The role of radiotherapy (RT) in the treatment of Adenoid Cystic Carcinoma of the Breast: case report of RT retreatment and literature review

Aim: This study reviews the recent literature on the role of definitive radiotherapy (RT) in the management of adenoid cystic carcinoma of the breast (ACCB) and presents comprehensive data on clinical outcomes. A case report of radiotherapy retreatment in ACCB is reported for first time in literature. Methods: The authors performed a literature review using PubMed (1981-2019) to identify all studies that match with keywords. Inclusion criteria were articles reporting patients underwent radiotherapy after ACCB diagnosis with follow up reporting. Data analyzed were number of pts, age, study design, multimodality treatment management with radiotherapy schedule, stage of disease, pathological risk factors, local relapse free survival (LFRS), metastases free survival (MFS) and overall survival (OS). Results: Of the 60 identified studies, 15 met the inclusion criteria. All studies had a retrospective design. Overall, 967 patients (median, 64; range, 1-478) were included. A high heterogeneity was found across studies in terms of pathological features available, local approach in multimodality management, adjuvant RT administration, and reported outcomes. Mean LRFS reported by case reports was 24 months (range 2048). Mean DFS reported by case series and retrospective series was 87.9% (range 69-100%). Mean OS reported in case reports was 30 months (range 12-84). Mean 5-years OS reported in retrospective series was 89.7%. Mean 10-years OS reported in retrospective series was 78.7%. In some retrospective series radiotherapy was found significantly related to local control (p=0.03) and with an absolute survival benefit of 9% at 5 year and of 21% at 10 years (p=0.005). Conclusion and implications for practice: To our knowledge this is the first report on radiotherapy retreatment in ACCB local relapse. This study also reviews the recent literature on the role of adjuvant RT in the management of ACCB and presents comprehensive data on long-term clinical outcome. Some significant results about RT are improvement in local control and survival benefit also since at 10 years in some series. Further studies are needed to confirm these results. © 2019 Valeria Masiello. Hosting by Science Repository. All rights reserved. The role of radiotherapy (RT) in the treatment of Adenoid Cystic Carcinoma of the Breast: case report of RT retreatment and literature review 2 Clinical Oncology & Research doi:10.31487/j.COR.2019.01.007 Volume 2(1): 2-6 Aim Adenoid Cystic Carcinoma of the Breast (ACCB) is a rare subtype, representing <0.1% of all breast cancer diagnosed [1]. ACCB usually affects women, in whom it is more frequent in the sixth decade of life [2]. Histologically presentation shows a double component both luminal epithelial and basal myoepithelial cells, without oestrogen, progesterone and Her-2 receptor expression [3, 4]. Despite its belonging to triplenegative class breast tumor, clinical presentation of this disease is usually isolated to breast gland, in 2% of pts patients (pts) there is a nodal involvement and rarely it can metastasize in other parenchyma[1, 2, 5, 6]. This is due to downregulation of genes involved in migration, proliferation and the immune response [7]. In a study of Ro JY et al. a grading of ACCB was reported as sequent: Grade 1 (no solid element), Grade 2 (<30% solid elements) and Grade 3 (>30% solid elements). In their study tumours with more solid elements tended to be more aggressive and at higher risk of recurrence, so surgery should be conservative for Grade1 and radical also on axilla for Grade 3 [21]. Surgery is an established indication for treating this tumor, but there are still controversies about management with local excision rather than mastectomy [6]. In this landscape, also adjuvant radiotherapy still represents a controversial treatment in local control due to lack of extensive prospective series [8]. This study report first case in literature of re-quadrantectomy followed by reirradiation for a local relapse of ACCB. A systematic review of the recent literature on the role of adjuvant radiotherapy (RT) in the management of ACCB reports comprehensive data on clinical outcomes.


Aim
Adenoid Cystic Carcinoma of the Breast (ACCB) is a rare subtype, representing <0.1% of all breast cancer diagnosed [1]. ACCB usually affects women, in whom it is more frequent in the sixth decade of life [2]. Histologically presentation shows a double component both luminal epithelial and basal myoepithelial cells, without oestrogen, progesterone and Her-2 receptor expression [3,4]. Despite its belonging to triplenegative class breast tumor, clinical presentation of this disease is usually isolated to breast gland, in 2% of pts patients (pts) there is a nodal involvement and rarely it can metastasize in other parenchyma [1,2,5,6]. This is due to downregulation of genes involved in migration, proliferation and the immune response [7]. In a study of Ro JY et al. a grading of ACCB was reported as sequent: Grade 1 (no solid element), Grade 2 (<30% solid elements) and Grade 3 (>30% solid elements). In their study tumours with more solid elements tended to be more aggressive and at higher risk of recurrence, so surgery should be conservative for Grade1 and radical also on axilla for Grade 3 [21]. Surgery is an established indication for treating this tumor, but there are still controversies about management with local excision rather than mastectomy [6]. In this landscape, also adjuvant radiotherapy still represents a controversial treatment in local control due to lack of extensive prospective series [8].
This study report first case in literature of re-quadrantectomy followed by reirradiation for a local relapse of ACCB. A systematic review of the recent literature on the role of adjuvant radiotherapy (RT) in the management of ACCB reports comprehensive data on clinical outcomes.

Case Report
A 64-year-old woman presented with a lump in her left breast. Examination showed a 1.5 cm mass in the superior-external quadrant. Mammography showed a nodular lesion localized between superiorexternal/SSQQs of left breast. Ultrasound reported an ipo-echogenous ovalar lesion of 2.4 cm with vascular spots both intra and peri-nodular. On January 2013, patient underwent conservative surgery with sentinel node biopsy. Definitive pathology exam reported a ACCB G1 of 1.7 cm, pT1c pN0, ER0%, PgR0%, Ki67 45% C-ERB-B2 0. For histological type, patient underwent adjuvant radiotherapy according to hypofractionated schedule (4005 cGy/267 cGy). Further follow up controls were negative since to May 2018, when a local relapse was diagnosed at instrumental exam. Mammography with tomosynthesis study reported a lesion with lobular margin of 2.2 cm at the superiorexternal quadrant of left breast. Echography described a polilobular lesion with regular margins disomogenous and ipo-echogenous of 2 cm with intralesional vascular behaviour. Total body CT was negative for distant relapse. On August 2018 patient underwent re-quadrantectomy of superior external left quadrant with sentinel node biopsy. Definitive pathology exam showed a relapse of tubule-glandular ACCB of 2.2 cm, pT2 pN0, ER0%, PgR0%, Ki67 7%, HER2 1+. The area around ACCB was surrounded by granulomatous lypophagic flogisis. Considering good performance status and local aesthetic result, the local relapse with absence of distant metastases, time from previous radiotherapy and total dose given with previous treatment, multidisciplinary discussion proposed a re-irradiation of tumor bed according to RTOG 1014 schedule (4500 cGy/150 cGy BID) [9]. Radiotherapy re-treatment was well tolerated and no acute toxicity more than G1 were recorded during treatment. Six months follow-up didn't show local or distant relapse neither sub-acute loco-regional toxicities.

Methods
In order to perform a clinical review on adjuvant RT role for ACCB in clinical practice a literature search on PUBMED was performed with keyword "adenoid cystic carcinoma radiotherapy", "adenoid cystic carcinoma adjuvant radiotherapy", "adenoid cystic carcinoma RT", "adenoid cystic carcinoma adjuvant RT". A further research was done into bibliography of paper selected. Inclusion criteria were case report, case series and retrospective analysis in which adjuvant radiotherapy was administered after surgery and follow up was reported. Data analysed in the studies were number of pts, age, study design, multimodality treatment management with radiotherapy schedule, stage of disease, pathological risk factors, local relapse free survival (LFRS), metastases free survival (MFS) and overall survival (OS).

Discussion
Most significant evidences about radiotherapy role were found in retrospective series. In Arpino et al. 6 pts who underwent radiotherapy did not present local relapse at 10-y follow up [2]. In a study of Khanfir K et al. based on data from 16 institutions participating to Rare Cancer Network, RT resulted significantly related to local control in the breastconserving surgery group (p=0.03) [16]. In addition, in a Surveillance, Epidemiology and End Results (SEER) registry analysis of patients from 1988 and 2005, univariate analysis showed a significant difference in overall survival based on receipt of RT with an absolute survival benefit of 9% at 5 years and 21 % at 10 years (p=0.005) [18]. This evidence was confirmed also at the multivariate analysis in which RT continued to be a significant factor with a HR of 0.44 (95% CI=0.22-0.88), even after accounting for demographic data, stage and type of surgery. In another SEER analysis conducted on patient from 1998 to 2011 by Sun JY et al., on 478 pts 5-y cancer specific survival results 96.1%, 91.8%, 90.2% and 94.1% respectively for pts who underwent BCS + RT, BCS, mastectomy and mastectomy + RT (p=0.026) [17]. Effect on OS was significant only for subgroup of patients who underwent BCS + RT (p=0.019).
In another review of literature, 5-year survival rate for ACCB is reported to be 85-90%, with a 100% disease-free survival rate [22]. Local recurrence for ACCB after conservative surgery are not so rare and can occur in a range from 6 to 37%, more frequently between patients not underwent adjuvant treatment [5,7,17]. Global reported recurrence interval in the literature was as short as 6 months and as long as 22 years after excision [2]. For this reason, an active 10 year follow up should be considered with also parenchymal evaluation. In a clinical review of Boujelbene N et al., published in 2012, some case series were reported to define adjuvant RT role [7]. Most significant conclusion were of this review were: adjuvant RT improves relapse-freesurvival; adjuvant RT improves by 12% the 5-year locoregional control rates in breast-conserving group (95% vs. 83%) without impact on survival; adjuvant RT is a strong prognostic factor for overall-and causespecific survival [13,17,22]. Finally, because metastases can occur without axillary involvement, adjuvant radiotherapy to the breast may decrease the burden of any residual microscopic disease, and therefore, reduce the likelihood of haematogenous spread [13]. Principal limitations of available literature are missing of uniformed data about pathological characterization in order to find useful prognostic factor to be related with an adjuvant RT.

Conclusion and Implication for Practice
Adjuvant radiotherapy is a controversial option for consolidating local control in ACCBs, especially after breast conserving surgery or if other risk factors for local relapse are present. Some series reported a significant role of radiotherapy in local control and also for 10-years survival for ACCB. Active follow up is mandatory for these patients because distant relapse can occur since after 9 years from diagnosis. In addition, to our knowledge, this is the first report in literature of ACCB radiotherapy retreatment. Retreatment is a safe and well tolerated option, as for common epithelial breast cancer. Possible criteria for conservative retreatment in ACCB are G1, absence of distant metastases, good aesthetic result. Multicentre pooled analysis or otherwise multicentre prospective studies would provide further consideration about radiotherapy indication in ACCB.