Elsevier

European Journal of Cancer

Volume 148, May 2021, Pages 440-450
European Journal of Cancer

Original Research
Ductal variant prostate carcinoma is associated with a significantly shorter metastasis-free survival

https://doi.org/10.1016/j.ejca.2020.12.030Get rights and content

Highlights

  • Ductal adenocarcinoma of the prostate is more clinically aggressive than acinar adenocarcinoma.

  • Ductal adenocarcinoma has shorter time to metastasis.

  • This is the first large non-registry–based study to use metastasis-free survival as an end-point.

  • RB1 loss may be a key molecular driver in clinical difference.

Abstract

Background

Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival.

Methods

Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8).

Results

A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p < 0.0001). Ductal variant histology was consistently associated with RB1 loss, as well as copy number gains in TAP1, SLC4A2 and EHHADH.

Conclusions

The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance.

Introduction

Ductal adenocarcinoma (DAC) of the prostate is an uncommon non-acinar variant of prostatic carcinoma. In its pure form, it accounts for only 0.2–0.8% of all prostate cancers [[1], [2], [3]]. However, it can be identified intermixed with acinar adenocarcinoma (AAC) in up to 3.2% of all radical prostatectomy specimens [4].

Although the presence of ductal histology was initially believed to be associated with a better prognosis [5], more recent studies suggest the contrary [[6], [7], [8]]. Some studies suggest that biochemical recurrence (BCR) rates are higher for DAC and may even progress without a significant rise in prostate-specific antigen (PSA) levels [8,9]. In addition, the presence of DAC has been associated with significantly worse cancer-specific and overall survival [[10], [11], [12]].

In determining the prognostic significance of the presence of DAC, there are a number of difficulties with interpreting existing studies. Majority of studies reporting on clinical outcomes (such as metastases and cancer-specific survival) are registry based [3,10,11,13] and lack the granularity of clinicopathological data to control for potentially important confounders. On the other hand, smaller case-control series, while benefiting from centralised pathology review, invariably use the BCR as a clinical end-point [7,8]. The latter is particularly important as the BCR has been shown to be a poor surrogate marker for more relevant disease end-points such as metastasis and death, and as mentioned previously, progression of DAC in the absence of a detectable PSA has previously been described in the study by Orihuela and Green [9].

To address these deficiencies, we performed an international, multi-institutional study to describe the clinical and pathological characteristics of DAC, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival. In selected cases, we then probed the genomic differences that may underlie the observed differences.

Section snippets

Patient selection

Patients with reported DAC on radical prostatectomy were retrospectively identified from a prospectively recorded pathology service database at TissuPath Specialist Pathology (Australia) and Oxford University Hospitals NHS Foundation Trust (United Kingdom) between January 2007 and June 2019. An independent comparative pure AAC cohort was additionally identified from a consecutive series of patients who underwent prostatectomies from Melbourne treated over the same time period. Clinical and

Results

We identified 207 DAC cases; of which, three were excluded for receiving neoadjuvant treatment and two were excluded for having distant metastases at the time of surgery. A total of 2351 cases were identified for a comparative AAC cohort; 39 and two patients were subsequently excluded for neoadjuvant treatment and distant metastases at the time of surgery, respectively. As the ductal cohort did not consist of any ISUP GG 1 pathologies, an additional 273 acinar ISUP GG 1 cases were excluded. The

Discussion

This study focuses on the clinicopathological outcomes of adenocarcinoma of the prostate with ductal variant pathology, and to our knowledge, this is the first large non-registry–based study to use metastasis-free survival as an end-point, an important clinical event in its own right and a more accurate surrogate marker for disease lethality than the more commonly used biochemical-free survival [23,24]. Consistent with previous reports, we have found that patients with DAC at prostatectomy have

Conclusion

In summary, DAC is more clinically aggressive than its acinar counterpart in terms of time to metastatic progression, despite having no significant difference in BCR-free survival. Preliminary investigation suggests that RB1 loss with associated increased cell proliferation and genomic instability may be a key molecular driver of these clinical differences.

Ethics approval and consent to participate

The study and collection of these data was institutionally reviewed and approved.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Authors’ contribution

Ken Chow: Conceptualization, Data curation, Formal analysis, Methodology, Investigation, Project administration, Writing - original draft, Writing - review & editing. Justin Bedo: Data curation, Formal analysis, Methodology, Investigation, Writing - original draft, Writing - review & editing. Andrew Ryan: Formal analysis, Methodology, Investigation, Writing - review & editing. Dinesh Agarwal: Investigation, Writing - review & editing. Damien Bolton: Investigation, Writing - review & editing.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

K.C. is supported by the Foundations for Surgery Research Scholarship from the Royal Australasian College of Surgeons, Postgraduate Medical Research Scholarship from the Prostate Cancer Research Fund and the Research Training Program Scholarship from the Australian Commonwealth Government. J.B. was supported by the Stafford Fox Medical Research Foundation. A.D.L. is funded by Cancer Research UK through a Clinician Scientist Fellowship (C57899/A25812). N.M.C. is supported by a Movember –

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