Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome.

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The similarity of clinical characteristics between the Z0011 trial cohort and our eligible group confirms the exportability of these criteria to another population. The worse prognosis of patients who did not meet the Z0011 criteria suggests prudence before disregarding or enlarging broadening the indications for omitting cALND.

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Determining the status of steroid hormone receptors [oestrogen (ER) and progesterone receptors (PR)] is a crucial part of the breast cancer workup. Thereby, breast cancers can be classified into four subtypes. However, the existence of ER−/PR+ tumours, often reported to be ill‐classified due to technical errors, remains controversial. In order to address this controversy, we reviewed the hormone receptor status of 49 breast tumours previously classified as ER−/PR+ by immunohistochemistry, and compared clinical, pathological and molecular characteristics of confirmed ER−/PR+ tumours with those of ER+ and triple‐negative tumours. We unequivocally confirmed the ER−/PR+ status in 27 of 49 tumours (0.3% of all breast cancers diagnosed in our institution between 2000 and 2014). We found that ER−/PR+ were morphologically and histologically similar to triple‐negative tumours, but very distinct from ER+ tumours, with more aggressive phenotypes and more frequent basal marker expression than the latter. On the molecular level, RNA sequencing revealed different gene expression profiles between the three groups. Of particular interest, several genes controlled by the suppressor of zest 12 (SUZ12) were upregulated in ER−/PR+ tumours. Overall, our results confirm that ER−/PR+ breast cancers are an extremely rare but ‘real’ tumour subtype that requires careful diagnosis and has distinct features warranting different responsiveness to therapies and different clinical outcomes. Studies on larger cohorts are needed to further characterise these tumours. The likely involvement of SUZ12 in their biology is an interesting finding which may – in a long run – give rise to the development of new therapeutic alternatives.