This is a phase II open-label, multicentre, randomized trial. The study assesses the treatment of postmenopausal patients with hormone receptor positive/HER2 positive early breast cancer with neoadjuvant palbociclib in combination with hormonal therapy and HER2 blockade, versus the treatment with paclitaxel in combination with HER2 blockade.

TOUCH is an open label, international, phase II neoadjuvant trial which will assess the treatment of elderly patients with hormone receptor positive / human epidermal growth factor receptor-2 (HER2) positive early breast cancer with neoadjuvant palbociclib in combination with hormonal therapy and HER2 blockade, versus the treatment with paclitaxel in combination with HER2 blockade.

The neo-adjuvant setting was chosen to evaluate these therapy combinations in a short time-frame and to provide access to biomaterial both at baseline and after the end of the treatment, at surgery. Biopsy specimens will be analyzed at the end of the trial by gene-expression profiling to assess RBsig status. This marker may represent a tool to identify the participants who are more likely to benefit from a chemotherapy-free regimen in this population.

Palbociclib is a potent, highly selective, reversible, orally active, inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6), therefore inhibiting cell growth and can be safely and effectively administered to older patients without need for dose adjustment based solely on age. Treatment de-escalation, namely harnessing and taking maximum advantage of targeted therapies vs conventional treatment (chemotherapy) in order to limit side effects, is particularly appealing in the older population.

Clinical data from the HR positive /HER2 negative setting show that combinations of palbociclib and letrozole are safe and effective. These combinations have not yet been tested in the HR positive /HER2 positive population that the investigators include in this trial. However, combinations of trastuzumab and endocrine treatment (ET), including letrozole have shown to be safe and to have some additional activity compared to ET alone in the HR positive /HER2 positive population. Therefore, the role of palbociclib in addition to letrozole and trastuzumab plus pertuzumab needs to be further studied.

Current standard of care for treatment of HER2 positive BC incorporates chemotherapy and anti-HER2 agents, with chemotherapy regimens of sequential anthracyclines and taxanes, used as single agents or in combination with other chemotherapy drugs. Trastuzumab is often administered concurrently with a single agent taxane to avoid the possible additive cardiac toxicity of combinations of anthracycline containing regimens and trastuzumab.

A regimen of weekly paclitaxel and trastuzumab plus pertuzumab was chosen as the comparator arm in this trial. More aggressive chemotherapy may not be justified in this population and trial participants may receive additional treatment after surgery, at the discretion of the treating doctor.

Preclinical and clinical rationale exists to support the proposal that palbociclib may represent a valuable option for increasing the activity of ET and anti-HER2 agents, such that a triple combination with these agents could prove superior to a standard treatment with chemotherapy and anti-HER2 agents.

The investigators hypothesize that the combination of palbociclib, letrozole and trastuzumab plus pertuzumab proposed in this trial will be more efficacious compared to the combinations of anti-HER2 agents and ET reported in other trials.

In 2019, it is estimated that of 260,600 newly diagnosed cases of invasive breast cancer in the United States, 82% occurred in women aged 50 or over. Furthermore, of the 41,760 breast cancer-related deaths in the same year, 90% occurred in this predominantly post-menopausal age group. Around 40% of BCs occur in women aged 65 and older. Of these, 10-15% have tumors that overexpress HER2. Elderly patients are generally underrepresented in clinical trials and may benefit from anti-HER2 agents as much as the younger population. Post-menopausal patients with HR positive /HER2 positive BC represent a unique group of patients with an unmet clinical need. This population is the focus of the TOUCH trial.

Inclusion Criteria:

1. Histologically confirmed invasive breast cancer, with the following characteristics:

   • Early breast cancer with tumor size >1 cm (as measured by at least one of the required examination methods of clinical examination, mammography and ultrasonography);
   • No clinical evidence of regional lymph node metastasis (via physical and/or radiological exam) (cN0) OR
   • Clinical evidence of cN1 status, defined by nodal involvement limited to clinically or radiologically detectable metastasis to movable ipsilateral level I, II axillary lymph node(s)
   • No evidence of metastasis (M0).

2. Postmenopausal, defined by women with:

   • Prior bilateral surgical oophorectomy; OR
   • Amenorrhea and age ≥60 years; OR
   • Age <60 years and amenorrhea for 12 or more consecutive months in the absence of alternative pathological or physiological cause (including chemotherapy, tamoxifen, toremifene, ovarian suppression, or hormonally-based contraception) plus FSH and serum estradiol levels within the laboratory's reference ranges for postmenopausal women

3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

4. Primary tumor must have positive estrogen receptor (ER) ≥10%

5. Primary tumor must be HER2-positive (by IHC and/or ISH)

6. Baseline LVEF ≥55% measured by Echocardiography (preferred) or MUGA scan

7. Normal hematologic status:

   • Absolute neutrophil count ≥1500/mm3 (1.5 × 109/L);
   • Platelets ≥100 × 109/L;
   • Hemoglobin ≥9 g/dL (≥90 g/L).

8. Normal renal function: serum creatinine ≤1.5 ULN

9. Normal liver function:

   • Serum total bilirubin ≤1.5 × upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (<2 × ULN) is allowed;
   • AST or ALT ≤2.5 × ULN;
   • Alkaline phosphatase ≤2.5 × ULN.

10. Written Informed Consent (IC) must be signed and dated by the patient and the Investigator prior to randomization.

11. The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.

12. The patient agrees in writing to make tumor (mandatory diagnostic core biopsy and surgical specimen) available for submission for central pathology review and to conduct translational studies as part of this protocol.

Exclusion Criteria:

1. Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules) (T4 according to AJCC 8th edition cancer staging TNM)
2. Inflammatory breast cancer
3. Bilateral invasive breast cancer
4. Received any prior treatment for primary invasive breast cancer
5. Any active tumor of non-breast-cancer histology
6. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (NYHA functional classification ≥II), cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
7. Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety
8. Contraindications or known hypersensitivity to any of the trial medications or excipients
9. Treatment with any investigational agents within 30 days prior to expected start of trial treatment
10. Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post major bowel resection
11. Evidence via physical and/or radiological exam of cN2 or cN3 nodal involvement defined by: metastasis to ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted, OR involvement of ipsilateral infraclavicular, internal mammary and/or supraclavicular lymph node(s)
12. History of extensive disseminated/bilateral or known presence of interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and pulmonary fibrosis. A history of prior radiation pneumonitis is not considered an exclusion criterion.