In March 2022, a 51-year-old woman was referred to our institution for a second opinion.
Her past medical history was significant for the diagnosis, at the age of 47 years, of endometrial cancer. In April 2018, she underwent a radical hysterectomy with pelvic lymphadenectomy. Histology revealed an intermediate differentiated endometrioid EC, FIGO stage IIIC1 (pT3pN1). Estrogen and progesterone receptors were positive. Mismatch-Repair-Proteins such as mutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2), mutS homolog 2 (MSH2) and mutS homolog 6 (MSH6) were expressed.
The risk factors suggested the need of adjuvant chemoradiation treatment.
Following multi-disciplinary discussion, a sequential adjuvant radio-chemotherapy was proposed to the patient. She consented to a course of 4 cycles of 3 weekly Carboplatin (AUC 5) and Paclitaxel (175 mg/m2), which she received from May to July 2018, and external beam radiotherapy completed in November 2018. Three months after finishing the adjuvant therapy cycle a follow-up thoracic and abdominal computed tomography (CT) scan showed complete remission.
Ten months after stopping adjuvant therapy, the patient showed a radiological disease progression to the peritoneal carcinomatosis nodules. In consideration of the platinum free-interval, the patient was treated with carboplatin plus paclitaxel chemotherapy at standard dose for a total of six cycles.
After approximately 2 months, she experienced disease progression with increased of peritoneal nodules for which she was subjected to cytoreductive surgery on peritoneum. The histological examination confirmed the diagnosis of endometrioid EC with a high expression of hormone receptors, microsatellite stability.
The patient then received hormonal therapy with megestrol acetate for 9 months until new peritoneal disease progression.
Therefore, from January to April 2021, the patient underwent second-line chemotherapy with liposomal doxorubicin until disease progression.
From April to July 2021, the patient received intravenous weekly topotecan without any benefit.
In August 2021 started fourth-line of oral chemotherapy with cyclophosphamide until the progression of disease.
In November 2021, a new clinical progression associated to radiologic progression to peritoneum occurred. Thus, the patient received a fifth-line therapy with oral etoposide.
In January 2022, for a new lymph node and peritoneal progression associated to painful abdominal symptoms, the patient started hormone therapy with letrozole at the dosage of 2,5 mg daily.
A timeline overview of the patient's management is summarized in  Figure 1 .
In March 2022, the patient referred to our institution in order to evaluate the potential enrollment in experimental clinical trials. Given the unavailability of clinical trials in our Institute for this type of patient, we proposed to perform a comprehensive genomic profiling through next generation sequencing (NGS) on archival tumor tissue from the last surgery. Importantly, the combination of pembrolizumab and lenvatinib was not yet available in Italy for patients with advanced EC that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting.
The patient had a personal history of hypertensive heart disease in pharmacological therapy, and iatrogenic hypothyroidism currently treated with thyroid hormone replacement. The patient was functioning well, as indicated by an Eastern Cooperative Oncology Group performance status of 1.
The NGS (FoundationOne CDx assay) was performed on tumor sample and showed microsatellite stability and low Tumor Mutational Burden (TMB) (1 mut/Mb) (see  Table 1 ). Moreover, the data analysis revealed several genomic alterations ( Table 1 ) including PIK3CA mutation in exon 20 (H1047R, variant allele frequency 78.2%), which was considered targetable.
In April 2022, given the lack of validated standard treatment, following discussion in the Molecular Tumor Board (MTB) of MITO for gynecological cancer patients, the patient started treatment with oral PI3K alpha-selective inhibitor namely alpelisib at the standard dose of 300 mg once daily on a continuous schedule in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.
Following approval by the Institute's ethics committee, alpelisib was provided for compassionate use by Novartis.
A CT scan at baseline revealed two bulky nodules of peritoneal carcinomatosis (83 mm, 85 mm), a 15 mm mass in the paraaortic lymph node, and a 22 mm mass in the right inguinal lymph node (see  Figures 2 ,  3 ).
During the course of alpelisib treatment, the patient experienced minimal toxicity, including fatigue (grade 1), and decreased appetite (grade 1), based on the CTCAE (version 5.0). Interestingly, the patient not experienced the onset of adverse events as hyperglycemia and skin reactions. To reduce the onset of skin adverse events, the patient was taking prophylactic non-sedating antihistamines such as cetirizine 10 mg once daily during the first 8 weeks of therapy then taper off.
Unfortunately, the patient developed grade 3 diarrhea (increase of >=7 stools/day) at 30 days of alpelisib requiring treatment with loperamide and temporary interruption of alpelisib until recovery to grade <=1. Then, the dose of alpelisib was reduced from 300 mg to 200 mg daily, which was well tolerated.
In terms of effectiveness, after just completing one 28-day cycle, she obtained a clinical benefit with meaningful improvement in her abdominal distension and discomfort, size reduction of peritoneal lesions associated to rapid and progressive reduction of tumor marker (CA 125, CA 19-9), as shown in  Figure 1 .
After only 4 months of alpelisib treatment, she achieved a partial radiologic response with complete disappearing of one of two nodules of peritoneal carcinomatosis and dimensional reduction of para-aortic and inguinal lymph nodes, as shown by the CT-scan (see  Figures 2 ,  3 ).
Therefore, in consideration of the objective and radiological partial response, the clinical benefit and the absence of unacceptable toxicity, by the time of writing (7 months after the start of treatment), the patient is still on therapy with alpelisib 200 mg daily.