## Protocol Section
### Identification Module
**NCT ID:** NCT02945579

**Brief Title:** Eliminating Surgery or Radiotherapy After Systemic Therapy in Treating Patients With HER2 Positive or Triple Negative Breast Cancer

**Official Title:** Multicenter Trial for Eliminating Breast Cancer Surgery or Radiotherapy in Exceptional Responders to Neoadjuvant Systemic Therapy

#### Organization Study ID Info
**ID:** 2016-0046
#### Organization
**Class:** OTHER
**Full Name:** M.D. Anderson Cancer Center
#### Secondary ID Infos
**Domain:** CTRP (Clinical Trial Reporting Program)
**ID:** NCI-2016-01929
**Type:** REGISTRY
**Domain:** M D Anderson Cancer Center
**ID:** 2016-0046
**Type:** OTHER
### Status Module
#### Completion Date
**Date:** 2026-01-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-03-07

**Type:** ACTUAL

**Last Update Submit Date:** 2024-03-05

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2026-01-31

**Type:** ESTIMATED

#### Start Date
**Date:** 2017-01-20

**Type:** ACTUAL

**Status Verified Date:** 2024-03

#### Study First Post Date
**Date:** 2016-10-26
**Type:** ESTIMATED
**Study First Submit Date:** 2016-10-24
**Study First Submit QC Date:** 2016-10-24
### Sponsor Collaborators Module

#### Collaborators

**Class:** NIH

**Name:** National Cancer Institute (NCI)

#### Lead Sponsor

**Class:** OTHER

**Name:** M.D. Anderson Cancer Center

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**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 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: To record 6 mo, 1, 2, 3, 5, 7, and 10 year breast cancer disease-free and overall survival.

OUTLINE:

For Cohorts A and B, 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.

After completion of study treatment, patients are followed up every 6 months for 5 years.

### Conditions Module

**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

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 120

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** * Neoadjuvant chemotherapy therapy
* Biopsy: if no disease remaining - stay on the study and receive radiation (skip breast surgery)
* H\&P and Imaging every 6 months

Treatment (whole breast irradiation, EBRT) Within 12 weeks of completing neoadjuvant systemic therapy, patients undergo whole breast irradiation over 15-25 fractions on consecutive days. Patients then undergo EBRT boost over 7 fractions on consecutive days beginning the day following completion of whole breast irradiation.

**Intervention Names:**

- Radiation: External Beam Radiation Therapy

- Other: Laboratory Biomarker Analysis

- Other: Quality-of-Life Assessment

- Other: Questionnaire Administration

- Radiation: Whole Breast Irradiation

**Label:** Cohort A

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** * Neoadjuvant endocrine therapy for 6 months
* Radiation if there is less than 25% tumor increase
* Biopsy: if negative - additional endocrine therapy under the guidance of medical oncologist (skip breast surgery)
* H\&P and Imaging every 6 months

Cohort B Radiation:

Treatment (Stereotactic ablative radiotherapy -SABR) Following 3-6 months of endocrine therapy, if less than 25% tumor increase, patients undergo SABR irradiation over 10 fractions every other business day.

**Intervention Names:**

- Radiation: External Beam Radiation Therapy

- Other: Laboratory Biomarker Analysis

- Other: Quality-of-Life Assessment

- Other: Questionnaire Administration

- Radiation: Whole Breast Irradiation

**Label:** Cohort B

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** * Optional biopsy for nanomechanical biomarker assessment
* Neoadjuvant chemotherapy therapy
* Surgery (\& optional biopsy nanomechanical biomarker assessment): if no disease remaining - stay on the study and skip radiation
* H\&P and Imaging every 6 months

**Intervention Names:**

- Other: Laboratory Biomarker Analysis

- Other: Quality-of-Life Assessment

- Other: Questionnaire Administration

**Label:** Cohort C

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Cohort A

- Cohort B

**Description:** Undergo EBRT

**Name:** External Beam Radiation Therapy

**Other Names:**

- Definitive Radiation Therapy

- EBRT

- External Beam Radiotherapy

- External Beam RT

- external radiation

- External Radiation Therapy

- external-beam radiation

**Type:** RADIATION

#### Intervention 2

**Arm Group Labels:**

- Cohort A

- Cohort B

- Cohort C

**Description:** Correlative studies

**Name:** Laboratory Biomarker Analysis

**Type:** OTHER

#### Intervention 3

**Arm Group Labels:**

- Cohort A

- Cohort B

- Cohort C

**Description:** Ancillary studies

**Name:** Quality-of-Life Assessment

**Other Names:**

- Quality of Life Assessment

**Type:** OTHER

#### Intervention 4

**Arm Group Labels:**

- Cohort A

- Cohort B

- Cohort C

**Description:** Ancillary studies

**Name:** Questionnaire Administration

**Type:** OTHER

#### Intervention 5

**Arm Group Labels:**

- Cohort A

- Cohort B

**Description:** Undergo whole breast irradiation

**Name:** Whole Breast Irradiation

**Type:** RADIATION

### Outcomes Module

#### Other Outcomes

**Description:** Biomarkers in blood and plasma, specifically CTC and cDNA, will be assessed by exploratory data analysis and graphical methods, which will be applied to examine distributions and to identify data errors and outliers. Linear mixed effect models for repeated measures analysis will be employed to assess the change of the data over time with multi-covariates including disease characteristics (tumor stage, site, pathology), and other patient prognostic factors.

**Measure:** Change in biomarkers in blood and plasma

**Time Frame:** Baseline, 6 months, 12 months

**Description:** The FACT-B+4 will assess the general quality of life of the patient.

**Measure:** Quality of Life measured by FACT-B+4 questionnaire

**Time Frame:** Baseline, 6 months, 12 months, 36 months, 60 months

**Description:** The Breast Cancer Treatment Outcome Scale (BCTOS) will assess patient-reported cosmetic outcome, breast pain, and functional status by comparing the affected breast with her unaffected breast.

**Measure:** Quality of Life measured by BCTOS questionnaire

**Time Frame:** Baseline, 6 months, 12 months, 36 months, 60 months

**Description:** The Decisional Regret Scale (DRS) questionnaire will assess the decisional comfort of the clinical trial participant.

Question answers range : Strongly Agree, Agree, Neither Agree Nor Disagree, Disagree, or Strongly Agree

**Measure:** Quality of Life measured by DRS questionnaire

**Time Frame:** Baseline, 6 months, 12 months, 36 months, 60 months

**Description:** Multivariable logistic regression analysis using generalized estimating equations to take the intra-patient correlation into account will be used to determine factors significantly associated with the outcome.

**Measure:** Incidence of ipsilateral breast and nodal recommendation and performance of biopsy based on breast imaging follow-up

**Time Frame:** Up to 5 years

**Description:** Will be assessed by biopsy and routine surgery. Descriptive statistics will be used. The final biopsy will be compared with the response status determined by routine pathologic examination of surgery specimens using McNemar test.

**Measure:** Residual cancer burden (RCB)

**Time Frame:** Up to 5 years

#### Primary Outcomes

**Description:** Will monitor IBT-RFS using the method of Thall et al. Will be estimated using the Kaplan-Meier method log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.

**Measure:** Ipsilateral breast tumor recurrence-free survival (IBT-RFS)

**Time Frame:** 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 5 years

**Description:** Will be estimated using the Kaplan-Meier method log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.

**Measure:** Overall survival

**Time Frame:** Up to 5 years

### Eligibility Module

**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\< 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.
* 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 involving the lymph nodes on pathologic review of the lymph node surgical specimen.
    10. Unifocal disease or limited multifocal disease that can be excised in a single lumpectomy specimen

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 \>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.

**Minimum Age:** 30 Years

**Sex:** FEMALE

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** hkuerer@mdanderson.org

**Name:** Henry Kuerer

**Phone:** 713-745-5043

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Phoenix

**Country:** United States

**Facility:** Banner Health/Banner Research

**State:** Arizona

**Status:** ACTIVE_NOT_RECRUITING

**Zip:** 85006

**Location 2:**

**City:** Jacksonville

**Contacts:**

***Contact 1:***

- **Email:** beth.lesnikoski@hcahealthcare.com

- **Name:** Beth A. Lesnikoski

- **Role:** CONTACT

***Contact 2:***

- **Name:** Beth A. Lesnikoski

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** United States

**Facility:** Baptist MD Anderson Cancer Center

**State:** Florida

**Status:** NOT_YET_RECRUITING

**Zip:** 32207

**Location 3:**

**City:** Honolulu

**Country:** United States

**Facility:** Queen's Medical Center

**State:** Hawaii

**Status:** COMPLETED

**Zip:** 96813

**Location 4:**

**City:** Rochester

**Contacts:**

***Contact 1:***

- **Email:** boughey.judy@mayo.edu

- **Name:** Judy C. Boughey

- **Phone:** 507-284-2511

- **Role:** CONTACT

***Contact 2:***

- **Name:** Judy C. Boughey

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** United States

**Facility:** Mayo Clinic

**State:** Minnesota

**Status:** RECRUITING

**Zip:** 55905

**Location 5:**

**City:** Voorhees

**Country:** United States

**Facility:** MD Anderson Cancer Center at Cooper-Voorhees

**State:** New Jersey

**Status:** ACTIVE_NOT_RECRUITING

**Zip:** 08043

**Location 6:**

**City:** Charlotte

**Contacts:**

***Contact 1:***

- **Email:** Richard.White@atriumhealth.org

- **Name:** Richard L. White

- **Phone:** 980-442-6358

- **Role:** CONTACT

***Contact 2:***

- **Name:** Richard L. White

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** United States

**Facility:** Carolinas Medical Center/Levine Cancer Institute

**State:** North Carolina

**Status:** RECRUITING

**Zip:** 28203

**Location 7:**

**City:** Pittsburgh

**Contacts:**

***Contact 1:***

- **Email:** diegoe@upmc.edu

- **Name:** Emilia J. Diego

- **Phone:** 412-641-3083

- **Role:** CONTACT

***Contact 2:***

- **Name:** Emilia J. Diego

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** United States

**Facility:** University of Pittsburgh Cancer Institute (UPCI)

**State:** Pennsylvania

**Status:** RECRUITING

**Zip:** 15232

**Location 8:**

**City:** Houston

**Contacts:**

***Contact 1:***

- **Email:** hkuerer@mdanderson.org

- **Name:** Henry M. Kuerer

- **Phone:** 713-745-5043

- **Role:** CONTACT

***Contact 2:***

- **Name:** Henry M. Kuerer

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** United States

**Facility:** M D Anderson Cancer Center

**State:** Texas

**Status:** RECRUITING

**Zip:** 77030

#### Overall Officials

**Official 1:**

**Affiliation:** M.D. Anderson Cancer Center

**Name:** Henry M Kuerer

**Role:** PRINCIPAL_INVESTIGATOR

### References Module

#### 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.

**PMID:** 36306810

**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.

**PMID:** 35617923

#### See Also Links

**Label:** MD Anderson Cancer Center

**URL:** http://www.mdanderson.org

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009375

- Term: Neoplasms, Glandular and Epithelial

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000001941

- Term: Breast Diseases

- ID: D000012871

- Term: Skin Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M5220

- Name: Breast Neoplasms

- Relevance: HIGH

- As Found: Breast Cancer

- ID: M5534

- Name: Carcinoma

- Relevance: HIGH

- As Found: Carcinoma

- ID: M30373

- Name: Triple Negative Breast Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M12320

- Name: Neoplasms, Glandular and Epithelial

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M5218

- Name: Breast Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M15674

- Name: Skin Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000002277

- Term: Carcinoma

- ID: D000001943

- Term: Breast Neoplasms

### Misc Info Module

- Version Holder: 2024-05-24
