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Carcinoma of unknown primary-, Stage IV

Female, 42 years old

Based on package plus analysis, this patient should be sensitive to taxane, toposiomerase I and II inhibitors, gemcitabine based chemotherapies and to PD-1/PD-L1 inhibitors.  The immunogram shows a high potential response to immunotherapy. Therefore, based on the level of CD8+ lymphocytes and PD-L1 expression,  treatment based on PD-1/PD-L1 inhibitors could be associated with potential clinical benefit for this patient. On the other hand this patient  should not be sensitive to platinum salt, 5-FU based chemotherapies.

Non-Small Cell Lung Cancer-, Stage IV

Male, 72 years old

Diagnosed in 2015 . Based on package plus this patient should be sensitive to taxane based chemotherapy and to MEK/ERK, PD-1/PD-L1 and mTOR inhibitors. With a high expression of p4EBP1 (an mTOR C1 effector), we have evidence of mTOR activation. In addition, PTEN negative expression is indicating that PTEN is not present to antagonize the PI3K pathway and to fulfill its function as a tumor suppressor. Moreover, NGS data show that this patient is WT for PIK3CA. Altogether, those results suggest that mTOR inhibitors would be associated with a clinical benefit for this patient whereas PIK3 inhibitors would be associated with a lack of clinical benefit for this patient. As for the PI3K/mTOR dual inhibitors, they would be associated with undetermined clinical benefit for the patient.  On the other hand this patient should not be sensitive to platinum salt, gemcitabine based chemotherapies and to ALK/RET/ROS1 and  MET inhibitors.

Non-Small Cell Lung Cancer-, Stage IV

Male, 70 years old

We found an EGFR L858R mutation. This is one of the most frequent EGFR mutations in NSCLC (26-40%) and the most common sensitizing mutation to EGFR-TKI therapies, it has been reported to double the phosphorylation effects of EGFR after ligand treatment. NSCLC patients carrying this mutation are responsive to gefitinib and erlotinib therapies. Based on package plus analysis, this patient should be sensitive to gemcitabine based chemotherapy. On the other hand this patient should not be sensitive to taxane, 5-FU based chemotherapies and to ALK/RET/ROS1/NTRK, MET, PI3K and dual PI3K/mTOR inhibitor.

Breast Cancer HR, Stage IV

Male, 58 years old

SOLID PART: We found a BRCA2 stop codon. BRCA2 loss of function mutations in the germline have become a hallmark for hereditary breast and ovarian cancers. PARP inhibitors attack tumours defective in the BRCA2 gene by a concept termed ‘synthetic lethality’. If a BRCA2 mutation is present, the breast cancer is less likely to be oestrogen-receptor-positive, which means that the patient may not be a candidate for treatment with hormonal therapy. Several PARP inhibitors are recommended by NCCN guidelines and FDA approved for the treatment of breast cancer HER2-negative, BRCA1/2 positive. Based on package plus analysis, this patient should be sensitive to ER, CDK4/6 inhibitors. On the other hand this patient should not be sensitive to 5-FU based chemotherapy and to HER2, PI3K, dual PI3K/mTOR inhibitors.

LIQUID PART: The hereditary germline cancer panel has been performed on the peripheral blood mononuclear cells. A BRCA2 variant at a frequency of 51% has been found.

Breast Cancer HR, Stage IV

Female, unknown age

We found an ESR1 D538G mutation. Located in the ligand-binding domain of the protein, this variant has been associated in vitro with a constitutive activity and continued responsiveness to anti-estrogen therapies and in vivo associated with resistance to anti-estrogen therapies.

This mutation has been associated with a worse prognosis and is one of the most frequent mutations in breast cancer associated with a progression through aromatase inhibitor therapy. Reported to constitutively activate the estrogen receptor and already associated with worse prognosis, retrospective studies and prospectives studies have shown that this variant is associated with patients that progressed after treatment by aromatase inhibitors (like letrozole or exemestane), but not after tamoxifen. It has also been reported that the PFS is increased from 2.6 months for patients who received exemestane to 5.7 months for those given fulvestrant.  In a retrospective analysis of a large clinical trial, in which patients harboring the D538G mutation benefited from the addition of everolimus (mTOR inhibitor) to exemestane (aromatase inhibitor) for metastatic breast cancer patients progressing on AI.

Breast Cancer HR, Stage IV

Female, 55 years old

We found a PIK3CA H1047R mutation, which is oncogenic in vivo. It has been associated with an increase in lipid kinase activity. Moreover, it requires binding to p85 regulatory subunit to induce cellular transformation. Considering as activating, this variant may lead to increased activation of the PI3K/Akt/mTOR pathway. Therefore, PI3K, mTOR and dual PI3K/mTOR inhibitors would show potential clinical benefit upon mTOR pathway activation and/or PTEN loss or mutated. Interestingly, the mTOR inhibitors temsirolimus and everolimus have been approved by the FDA for use in various solid tumors. Moreover, it has been reported that PIK3CA mutations are associated with lower rates of pathologic complete response to anti-HER2 therapy in HER2-positive breast carcinomas. Moreover, it seems that PIK3CA exon 20 mutations are associated with resistance to anti-EGFR in colorectal cancer (PMID: 28002810).  Finally, PIK3CA mutations have been identified in ~5% of EGFR mutant lung cancers that developed acquired EGFR TKI resistance.

Head and Neck Cancer, Stage IV

Male, 71 years old

We found a HER2 L755S mutation. This variant is associated in vitro with strong resistance to lapatinib treatment and to some extent to AEE788 treatment. Nonetheless, it has been also shown in vitro that this variant is sensitive to the irreversible kinase inhibitor like neratinib and canertinib. The clinical impact on the trastuzumab and pertuzumab is unknown.

This variant has also been associated with resistance to anti-estrogen therapies. But we can't make any conclusion about the lack of clinical benefit of such therapy.