Clinical trial NCT02945579: Multicenter Trial for Eliminating Breast Cancer Surgery or Radiotherapy in Exceptional Responders to Neoadjuvant Systemic Therapy
Official title: Multicenter Trial for Eliminating Breast Cancer Surgery or Radiotherapy in Exceptional Responders to Neoadjuvant Systemic Therapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Estrogen Receptor Negative
HER2 Positive Breast Carcinoma
HER2/Neu Negative
Invasive Breast Carcinoma
Progesterone Receptor Negative
Stage I Breast Cancer AJCC v7
Stage IA Breast Cancer AJCC v7
Stage IB Breast Cancer AJCC v7
Stage II Breast Cancer AJCC v6 and v7
Stage IIA Breast Cancer AJCC v6 and v7
Stage IIB Breast Cancer AJCC v6 and v7
Triple-Negative Breast Carcinoma
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Artidis
First posted: 2016-10-26
Enrollment: 120
Sex: FEMALE
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This clinical trial studies eliminating surgery and how well radiation therapy after systemic therapy works in treating patients with HER2 positive or triple negative breast cancer when image-guided biopsy shows no residual cancer. Patients then receive standard breast radiotherapy.

Detailed description: PRIMARY OBJECTIVES:

I. Cohort A1 and A2: To determine the 6 mo, 1, 2, 3, 5, 7, and 10 year biopsy confirmed ipsilateral breast tumor recurrence rate (IBTR, invasive and/or in situ) among patients who do not undergo surgery.

II. Cohort B: To determine the pCR rate 6 or 12 months after radiation therapy based on image-guided biopsy.

III. Cohort C: To determine the 6 mo, 1, 2, 3, 5, 7 and 10-year ipsilateral breast tumor recurrence rate among patients who undergo surgery alone without radiation.

SECONDARY OBJECTIVES:

I. Cohort B: To determine the 6 mo, 1, 2, 3, 5, 7 and 10--year biopsy confirmed ipsilateral breast tumor recurrence rate (IBTR, invasive and/or in situ) among patients who do not undergo surgery.

II. To determine the number (%) of patients where final biopsy reveals residual disease and quantify the residual disease (residual cancer burden, RCB) determined by routine pathologic examination of surgery specimens.

III. To assess baseline, 6 months, 1, 3, 5, 7, and 10 years decisional comfort of clinical trial participation using the Decisional Regret Scale (DRS).

IV. To determine patient-reported cosmetic outcome, breast pain, and functional status using the Breast Cancer Treatment Outcomes Scale (BCTOS) at baseline, 6 months, 1, 3, 5, 7, and 10 years.

V. To determine the 6 mo, 1, 2, 3, 5, 7, and 10 years incidence of ipsilateral breast and nodal recommendation and performance of biopsy based on breast imaging follow-up.

VI. Correlate "liquid biopsy" analyses (after standard routine NST, 6 months and one year post-radiotherapy or surgery) among protocol participants with pCR, utilizing circulating tumor cells (CTCs) and circulating tumor-DNA (ctDNA).

VII. Among patients who decide to proceed with routine surgery, record the results of final biopsy compared with routine pathologic examination of surgery specimens.

VIII. To determine patient-reported quality of life using the FACT B+4 instrument at baseline, 6 months, 1, 3, 5, 7, and 10 years after treatment.

IX. To explore if radiation genomic sensitivity scores and Oncotype performed on the initial diagnostic core biopsy specimen correlate with pCR rates in Cohort B.

X. To determine if changes in blood-based RNA Sequencing are elicited with radiation in Cohort B, measured at baseline, at the first 4-6 week follow-up after radiation, and at the 6 month post-radiation follow-up.

XI. In Cohort B to determine the 3-year rate of tumor control/ progression free survival (PFS).

XII. In Cohort C/D to determine whether nanomechanical biomarkers or quantification of stromal and tumor TILS can predict for low risk of local recurrence in exceptional responders who omit radiation therapy.

XIII. In Cohorts A/B/C/D: To record 6 mo, 1, 2, 3, 5, 7, and 10 year breast cancer disease-free and overall survival.

XIV. In Cohort D: Correlate nanomechanical biomarker analyses with pCR and/or local recurrence in patients with triple negative or her-2 positive breast cancer treated with lumpectomy +/- radiation.

OUTLINE:

For Cohorts A, within 12 weeks of completing neoadjuvant systemic therapy, patients undergo whole breast irradiation over 15-25 fractions on consecutive days. Patients then undergo external beam radiation therapy (EBRT) boost over 7 fractions on consecutive days beginning the day following completion of whole breast irradiation.

For Cohort B, patients will receive 3 months of neoadjuvant endocrine therapy, after which they will receive ablative partial breast irradiation over 5 fractions. Patients will then continue with endocrine therapy.

After completion of study treatment, patients are followed up every 6 months for 10 years.

Eligibility criteria: Inclusion Criteria:

* Cohort A1 and A2

  • Conditions for patient eligibility: Patients on this portion of the study can receive radiation treatment at any MD Anderson Cancer Center or any outside hospital and may be enrolled prior to, during, or following neoadjuvant systemic therapy provided they meet the following eligibility and ineligibility requirements noted below:
  1. Pathologically confirmed unicentric invasive breast cancer defined as radiologic clinical stage T1 or T2 (≤ 5 cm), N0 or N1 (≤ 4 abnormal axillary nodes on initial ultrasound), clinical stage M0.
  2. HER2 positive (IHC 3+ and or FISH amplified) or triple receptor negative (TN, ER/PR\&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 10% HER2 negative (IHC 1+ or 2+ FISH non-amplified) receiving any standard routine clinical NST regimen.
  3. Patient desires breast conserving therapy.
  4. Age 40 years or older. This age cutoff is justified because breast cancers in women under the age of 40 are known to have a significantly higher risk of IBTR presumably due to underlying biologic differences \[124, 125\].
  5. Female sex.
  6. If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to study registration and the patient must have no evidence of disease for this prior non-breast cancer.
  7. Patient must have an initial nodal ultrasound that does not demonstrate more than four suspicious lymph nodes, any suspicious lymph nodes should be biopsied to determine if nodal metastatic disease present.
  8. Patient understands that the breast lesion size on final breast imaging must be less than or equal to 2 cm prior to the biopsy procedure being performed on study and if the biopsy shows residual carcinoma the patient will be taken off study.
* Cohort B1 and B2

  • Conditions for patient eligibility: Patients on this portion of the study will be limited to receive radiation treatment at MD Anderson Cancer Center or other approved locations and must be enrolled prior to any neoadjuvant systemic therapy provided they meet the following eligibility and ineligibility requirements noted below:
  1. ER and/or PR positive, HER2 negative
  2. Clinical stage T1N0M0, unicentric non-lobular breast cancer, no lymphovascular space invasion,
  3. At least 40 years of age.
  4. Oncotype ≤ 25 if age ≥ 50 years
  5. Oncotype 0-20 and tumor size ≤ 1.5cm if age 40-49 years.
  6. Patient agrees to take anti-estrogen therapy and is interested in breast conservation
  7. Female sex.
  8. If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to study registration and the patient must have no evidence of disease for this prior non-breast cancer.
  9. No history of prior radiation to the area of the breast that would require protocol-mandated treatment
* Cohort C

  • Conditions for patient eligibility: Patients on this portion of the study can receive surgical treatment at any MD Anderson Cancer Center or any outside hospital and may be enrolled prior to or following neoadjuvant systemic therapy provided they meet the following eligibility and ineligibility requirements noted below:
  1. Pathologically confirmed invasive breast cancer defined as radiologic clinical stage T1 or T2 (≤ 5 cm), N0, clinical stage M0 and HER2 positive (IHC 3+ and or FISH amplified) receiving any standard routine clinical NST regimen containing her-2 directed therapy OR Pathologically confirmed invasive breast cancer defined as radiologic clinical stage T1 (≤ 2 cm), N0, clinical stage M0 and triple negative, receiving any standard routine clinical NST regimen.
  2. For cohort C patients participating in the optional pretreatment biopsy, the patient should be able undergo biopsy or surgery of the primary tumor site of suspected or proven invasive breast cancer and should be planned to receive neoadjuvant systemic therapy.
  3. Patient desires breast conserving therapy.
  4. Age 30 years or older if HER2 positive. Age 50 or older if HER2 negative (triple negative).
  5. Female sex.
  6. If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to study registration and the patient must have no evidence of disease for this prior non-breast cancer.
  7. Patient must have an initial nodal ultrasound that does not demonstrate suspicious lymph nodes; any suspicious lymph nodes should be biopsied to determine if nodal metastatic disease present.
  8. Patient must have no evidence of residual invasive tumor or DCIS on pathologic review of the lumpectomy surgical specimen
  9. Patient must have no evidence of metastatic disease or isolated tumor cells involving the lymph nodes on pathologic review of the lymph node surgical specimen. If treatment effect in the nodes is noted on the pathology report, the investigators would generally discourage enrollment on this protocol.
  10. Unifocal disease or limited multifocal disease that can be excised in a single lumpectomy specimen
* Cohort D (MD Anderson Houston patients only)

  * Conditions for patient eligibility: Patients on this portion of the study meet all eligibility requirements for cohort C, but have not enrolled onto the study to omit radiation. Patients in Cohort D can be identified at the time of diagnosis or prior to lumpectomy. They are not required to participate in one of the treatment arms of the study, but can ultimately choose to move to an omission Cohort at a later time point.

3.5.1 Patients with triple negative or her-2 positive tumor who are amenable to breast conserving treatment and have received or are planned for neoadjuvant systemic therapy prior to surgery are eligible for Cohort D.

3.5.2 Eligible patients in cohort D who have undergone optional ARTIDIS biopsies of the primary breast tumor at the time of diagnosis, prior to starting neoadjuvant therapy, or following completion of systemic therapy, at the time of surgery, may later move to Cohort A or C if they meet all eligibility requirements and ultimately desire surgery or radiation omission

Exclusion Criteria:

1. Radiologic evidence for a stage T3 or clinical stage T4 breast cancer in Cohort A1/A2/C; radiologic evidence for a stage T2-T3 or clinical stage T4 breast cancer in Cohort B1/B2.
2. Clinical or pathologic evidence for distant metastases.
3. Prior diagnosis of invasive or ductal carcinoma in situ breast cancer in the ipsilateral breast.
4. Clinical evidence of progression of disease \&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;20% in the breast or new evidence of nodal metastases.
5. Patient is known to be pregnant.
6. Patient is participating in a NST protocol in which surgical excision of the breast and or lymph nodes are required in Cohort A1/A2/B1/B2.

Primary outcomes:
measure: Ipsilateral breast tumor recurrence-free survival (IBT-RFS)
timeFrame: From confirmation of pathologic complete response (pCR) to the time of ipsilateral breast tumor recurrence or death, whichever occurs first or the time of last contact, assessed for up to 10 years
measure: Overall survival
timeFrame: Up to 10 years
Secondary outcomes:
Other outcomes:
measure: Change in biomarkers in blood and plasma
timeFrame: 3 months, 3-8 weeks post radiation therapy (if applicable), 6 months, 12 months]
measure: Residual cancer burden (RCB)
timeFrame: Up to 10 years
measure: Incidence of ipsilateral breast and nodal recommendation and performance of biopsy based on breast imaging follow-up
timeFrame: Up to 10 years
measure: Quality of Life measured by DRS questionnaire
timeFrame: Baseline, 6 months, 12 months, 36 months, 60 months, 84 months, and 120 months]
measure: Quality of Life measured by BCTOS questionnaire
timeFrame: Baseline, 6 months, 12 months, 36 months, 60 months, 84 months, and 120 months]
measure: Quality of Life measured by FACT-B+4 questionnaire
timeFrame: Baseline, 6 months, 12 months, 36 months, 60 months, 84 months, and 120 months]
Locations:
city: Gilbert
country: United States
facility: MD Anderson Cancer Center - Banner
state: Arizona
city: Jacksonville
country: United States
facility: Baptist MD Anderson Cancer Center
state: Florida
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Voorhees
country: United States
facility: Cooper Hospital Univ Med Ctr, MD Anderson at Cooper Voorhees
state: New Jersey
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Henry M Kuerer
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kuerer HM, Smith BD, Krishnamurthy S, Yang WT, Valero V, Shen Y, Lin H, Lucci A, Boughey JC, White RL, Diego EJ, Rauch GM; Exceptional Responders Clinical Trials Group. Eliminating breast surgery for invasive breast cancer in exceptional responders to neoadjuvant systemic therapy: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2022 Dec;23(12):1517-1524. doi: 10.1016/S1470-2045(22)00613-1. Epub 2022 Oct 25.
citation: Hariharan N, Rao TS, Rajappa S, Naidu CCK. Precision medicine - A new era in multidisciplinary care. Cancer Treat Res Commun. 2022;32:100577. doi: 10.1016/j.ctarc.2022.100577. Epub 2022 May 17. No abstract available.