdCC. Due to the rarity of SB-AdCC, no standard recommendations are available for its management. Data on the use and benefit of chemotherapy in patients with SB-AdCC are sparse and the response to neoadjuvant chemotherapy has not been reported. We present the clinical and pathologic findings of a patient with SB-AdCC treated with neoadjuvant chemotherapy who achieved a remarkable pathologic response. npj Breast Cancer (2022) 8:93 ; https://doi.org/10.1038/s41523-022-00469-z INTRODUCTION of the right axilla showed a suspicious lymph node. An ultrasound guided biopsy of the breast mass yielded an infiltrating Breast adenoid cystic carcinoma (AdCC) is a rare histologic moderately differentiated mammary carcinoma with associated subtype of breast cancer, usually of triple negative phenotype. intermediate grade intraductal carcinoma, solid and cribriform These tumors account for <1% of all breast cancers, composed of type. Subsequently, the patient presented to Memorial Sloan a dual population of epithelial and myoepithelial neoplastic cells, Kettering Cancer Center (MSK) for cancer care. arranged in cribriform, tubular and/or solid growth patterns. Physical examination revealed a palpable right breast mass AdCCs have been shown to be driven by activation of the MYB measuring approximately 10 mm immediately deep to the nipple, pathway, most commonly due to a MYB-NFIB fusion gene, focally inseparable from the skin. There was no obvious palpable followed by fusion genes involving MYBL1 or MYB gene adenopathy. Breast MRI revealed a 13 × 13 × 12 mm irregular amplification . The solid basaloid variant of AdCC (SB-AdCC) is composed of cells with scant cytoplasm, marked nuclear atypia enhancing mass with T2 hyperintensity in the retroareolar region and increased mitotic activity . In contrast to the classic form of along with an abnormal right level 1 axillary lymph node, measuring AdCC (C-AdCC), which typically follows a relatively indolent 10 mm (Fig. 1). As per protocol, the initial core biopsy was reviewed 2–4 course, the SB-AdCC variant has an aggressive clinical behavior . by the MSK Pathology Department. Microscopically, multiple tissue Vanishingly rare (there are less than 100 published cases of SB- cores were involved by an infiltrating basaloid carcinoma with solid AdCC), currently there are no standardized recommendations nests and focal cribriform architecture within a desmoplastic stroma regarding management. In the limited series available, most showing approximately 5–10% stromal tumor infiltrating lympho- patients were treated with surgical excision and post-operative cytes (Fig. 2). The neoplastic cells displayed a high nuclear to radiation but adjuvant chemotherapy was often omitted, similar to cytoplasmic ratio, moderate nuclear atypia and conspicuous mitoses. 5–7 the management of C-AdCC . At present, there is a paucity of Immunohistochemistry (IHC) demonstrated diffuse expression of data on chemotherapy benefit for SB-AdCC and its response to cytokeratin 7 (CK7), CK8/18, CK5/6 and c-kit (CD117), occasional p63 neoadjuvant treatment is unknown. Here, we describe a case of reactivity, and MYB nuclear expression (Fig. 2). A MYB translocation SB-AdCC treated with neoadjuvant chemotherapy with a near was identified by fluorescence in situ hybridization (FISH) utilizing complete pathologic response. break apart probes. The tumor lacked estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) expression. The Ki67 proliferation index was RESULTS approximately 40% (Fig. 2). The histologic, IHC and molecular Case presentation findings supported a diagnosis of SB-AdCC. Focal in situ carcinoma A 56 years old woman of Ashkenazi Jewish descent with no was also identified. Fine needle aspiration (FNA) of the suspicious significant past medical history or family history of breast or right axillary node yielded malignant cells, consistent with metastatic ovarian cancer, initially presented to an outside hospital after carcinoma. palpating a right breast mass. The patient underwent bilateral Breast conservation surgery (BCS) and mastectomy, along with mammogram that revealed a right breast 9 mm spiculated mass sentinel lymph node biopsy were discussed with the patient. Due with associated calcifications and nipple retraction, corresponding to the central location of the tumor and imaging suggesting involvement of areolar skin, a wide excision would also require to the sonographic finding of an 8 mm irregular, retroareolar mass removal of the nipple areolar complex. In this context, a medical which appeared to invade the nipple-areolar complex. Ultrasound 1 2 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. email: grabensa@mskcc.org Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A. Grabenstetter et al. oncology consultation was obtained. Given the triple negative could provide a complete pathologic response in the axilla that would obviate the need for axillary dissection. The patient elected phenotype and biopsy proven positive lymph node status, to have an attempt at BCS and thus was given pre-operative dose- neoadjuvant chemotherapy was recommended because if it dense AC-T (doxorubicin plus cyclophosphamide each two weeks with G-CSF support for four cycles followed by carboplatin each 3 weeks for four cycles plus twelve cycles of weekly paclitaxel), which was well tolerated. Because AdCC is often regarded to be a chemotherapy-resistant subtype of breast cancer the patient was monitored with monthly imaging studies to assess response and ensure there was continued shrinkage of disease. After FDA approval, she was also started on pembrolizumab. However, she developed immune-mediated nephritis after the second dose of pembrolizumab resulting in its discontinuation. An MRI was performed following completion of therapy which showed very faint, residual 7 mm linear enhancement extending towards the nipple, significantly decreased from prior study (Fig. 1). On pre- surgical physical examination, the palpable mass was no longer appreciated, the areolar skin did not feel tethered to the underlying breast tissue and there was no axillary adenopathy. The patient underwent breast conserving surgery with removal of nipple and sentinel lymph node biopsy upon completion of neoadjuvant treatment. The resection specimen obtained post-neoadjuvant treatment showed a single focus of residual invasive carcinoma, spanning <0.5 mm microscopically, along with approximately 5 mm of residual in situ carcinoma, present in a fibrotic tumor bed grossly measuring 12 × 7 mm (Fig. 3). The carcinoma harbored a MYB rearrangement as detected by in situ hybridization and lacked ER, PR and HER2 expression by IHC. Lymphovascular invasion was not identified. The margins of resection were uninvolved by carci- noma. Three sentinel lymph nodes were retrieved and showed no residual metastatic disease. Treatment related changes were not identified in the lymph nodes. The patient was referred to Fig. 1 Pre and post neoadjuvant chemotherapy imaging. a Pre- therapy MRI showing retroareolar, irregular enhancing mass, 1.3 cm; radiation oncology and received adjuvant radiation therapy to 50 b Post-therapy MRI showing faint linear enhancement, 0.7 cm. Gray in 25 fractions. The patient developed mild erythema during Fig. 2 Core needle biopsy, treatment naïve. a Core biopsy showing infiltrating basaloid carcinoma with solid and cribriform nests (H&E, 50X); b Ki67 proliferation index of approximately 40% (50X); c Diffuse nuclear expression with MYB immunohistochemistry (50X); d p63 immunohistochemistry demonstrates loss of myoepithelial cells surrounding invasive nests, inset reveals focal in situ carcinoma with rim of p63 positive myoepithelial cells (50X, inset 200X). npj Breast Cancer (2022) 93 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A. Grabenstetter et al. Fig. 3 Excision specimen, post neoadjuvant chemotherapy. a Residual carcinoma, H&E, 10X; b Residual invasive (lower right corner) and in situ carcinoma, H&E, 100X; c p63 immunohistochemistry, 10X; inset MYB in situ hybridization, 100X; d p63 immunohistochemistry, 100X. radiotherapy but otherwise tolerated it well. She is currently six achieved an excellent pathologic response, showing complete months status post operation and has recovered well from resolution of the patient’s axillary disease and less than 0.5 mm of neoadjuvant chemotherapy and radiation without major compli- residual invasive carcinoma. Published data on the effect of chemotherapy in patients with SB- cations. She was then started on adjuvant capecitabine, which she AdCC is based on small trials and more frequently involve AdCC is tolerating well. She has remained clinically disease free and is undergoing active surveillance as per guidelines. arising in organs other than the breast. Laurie et al. performed a systematic review of 34 studies, including prospective and retro- spective data, examining the systemic treatment of metastatic or DISCUSSION locally recurrent AdCC, all but one of which included only tumors of The mammary SB-AdCC variant was first described in a report by salivary gland origin. In the trials which looked at single agent Shin and Rosen , in which they detailed 9 cases collected over a cytotoxic therapy, the observation of stable disease, noted in 58% period of 11 years. While none of the patients in their series had (64/111) of patients, was more common than objective major evidence of local recurrence or distant metastases despite a follow responses which were seen in only 13% (18/141) of patients. Overall, up period of up to 7.3 years (mean 32 months), the data presented in trials utilizing combination therapy, 25% of patients responded, in that study suggested that SB-AdCC had a higher propensity for most commonly to regimens composed of cisplatin, doxorubicin lymph node metastases than C-AdCC. Subsequent studies and cyclophosphamide (CAP) . These results should be interpreted confirmed this observation, which lead to the recommendation with caution, though, as none of these multi-agent trials enrolled for routine axillary staging in these patients, and also noted more more than 12 patients. The authors also found discrepant response 3,6,8 aggressive clinical behavior . In the largest series reported to rates amongst reports, with higher rates observed in retrospective date, Schwartz et al. compared the clinicopathologic features and reviews versus clinical trials and ultimately conclude further study is follow-up data of 29 SB-AdCC and 75 C-AdCC from MSK. SB-AdCCs needed to develop a standardized management approach. The had significantly higher histologic grade, higher rates of lympho- patient reported here had a remarkable response, providing further vascular invasion and lymph node metastases, and were more support to the notion that chemotherapy may be effective in at least likely to recur locally and develop distant metastatic disease. In a subset of SB-AdCCs. contrast, C-AdCC had a favorable clinical course, with higher Additionally, novel drug therapies targeting specific molecular survival rates than invasive breast carcinoma of no special type, alterations may prove to be efficacious in the rare SB-AdCC. The and 5- and 10-year disease free survival (DFS) rates greater than 95 translocation t(6;9)(q23;p23) leading to the MYB-NFIB fusion gene 1,8 6 and 90%, respectively . In the cohort described by ref. , the is identified in up to 86% of C-AdCC and has been confirmed to be surgical approach and use of adjuvant radiotherapy were similar present in the solid-basaloid variant as well, however it is seen between the variants, however patients with SB-AdCC were much less frequently, reported in only 12.5% of cases in one significantly more likely to receive adjuvant chemotherapy than series . Additionally, MYB expression by IHC has been observed in C-AdCC (68.4% versus 17.3%, respectively). Despite this, DFS was up to 63% of other basal-like, triple negative breast cancers and is significantly reduced in patients with SB-AdCC, with a median DFS not pathognomonic for SB-AdCC . We do not recommend using of 46.5 months for SB-AdCC versus 151.8 months in those with FISH or IHC testing for MYB unless there are morphologic features C-AdCC. While the optimal chemotherapy regimen and benefitof strongly raising the differential for SB-AdCC, to avoid over- chemotherapy for SB-AdCC are unknown, the poor outcomes of diagnosis. The most definitive feature pointing to the diagnosis the solid and basaloid variant suggest systemic therapy may be is the identification of areas showing C-AdCC features, particularly warranted. We present a case of SB-AdCC treated with platinum identifying the dual cell population and pseudolumina filled with and anthracycline containing neoadjuvant chemotherapy which basement membrane material. In the core biopsy presented here Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 93 A. Grabenstetter et al. the tumor showed focal “cribriforming” areas along with typical 10. D’Alfonso, T. M. et al. MYB-NFIB gene fusion in adenoid cystic carcinoma of the breast with special focus paid to the solid variant with basaloid features. Hum. basaloid cytologic features suggesting the diagnosis. Another Pathol. 45, 2270–2280 (2014). feature of SB-AdCC is the characteristic nested growth pattern 11. Poling, J. S. et al. MYB labeling by immunohistochemistry is more sensitive and embedded in a markedly desmoplastic stroma which contrasts specific for breast adenoid cystic carcinoma than MYB labeling by FISH. Am. J. with the typically solid, dense mass seen in poorly differentiated Surg. Pathol. 41, 973–979 (2017). triple negative tumors of no special type. 12. Andersson, M. K. et al. ATR is a MYB regulated gene and potential therapeutic While there are currently no drugs available to target the MYB target in adenoid cystic carcinoma. Oncogenesis 9, 5 (2020). gene, recent analysis has revealed that ATR gene expression is significantly upregulated in MYB overexpressing cells . Andersson et al. observed a dose dependent decrease in proliferation and ACKNOWLEDGEMENTS increase in apoptosis following inhibition of ATR, a gene involved This work was partly supported by the National Institutes of Health (NIH)/National in DNA damage repair, and in vivo experimentation demonstrated Cancer Institute (NCI) Cancer Center Support Grant (P30 CA008748). J. S. Reis-Filho is significant tumor suppression and, in one case, tumor regression, funded in part by the NIH/NCI P50 CA247749 01 and Breast Cancer Research Foundation. supporting the development of therapeutic targets to ATR in the treatment of C-AdCC and possibly a subset of SB-AdCC. Furthermore, it has been reported that the mutation rate of AUTHOR CONTRIBUTIONS NOTCH genes is significantly higher in SB-AdCC compared to A.G. and H.Y.W. conceptualized manuscript. A.G. wrote original draft of manuscript. C-AdCC . Clinical trials involving Notch signaling inhibitors are 3 H.Y.W. supervised and contributed to review and editing of manuscript. E.B., H.Z. and currently ongoing and may show usefulness in this variant . L.N. analyzed data and reviewed and edited manuscript. K.J.V., P.R., and J.S.R.F. In conclusion, SB-AdCC is a rare subtype of AdCC. While scant reviewed and edited manuscript. All authors read and approved the final paper. data on optimal management are available, we demonstrate that neoadjuvant chemotherapy may induce an excellent response. Our case suggests that combination chemotherapy has a role in COMPETING INTERESTS treatment. If ongoing studies are successful, additional targeted The authors declare the following competing financial interests: A.G. is a consultant for therapies could provide desirable outcomes in this more Paige.AI. J.S.R.-F. reports receiving personal/consultancy fees from Goldman Sachs, aggressive subtype. REPARE Therapeutics, Paige.AI and Eli Lilly, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics, Paige.AI and Personalis, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientificadvisory METHODS boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech and InVicro, outside the scope of this study. P.R. reports receiving institutional grant/funding Data collection from Grail/Illumina, Novartis, AstraZeneca, Epic Sciences, Invitae/ArcherDx, Tempus, Written informed consent was obtained from the patient to publish this Inivata, Biothernostics; and Consultation/Ad board/Honoraria from Novartis, Foundation case report and associated clinical details. Clinical and radiologic data for Medicine, AstraZeneca, Pfizer, Daiichi, Epic Sciences, Inivata, Natera, Biovica, and this case were obtained from the electronic medical record. IHC was Tempus. H.Y.W. reports consultancy fees from AstraZeneca. L.N. declares no competing performed according to manufacturer’s manual. FISH was done using DNA financial interests. L.N. and J.S.R.-F. are Editors-in-chief of npj Breast Cancer. A.G., P.R., breakapart signal analysis. and H.Y. Wen declare no competing non-financial interests. E.B., H.Z., and K.J.V.Z. declare no competing financial or non-financial interests. DATA AVAILABILITY All the data supporting the findings in this case report are contained within the text. ETHICS APPROVAL IRB approval was not required per Memorial Sloan Kettering institutional policy, and Received: 11 April 2022; Accepted: 28 July 2022; all additional relevant ethical considerations were complied with. ADDITIONAL INFORMATION Correspondence and requests for materials should be addressed to Anne REFERENCES Grabenstetter. 1. Lokuhetty, D., White, V. A., Watanabe, R. & Cree, I. A. WHO Classification of Reprints and permission information is available at http://www.nature.com/ Tumours Editorial Board. Breast tumors. Lyon 2, 142–145 (2019). reprints 2. Shin, S. J. & Rosen, P. P. Solid variant of mammary adenoid cystic carcinoma with basaloid features: a study of nine cases. Am. J. Surg. Pathol. 26, 413–420 (2002). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 3. Masse, J. et al. Solid-type adenoid cystic carcinoma of the breast, a distinct in published maps and institutional affiliations. molecular entity enriched in NOTCH and CREBBP mutations. Mod. Pathol. 33, 1041–1055 (2020). 4. Schwartz, C. J. et al. The clinical behavior and genomic features of the so-called adenoid cystic carcinomas of the solid variant with basaloid features. Mod. Pathol. 35, 193–201 (2022). Open Access This article is licensed under a Creative Commons 5. Chae, Y. K. et al. Adenoid cystic carcinoma: current therapy and potential therapeutic Attribution 4.0 International License, which permits use, sharing, advances based on genomic profiling. 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Surg. 86, 1684–1690 (2020). regulation or exceeds the permitted use, you will need to obtain permission directly 8. Slodkowska, E. et al. Predictors of outcome in mammary adenoid cystic carci- from the copyright holder. To view a copy of this license, visit http:// noma: a multi-institutional study. Am. J. Surg. Pathol. 44, 214–223 (2020). creativecommons.org/licenses/by/4.0/. 9. Laurie, S. A., Ho, A. L., Fury, M. G., Sherman, E. & Pfister, D. G. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol. 12, 815–824 (2011). © The Author(s) 2022 npj Breast Cancer (2022) 93 Published in partnership with the Breast Cancer Research Foundation

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