Highlights in Pathology: Breast Pathology (February 2019)

Dr. Hala Faragalla, St. Michael's Hospital

1. Human epidermal Growth Factor Receptor 2 Testing in Breast Cancer. American Society of Clinical Oncology/College of American Pathologists. Clinical Practice Guideline Focused Update

Wolff A C, et al. (2018) Arch Pathol and Lab Med 142: 1364-1382

This article summarizes the focused clinical practice guidelines update in HER2 interpretation in breast cancer.

The recommendations are aimed at improving the diagnostic validity and clinical utility of HER2 testing as a predictive biomarker for response to targeted therapy.

The HER2 guidelines were first released in 2007 and updated in 2013. Two recommendations also addressed through correspondence in 2015 were included as well in this update.  

Some of these recommendations are. 1

1. The revised definition of IHC 2+ (equivocal) is defined as invasive carcinoma with “weak to moderate complete membranous staining in >10% of the tumor cells”.
2. On the basis of some criteria, if the initial HER2 test on a needle core biopsy is negative, “if the initial HER2 test in a core needle biopsy is negative, a new HER2 test may (not must) be ordered on the excision specimen based on specific clinical criteria.
3. The HER2 testing algorithm is updated to address the workup for some of the less common clinical scenarios observed when using a dual-probe ISH assay. Some of these scenarios addressed include cases that have a HER2/chromosome 17 enumeration probe ratio ≥2 but the average HER2 signal per cells is <
4. The other two scenarios include cases which have an average of ≥ 6 HER2 signals per cell with an HER2/CEP17 ratio < 2, formerly diagnosed as ISH positive for HER2. The third scenario addressed includes cases that have HER2 signals per tumor cells of ≥4 and < 6 and the HER2 /CEP17 ratio is <2, formerly diagnosed as ISH equivocal for HER2. In all these scenarios a definitive diagnosis will be rendered based on additional work-up. The diagnostic approach includes more rigorous interpretation criteria for ISH and also requires concomitant review of the ISH and IHC to arrive to the most accurate HER2 status.
5. The panel also requires laboratories using single probe ISH assays to include concomitant IHC as part of their interpretation.

2. Impact of breast cancer grade discordance on prediction of outcome

Rakha E A et al. (2018) Histopathology 73, 904-915.

Histologic grade is an independent prognostic factor in breast cancer (BC).

Previous concordance studies have reported moderate level of agreement which is expected in any morphologic assessment of some biologic variables.

The study identified a large (1675) cohort of BC originally graded in routine practise.

These cases were graded twice by an expert breast pathologist using virtual microscopy with 3-month washout period.

58% of the cases showed absolute agreement in the three separate grading sessions, whereas grades 1/2 and 2/3 discordance were observed in 21% and 21 % of cases respectively.

Despite the concordance, outcome analysis revealed significant association between tumor grade and patients outcome in the three grading sessions.

• Grades 1/2 and 2/3 discordant cases showed intermediate survival between grades 1 and 2 tumors and grades 2 and 3 tumors respectively.
• Grades 1/2 showed a worse outcome compared to grade 1 tumors but no difference when compared to the grade 2 tumors.
• Similarly grades 2/3 discordant cases showed a significant difference from grade 2 tumors, but no statistical difference was identified when compared with the grade 3 tumors.

The authors concluded that the breast cancer grade discordance is probably a reflection of biologically and morphologically, borderline tumors.

Cases with borderline features are more likely to behave similarly to the higher-grade category. The authors suggest repeat grading of borderline BC or double reporting to improve outcome.

3. SOX10, GATA3, GCDFP15, Androgen Receptor, and Mammaglobin for the Differential Diagnosis Between Triple-negative Breast Cancer and TTF-1-negative Lung Adenocarcinoma

Laurent E et al. (2019). Am J Surg Pathol, 43:293-302

It is an early 2019 article but found it very useful.

Triple-negative breast cancer patients have an increased risk of developing metastases and also other non-primary breast cancers including lung.

The differential diagnosis of metastatic triple negative breast cancer may be difficult due to a lack of a standard immuno panel.  

The diagnostic utility of estrogen receptor, progesterone receptor, HER2, TTF-1, Napsin-A, mammaglobin, GCDFP-15, SOX10, androgen receptor and GATA-3 in a series of 207 TNBC and 152 primary lung adenocarcinoma (LA) is studied.

All tested TNBC were TTF-1 and Napsin-A negative.

When comparing TNBC and TTF-1 positive or negative LA, SOX10 had the best Sensitivity (62%) as a marker in favor of TNBC compared with LA. Irrespective of TTF-1 status, GATA3 had moderate sensitivity (30.4%) and excellent specificity and misclassified only 2/152 LA.

In multivariate analysis, the best markers to distinguish between SOX10 negative TNBC and TTF-1, Napsin-A negative LA were GATA3 and GCDFP15.

Based on their results, the authors suggests that the best sequence when ordering immunostains to workup small lung biopsies from women with history of TNBC is SOX10, followed by GATA3 and finally GCDFP15.

4. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

Sparano J A. (2018). N Engl J Med 379, 111-21

This article summarizes the results of TAILORx clinical trial which came out in early 2018.

Oncotype is one of the several commercially available gene-expression assays that provide prognostic information in hormone receptor positive breast cancer.

The recurrence score based on 21-gene breast cancer assays predicts benefit from chemotherapy in when it is high, when the recurrence score is low, it is prognostic for a very low rate of distant recurrence at 10 years and is unlikely to benefit from adjuvant chemotherapy. However, there is uncertainty about the benefit of chemotherapy for most patients who have a midrange score.

The TAILORx study was a prospective study that enrolled 10, 273 women with hormone receptor positive, HER2 negative, node negative BC.

Of the 9719 eligible patients with follow up information, 6711 (69%) had a midrange RS 11-25 and were randomly assigned to receive either chemoendocrine or endocrine therapy alone.

The study was designed to show non-inferiority of endocrine therapy alone for BC disease free survival.

The results of the study showed that endocrine was non inferior to chemoendocrine in the analysis of invasive disease-free survival.  

At 9 years, the two groups had similar rates of disease free survival and overall survival.

The chemotherapy benefit for invasive disease-free survival varied with combination of the RS with age with some chemotherapy benefit found in women 50 years of younger with RS of 16-25.