Award Title: Alpelisib with fulvestrant for HR positive, HER2 negative, PIK3CA positive breast cancer (ID3929)
Funder: Department of Health and Social Care

Abstract: Breast cancer arises from the tissues of the ducts or lobules of the breast. The cancer is said to be 'advanced' if it has spread to other parts of the body such as the bones, liver, and lungs (metastatic cancer), or if it has grown directly into nearby tissues and cannot be completely removed by surgery._x000D_
_x000D_
In 2017 in England, around 46,109 people were diagnosed with breast cancer.[1] In 2018 there were 9,640 deaths from breast cancer in England.[2] Approximately 13% of women with breast cancer have advanced disease (stage III or IV) in England when they are diagnosed.[3] The 1-year survival rate for adults diagnosed at stage IV (metastatic breast cancer) in England is 66%.[4] Around 35% of people with early or locally advanced disease will progress to metastatic breast cancer in the 10 years following diagnosis.[5]_x000D_
_x000D_
Current treatments for advanced breast cancer aim to relieve symptoms, prolong survival and maintain a good quality of life with minimal adverse events. Treatment depends on whether the cancer cells have particular receptors, the extent of the disease, and previous treatments. Most (80%) breast cancers in are hormone-receptor positive and around two-thirds are oestrogen receptor positive. Human epidermal growth factor receptor 2 (HER2) is present in about 10-15% of breast cancers.[6] Approximately 64% of women with metastatic breast cancer in the UK have hormone-receptor positive, HER2 negative disease.[7] PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutations have been found in 30% to 40% of oestrogen receptor positive, HER2-negative tumours.[8]_x000D_
_x000D_
NICE clinical guideline 81 (CG81) recommends first-line treatment with endocrine therapy for most people with advanced hormone receptor-positive breast cancer. For people whose disease is life-threatening or requires early relief of symptoms, CG81 recommends chemotherapy. The endocrine therapies used in clinical practice in postmenopausal women include aromatase inhibitors (anastrozole and letrozole), or tamoxifen, if aromatase inhibitors are not tolerated or are contraindicated. Women who arepremenopausal or perimenopausal will receive first-line treatment with tamoxifen and ovarian suppression if they have not previously received tamoxifen, while men will receive tamoxifen as a first-line endocrine treatment. NICE technology appraisals 495, 496 and 563 recommend cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors (palbociclib, ribociclib and abemaciclib respectively) in a combination with an aromatase inhibitor for treating hormone receptor positive, HER2-negative, locally advanced or metastatic breast cancer as initial endocrine based therapy in adults. Fulvestrant is not recommended for untreated locally advanced or metastatic oestrogen-receptor positive breast cancer (NICE technology appraisal 503)._x000D_
_x000D_
For people who receive first-line treatment with anastrozole or letrozole, second-line treatment may be either tamoxifen, exemestane, or everolimus and exemestane (NICE technology appraisal 421). NICE technology appraisal 687 recommends ribociclib in combination with fulvestrant as an option for hormone receptor-positive, HER2-negative, advanced breast cancer in people who have had previous endocrine therapy if exemestane plus everolimus is the most appropriate alternative to a CDK 4/6 inhibitor. NICE technology appraisals 579 and 619 recommend abemaciclib and palbociclib respectively in the same population for use within the Cancer Drugs Fund.[a] Subsequent treatment options also include chemotherapy for some people. Fulvestrant monotherapy is not recommended for use following anti-oestrogen therapy, as an alternative to aromatase inhibitors (NICE technology appraisal 239), however, it is sometimes used after exemestane and tamoxifen in people who would otherwise receive chemotherapy._x000D_
_x000D_
References_x000D_
1 Office for National Statistics (2019) Cancer registration statistics, England, 2017. Accessed January 2020._x000D_
2 Nomis (2020) Office for National Statistics. Mortality statistics – underlying cause, sex and age: 2018 data. Accessed January 2020._x000D_
3 Cancer Research UK (2020) Breast cancer incidence statistics: England 2014 data. Accessed January 2020_x000D_
4 Cancer Research UK (2020) Breast cancer survival statistics: adults diagnosed 2013-2017, followed up to 2018. Accessed January 2020._x000D_
5 Dewis R and Gribbin J (2009) Breast cancer: diagnosis and treatment, an assessment of need. Cardiff: National Collaborating Centre for Cancer. Accessed August 2018_x000D_
6.NIHR Evidence Briefing (2017) Alpelisib in combination with fulvestrant for advanced HR positive, HER2-negative breast cancer in men and postmenopausal women. Accessed September 2018._x000D_
7 NICE (2017) Resource impact report: Palbociclib with an aromatase inhibitor for previously untreated, hormone receptor positive, HER2-negative, locally advanced or metastatic breast cancer (TA495). Accessed September 2018._x000D_
8 Kratz J, Burkard M, O’Meara T, Pusztai L, Veitch Z, Bedard PL (2018) Incorporating Genomics Into the Care of Patients With Advanced Breast Cancer. American Society of Clinical Oncology. Volume 38, 56-64. Accessed September 2018._x000D_
_x000D_
a Products recommended for use in the Cancer Drugs Fund after 1 April 2016 should not be considered as comparators, or appropriately included in a treatment sequence, in subsequent relevant appraisals. NICE’s position statement.

Lay Abstract: To appraise the clinical and cost effectiveness of alpelisib within its marketing authorisation for treating advanced hormone-receptor positive, HER2-negative, PIK3CA-mutated breast cancer.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS