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D'Angelo et al. J Cancer Metastasis Treat 2019;5:30 I http://dx.doi.org/10.20517/2394-4722.2018.86 Page 13 of 18
[75]
lesions in up to 42% and this change does not correlate with an impairment of overall survival : ER and
PR status are different in 14.6% and 16.7% of cases respectively, while HER2 changes in about 8.3% of cases.
During treatment it can be useful to take several biopsies to modify chemotherapy or endocrine therapy in
[70]
the light of ER, Pr and HER2 status . Following chemotherapy, in particular anthracycline-based ones, the
[75]
level of expression of ER, PR and HER2 can change ; these modifications imply a change also in tumor
progression and aggressiveness and a resistance to endocrine therapy or trastuzumab, producing a change
[43]
in clinical strategy. In our study the male patient had different patterns between gastric metastasis and
[22]
primary breast tumor (ER-/PgR- in the stomach and ER+/PgR+ in the breast), one had different expression
[40]
of HER2 (HER2- in the breast, HER2+ in the stomach) and one patient showed a change in receptor status
during treatment passing from a Luminal A type to a Luminal B and then to a triple negative.
Combination of CK7/CK20 is also useful to distinguish between metastasis from breast carcinoma
and primary gastric tumor; CK20 is expressed in gastric, colorectal, pancreatic and in transitional cell
[76]
carcinomas, but it’s negative in breast cancer . The CK7+/CK20- pattern is typical of adenocarcinoma of
the breast, lung, and ovary, while CK7-/CK20+ is expressed in intestinal adenocarcinoma. CDX2 is a tumor
suppressor gene that is implied in intestinal cell proliferation, differentiation, adhesion and apoptosis; it’s
an important marker of intestinal differentiation, usually expressed in gastric cancer and in intestinal
metaplasia [77,78] .

Mammoglobine (MGB) is a 93-amino acid glycoprotein and a recent marker for breast cancer with a
sensitivity of 93.1%. It can be useful in diagnosis of gastric metastasis from breast tumor in combination
with other receptor expression [79,80] . GCDFP-15 is never expressed in gastrointestinal cancer, but it’s found
in malignant tumor from the breast, and also salivary gland, external genitals, eyelid, apocrine duct of the
[81]
bronchial tubes and gynecologic adenocarcinoma . MGB is more sensitive than GCDFP-15 but has less
[79]
specificity . GATA-3 is a nuclear transcription correlated to breast glandular epithelial cells and shows the
[81]
highest sensitivity in comparison to MGB and GCDFP-15 .
Diagnosis of metastatic disease stems from the analysis of all these markers. Gastric metastases are usually
positive for ER, PgR, mammoglobine, GCDFP-15, GATA-3 and CK7 and negative for CK20. Gastric cancer
is normally positive for CK20, but it’s usually negative for GCDFP-15, ER and PgR, even if ER and PgR
expression is controversial.

HNF4A (hepatocyte nuclear factor 4 alpha) was introduced as a new marker to differentiate gastric
metastasis from primary malignant tumor. HNF4A is a nuclear transcription factor correlated with invasion,
metastasis and epithelial-to-mesenchymal transition, due to activation of MMP-14 and promoting tumor
[82]
angiogenesis, migration and invasion . A recent Brazilian study shows that HNF4A has positive expression
in all patients with primary gastric adenocarcinoma, negative in all cases of primary breast carcinoma and
also negative in all gastric metastases from breast carcinoma. In combination with ER and PR expression, it
[83]
exhibits high sensitivity (100%) and specificity (96%) .
Therapy
Establishing the primary site of malignancy determines the right treatment. Gastric metastasis from
breast cancer are considered as a systemic disease because they usually present along with other metastatic
localization, therefore the appropriate therapy is systemic, such as chemotherapy or endocrine therapy,
whereas for primary gastric cancer first line therapy involves surgery [5,15,84] . Chemotherapy, hormonal
therapy or a combination of both of them lead to a remission rate of 32% to 53% and a prolonged survival of
[3]
2 or 3 years .

In case of metastatic disease surgery is considered in case of obstruction, bleeding or perforation of gastric
[85]
wall even if more conservative treatments (endoscopic hemostatic procedures or stent) can be performed