Amendment 1_75N91022Q00180 dated 10.20.22.pdf

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Offers must acknowledge receipt of this amendment prior to the hour and date specified in the solicitation or as amended, by one of the following methods:

(a) By completing items 8 and 15, and returning or (c) By separate letter or electronic communication which includes a reference to the solicitation and amendment numbers. FAILURE OF YOUR ACKNOWLEDGMENT TO BE RECEIVED AT THE PLACE DESIGNATED FOR THE RECEIPT OF OFFERS PRIOR TO THE HOUR AND DATE SPECIFIED MAY RESULT IN REJECTION OF YOUR OFFER. If by virtue of this amendment you desire to change an offer already submitted, such change may be made by letter or electronic communication, provided each letter or electronic communication makes reference to the solicitation and this amendment, and is received prior to the opening hour and date specified.

E. IMPORTANT: Contractor is not is required to sign this document and return copies to the issuing office.

AMENDMENT OF SOLICITATION/MODIFICATION OF CONTRACT 1. CONTRACT ID CODE

2. AMENDMENT/MODIFICATION NUMBER 3. EFFECTIVE DATE 4. REQUISITION/PURCHASE REQUISITION NUMBER 5. PROJECT NUMBER (If applicable)

7. ADMINISTERED BY (If other than Item 6) CODE

STANDARD FORM 30 (REV. 11/2016)

Prescribed by GSA FAR (48 CFR) 53.243

FACILITY CODE

9A. AMENDMENT OF SOLICITATION NUMBER

9B. DATED (SEE ITEM 11)

10A. MODIFICATION OF CONTRACT/ORDER NUMBER

10B. DATED (SEE ITEM 13)

11. THIS ITEM ONLY APPLIES TO AMENDMENTS OF SOLICITATIONS

The above numbered solicitation is amended as set forth in Item 14. The hour and date specified for receipt of Offers is extended. is not extended.

12. ACCOUNTING AND APPROPRIATION DATA (If required) copies of the amendment; (b) By acknowledging receipt of this amendment on each copy of the offer submitted;

13. THIS ITEM APPLIES ONLY TO MODIFICATIONS OF CONTRACTS/ORDERS.

IT MODIFIES THE CONTRACT/ORDER NUMBER AS DESCRIBED IN ITEM 14.

CHECK ONE A. THIS CHANGE ORDER IS ISSUED PURSUANT TO: (Specify authority) THE CHANGES SET FORTH IN ITEM 14 ARE MADE IN THE CONTRACT ORDER

NUMBER IN ITEM 10A.

B. THE ABOVE NUMBERED CONTRACT/ORDER IS MODIFIED TO REFLECT THE ADMINISTRATIVE CHANGES (such as changes in paying office, appropriation data, etc.) SET FORTH IN ITEM 14, PURSUANT TO THE AUTHORITY OF FAR 43.103(b).

C. THIS SUPPLEMENTAL AGREEMENT IS ENTERED INTO PURSUANT TO AUTHORITY OF:

D. OTHER (Specify type of modification and authority)

Except as provided herein, all terms and conditions of the document referenced in Item 9A or 10A, as heretofore changed, remains unchanged and in full force and effect.

15C. DATE SIGNED

15A. NAME AND TITLE OF SIGNER (Type or print)

16C. DATE SIGNED

16A. NAME AND TITLE OF CONTRACTING OFFICER (Type or print)

14. DESCRIPTION OF AMENDMENT/MODIFICATION (Organized by UCF section headings, including solicitation/contract subject matter where feasible.)

PAGE OF PAGES

6. ISSUED BY CODE

8. NAME AND ADDRESS OF CONTRACTOR (Number, street, county, State and ZIP Code) (X)

CODE

15B. CONTRACTOR/OFFEROR

(Signature of person authorized to sign)

16B. UNITED STATES OF AMERICA

(Signature of Contracting Officer)

Previous edition unusable

INSTRUCTIONS (Back Page):

Instructions for items other than those that are self-explanatory, are as follows:

Item 1 (Contract ID Code). Insert the contract type identification code that appears in the title block of the contract being modified.

Item 3 (Effective date).

(1)

(2)

(3)

(4)

(5)

For a solicitation amendment, change order, or administrative change, the effective date shall be the issue date of the amendment, change order, or administrative change.

For a supplemental agreement, the effective date shall be the date agreed to by the contracting parties.

For a modification issued as an initial or confirming notice of termination for the convenience of the Government, the effective date and the modification number of the confirming notice shall be the same as the effective date and modification number of the initial notice.

For a modification converting a termination for default to a termination for the convenience of the Government, the effective date shall be the same as the effective date of the termination for default.

For a modification confirming the contracting officer's determination of the amount due in settlement of a contract termination, the effective date shall be the same as the effective date of the initial decision.

(a)

(b)

(c)

(d)

(e)

(f)

Item 6 (Issued By). Insert the name and address of the issuing office. If applicable, insert the appropriate issuing office code in the code block.

Item 8 (Name and Address of Contractor). For modifications to a contract or order, enter the contractor's name, address, and code as shown in the original contract or order, unless changed by this or a previous modification.

Items 9, (Amendment of Solicitation Number - Dated), and 10, (Modification of Contract/Order Number - Dated). Check the appropriate box and in the corresponding blanks insert the number and date of the original solicitation, contract, or order.

Item 12 (Accounting and Appropriation Data).

When appropriate, indicate the impact of the modification on each affected accounting classification by inserting one of the following entries:

(2) Accounting classification Net decrease $

Include subject matter or short title of solicitation/contract where feasible.

Item 16B. The contracting officer's signature is not required on solicitation amendments. The contracting officer's signature is normally affixed last on supplemental agreements.

(i)

NOTE: If there are changes to multiple accounting classifications that cannot be placed in block 12, insert an asterisk and the words "See continuation sheet".

Item 13. Check the appropriate box to indicate the type of modification. Insert in the corresponding blank the authority under which the modification is issued. Check whether or not contractor must sign this document. (See FAR 43.103.)

Item 14 (Description of Amendment/Modification).

Organize amendments or modifications under the appropriate Uniform Contract Format (UCF) section headings from the applicable solicitation or contract. The UCF table of contents, however, shall not be set forth in this document.

Indicate the impact of the modification on the overall total contract price by inserting one of the following entries:

(i) Total contract price increased by $

(ii) Total contract price decreased by $

(iii) Total contract price unchanged.

State reason for modification.

When removing, reinstating, or adding funds, identify the contract items and accounting classifications.

(g)

(h)

When the SF 30 is used to reflect a determination by the contracting officer of the amount due in settlement of a contract terminated for the convenience of the Government, the entry in Item 14 of the modification may be limited to --

(i) A reference to the letter determination; and

(ii) A statement of the net amount determined to be due in settlement of the contract.

(2)

(3)

(4)

(5)

(6)

STANDARD FORM 30 (REV. 11/2016) BACK

(1) Accounting classification Net increase $

1.2

C:\PERFORM\FORMS\S30.FRP

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C:PERFORMFORMSS30.FRP

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D:19990614133004

C:PERFORMFORMSS30.FRP

Standard Form 30 - Amendment of Solicitation/Modification of Contract

Offers must acknowledge receipt of this amendment prior to the hour and date specified in the solicitation or as amended, by one of the following methods:

(a) By completing items 8 and 15, and returning or (c) By separate letter or electronic communication which includes a reference to the solicitation and amendment numbers. FAILURE OF YOUR ACKNOWLEDGMENT TO BE RECEIVED AT THE PLACE DESIGNATED FOR THE RECEIPT OF OFFERS PRIOR TO THE HOUR AND DATE SPECIFIED MAY RESULT IN REJECTION OF YOUR OFFER. If by virtue of this amendment you desire to change an offer already submitted, such change may be made by letter or electronic communication, provided each letter or electronic communication makes reference to the solicitation and this amendment, and is received prior to the opening hour and date specified.

E. IMPORTANT: Contractor is not is required to sign this document and return copies to the issuing office.

AMENDMENT OF SOLICITATION/MODIFICATION OF CONTRACT

1. CONTRACT ID CODE

2. AMENDMENT/MODIFICATION NUMBER

3. EFFECTIVE DATE

4. REQUISITION/PURCHASE REQUISITION NUMBER

5. PROJECT NUMBER (If applicable)

7. ADMINISTERED BY (If other than Item 6)

CODE

STANDARD FORM 30 (REV. 11/2016) Prescribed by GSA FAR (48 CFR) 53.243

FACILITY CODE

9A. AMENDMENT OF SOLICITATION NUMBER

9B. DATED (SEE ITEM 11)

10A. MODIFICATION OF CONTRACT/ORDER NUMBER

10B. DATED (SEE ITEM 13)

11. THIS ITEM ONLY APPLIES TO AMENDMENTS OF SOLICITATIONS

The above numbered solicitation is amended as set forth in Item 14. The hour and date specified for receipt of Offers is extended.

is not extended.

12. ACCOUNTING AND APPROPRIATION DATA (If required) copies of the amendment; (b) By acknowledging receipt of this amendment on each copy of the offer submitted;

13. THIS ITEM APPLIES ONLY TO MODIFICATIONS OF CONTRACTS/ORDERS.

IT MODIFIES THE CONTRACT/ORDER NUMBER AS DESCRIBED IN ITEM 14.

CHECK ONE

A. THIS CHANGE ORDER IS ISSUED PURSUANT TO: (Specify authority) THE CHANGES SET FORTH IN ITEM 14 ARE MADE IN THE CONTRACT ORDER

NUMBER IN ITEM 10A.

B. THE ABOVE NUMBERED CONTRACT/ORDER IS MODIFIED TO REFLECT THE ADMINISTRATIVE CHANGES (such as changes in paying office, appropriation data, etc.) SET FORTH IN ITEM 14, PURSUANT TO THE AUTHORITY OF FAR 43.103(b).

C. THIS SUPPLEMENTAL AGREEMENT IS ENTERED INTO PURSUANT TO AUTHORITY OF:

D. OTHER (Specify type of modification and authority)

Except as provided herein, all terms and conditions of the document referenced in Item 9A or 10A, as heretofore changed, remains unchanged and in full force and effect.

15C. DATE SIGNED

15A. NAME AND TITLE OF SIGNER (Type or print)

16C. DATE SIGNED

16A. NAME AND TITLE OF CONTRACTING OFFICER (Type or print)

14. DESCRIPTION OF AMENDMENT/MODIFICATION (Organized by UCF section headings, including solicitation/contract subject matter where feasible.)

PAGE OF PAGES

6. ISSUED BY

CODE

8. NAME AND ADDRESS OF CONTRACTOR (Number, street, county, State and ZIP Code)

(X)

CODE

15B. CONTRACTOR/OFFEROR

(Signature of person authorized to sign)

16B. UNITED STATES OF AMERICA

(Signature of Contracting Officer)

Previous edition unusable

INSTRUCTIONS (Back Page):

Instructions for items other than those that are self-explanatory, are as follows:

Item 1 (Contract ID Code). Insert the contract type identification code that appears in the title block of the contract being modified.

Item 3 (Effective date).

(1)

(2)

(3)

(4)

(5)

For a solicitation amendment, change order, or administrative change, the effective date shall be the issue date of the amendment, change order, or administrative change.

For a supplemental agreement, the effective date shall be the date agreed to by the contracting parties.

For a modification issued as an initial or confirming notice of termination for the convenience of the Government, the effective date and the modification number of the confirming notice shall be the same as the effective date and modification number of the initial notice.

For a modification converting a termination for default to a termination for the convenience of the Government, the effective date shall be the same as the effective date of the termination for default.

For a modification confirming the contracting officer's determination of the amount due in settlement of a contract termination, the effective date shall be the same as the effective date of the initial decision.

(a)

(b)

(c)

(d)

(e)

(f)

Item 6 (Issued By). Insert the name and address of the issuing office. If applicable, insert the appropriate issuing office code in the code block.

Item 8 (Name and Address of Contractor). For modifications to a contract or order, enter the contractor's name, address, and code as shown in the original contract or order, unless changed by this or a previous modification.

Items 9, (Amendment of Solicitation Number - Dated), and 10, (Modification of Contract/Order Number - Dated). Check the appropriate box and in the corresponding blanks insert the number and date of the original solicitation, contract, or order.

Item 12 (Accounting and Appropriation Data). When appropriate, indicate the impact of themodification on each affected accounting classification by inserting one of the following entries:

(2)

Accounting classification

Net decrease $

Include subject matter or short title of solicitation/contract where feasible.

Item 16B. The contracting officer's signature is not required on solicitation amendments. The contracting officer's signature is normally affixed last on supplemental agreements.

(i)

NOTE: If there are changes to multiple accounting classifications that cannot be placed in block 12, insert an asterisk and the words "See continuation sheet".

Item 13. Check the appropriate box to indicate the type of modification. Insert in the corresponding blank the authority under which the modification is issued. Check whether or not contractor must sign this document. (See FAR 43.103.)

Item 14 (Description of Amendment/Modification).

Organize amendments or modifications under the appropriate Uniform Contract Format (UCF) section headings from the applicable solicitation or contract. The UCF table of contents, however, shall not be set forth in this document.

Indicate the impact of the modification on the overall total contract price by inserting one ofthe following entries:

(i) Total contract price increased by $

(ii) Total contract price decreased by $

(iii) Total contract price unchanged.

State reason for modification.

When removing, reinstating, or adding funds, identify the contract items and accounting classifications.

(g)

(h)

When the SF 30 is used to reflect a determination by the contracting officer of the amount due in settlement of a contract terminated for the convenience of the Government, the entry in Item 14 of the modification may be limited to --

(i) A reference to the letter determination; and

(ii) A statement of the net amount determinedto be due in settlement of the contract.

(2)

(3)

(4)

(5)

(6)

STANDARD FORM 30 (REV. 11/2016) BACK

(1)

Accounting classification

Net increase $

9A. AMENDMENT OF SOLICITATION NUMBER: 1

9A. AMENDMENT OF SOLICITATION NUMBER: 75N91022Q00180

7. CODE: N/A

12. ACCOUNTING AND APPROPRIATION DATA (If required):

13A. THIS CHANGE ORDER IS ISSUED PURSUANT TO. Specify authority. THE CHANGES SET FORTH IN ITEM 14 ARE MADE IN THE CONTRACT ORDER NUMBER IN ITEM 10A.:

13C. THIS SUPPLEMENTAL AGREEMENT IS ENTERED INTO PURSUANT TO AUTHORITY OF:

13D. OTHER. Specify type of modification and authority.:

15A. NAME AND TITLE OF SIGNER. Type or print.:

16A. NAME AND TITLE OF CONTRACTING OFFICER. Type or print.: Angela Moore, Contracting Officer

14. DESCRIPTION OF AMENDMENT OR MODIFICATION (Organized by UCF section headings, including solicitation or contract subject matter where feasible.): The purpose of this amendment is to: 1) Provide responses to solicitation questions received by the deadline of October 19, 2022; and 2) to add Attachment 10 "POC 2022 Data Acquisition Manual, 2020 Diagnosis Year, Breast Cancer and Colon/Rectum Cancer DRAFT dated10/17/2022."

Quoters are required to acknowledge each Solicitation Amendment by including each Standard Form 30 (SF-30) signed by your organization’s signature authority and submitted with the quote.

Quote Due Date: November 1, 2022; 3:00pm ET (Unchanged)

FACILITY CODE:

6. ISSUED BY: National Institutes of Health National Cancer Institute Office of Acquisitions 9609 Medical Center Dr., MSC 9705 Bethesda, MD 20892-9705

8. NAME AND ADDRESS OF CONTRACTOR (Number, street, county, State and ZIP Code):

7. ADMINISTERED BY (If other than Item 6):

1. CONTRACT ID CODE: N/A

4. REQUISITION/PURCHASE REQUISITION NUMBER:

10A. MODIFICATION OF CONTRACT/ORDER NUMBER:

5. PROJECT NUMBER. If applicable.: N/A

PAGE: 1

PAGES: 1

3. EFFECTIVE DATE. Enter 2 digit month, 2 digit day and 4 digit year.: 2022-10-20

9B. DATED. SEE ITEM 11. Enter 2 digit month, 2 digit day and 4 digit year.: 2022-10-12

10B. DATED. SEE ITEM 13. Enter 2 digit month, 2 digit day and 4 digit year.:

9A. AMENDMENT OF SOLICITATION NUMBER: 0

10A. MODIFICATION OF CONTRACT/ORDER NUMBER: 0

11. The above numbered solicitation is amended as set forth in Item 14. : 1

13A. THIS CHANGE ORDER IS ISSUED PURSUANT TO. Specify authority. THE CHANGES SET FORTH IN ITEM 14 ARE MADE IN THE CONTRACT ORDER NUMBER IN ITEM 10A.: 0

13B. THE ABOVE NUMBERED CONTRACT OR ORDER IS MODIFIED TO REFLECT THE ADMINISTRATIVE CHANGES. Such as changes in paying office, appropriation date, etc. SET FORTH IN ITEM 14, PURSUANT TO THE AUTHORITY OF FAR 43.103b.: 0

13C. THIS SUPPLEMENTAL AGREEMENT IS ENTERED INTO PURSUANT TO AUTHORITY OF: 0

13D. OTHER Specify type of modification and authority.: 0

13E. IMPORTANT: Contractor is not required to sign this document and return copies to the issuing office.: 0

13E. IMPORTANT: Contractor is required to sign this document and return copies to the issuing office.: 1

11. The hour and date specified for receipt of Offers is extended : 0

11. The hour and date specified for receipt of Offers is not extended : 1

15B. CONTRACTOR OR OFFEROR. Signature of person authorized to sign. Digital Signature.:

16C. DATE SIGNED. Enter 2 digit month, 2 digit day and 4 digit year.: 2022-10-20 number of copies: 1.00000000 number of copies: 1.00000000

Enter the total (in dollars) the contract price increased. :

Version 2022.1 10/17/2022

POC 2022 DATA ACQUISITION MANUAL

2020 DIAGNOSIS YEAR

BREAST CANCER

COLON/RECTUM CANCER

DRAFT 10/17/2022: SUBJECT TO REVISION

TABLE OF CONTENTS

SECTIONS Page

I. INTRODUCTION

1. Study overview ............................................................................................... I-5

2. Objectives .....................................................................................................I-48

3. Study plan .......................................................................................................I-48

4. Timetable ........................................................................................................I-49

5. Submission of data ........................................................................................I-50

6. Quality control ................................................................................................I-50

7. Confidentiality ..............................................................................................I-50

II. PATIENT ELIGIBILITY

1. Patient selection .........................................................................................II-3

2. Sampling.....................................................................................................II-3

3. Reportable cases ......................................................................................II-4

4. Breast cancer cases......................................................................................II-4

5. Colon and rectum cancer cases ..................................................................II-5

6. General non-reportable cases and malignancies ........................................II-7

7. Reportability Summary by site .................................................................II-8

III. COMMON DATA SET

1. Codes and definitions .................................................................................... III-5

IV. BREAST CANCER DATA SET

1. Codes and definitions .....................................................................................IV-5

V. COLON AND RECTUM CANCER DATA SET

1. Codes and definitions ......................................................................................V-5

POC DATA ACQUISITION MANUAL

SECTION I

INTRODUCTION/DATA MANAGEMENT

I-2 POC Data Acquisition Manual: Introduction

POC Data Acquisition Manual: Introduction I-3

SECTION I - INTRODUCTION/DATA MANAGEMENT

CONTENTS

1. STUDY OVERVIEW

2. OBJECTIVES

3. STUDY PLAN

4. TIMETABLE

5. SUBMISSION OF DATA

6. QUALITY CONTROL

7. CONFIDENTIALITY

I-4 POC Data Acquisition Manual: Introduction

I-5 POC Data Acquisition Manual: Introduction

SECTION I - INTRODUCTION

1. STUDY OVERVIEW

1.1 The Patterns of Care Study funded in fiscal year 2022 will examine the diagnosis, demographic and tumor characteristics, biomarkers, and therapies offered to patients diagnosed in 2020 with breast cancer (AJCC stage 0 ‐ IV) and colon/rectum cancer (AJCC stage I ‐ IV). The study will also collect data on documentation of the effects of the COVID-19 pandemic on screening, diagnosis, treatment, and palliative care for these cancers from the medical record. The National Cancer Institute has a Congressional Mandate to report on the dissemination of state-of-the-art therapy into community practice.

1.2 BREAST CANCER

Estimated new cases and deaths from breast cancer in the United States in 2022 are:

New cases: 290,560 Deaths: 43,780

Breast cancer is the most common noncutaneous cancer in U.S. women, fewer than one of six women diagnosed with breast cancer die of the disease. Men account for 1% of breast cancer cases and breast cancer deaths. Widespread adoption of screening increases breast cancer incidence in a given population and changes the characteristics of cancers detected, with increased incidence of lower-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS). Population studies from the United States and the United Kingdom demonstrate an increase in DCIS and invasive breast cancer incidence since the 1970s, attributable to the widespread adoption of both postmenopausal hormone therapy and screening mammography. In the last decade, women have refrained from using postmenopausal hormones, and breast cancer incidence has declined, but not to the levels seen before the widespread use of screening mammography.

Staging Information for Breast Cancer

The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but also according to other clinical factors such as the following, some of which are included in the determination of stage:

• Tumor size.

• Lymph node status.

• Estrogen-receptor and progesterone-receptor levels in the tumor tissue.

• Human epidermal growth factor receptor 2 (HER2/neu) status in the tumor.

• Tumor grade.

• Menopausal status.

• General health of the patient.

The standards used to define biomarker status are described as follows:

I-6 POC Data Acquisition Manual: Introduction

• Estrogen receptor (ER) expression: ER expression is measured primarily by immunohistochemistry (IHC). Any staining of 1% of cells or more is considered positive for ER.

• Progesterone receptor (PR) expression: PR expression is measured primarily by IHC. Any staining of 1% of cells or more is considered positive for PR.

• HER2 expression: HER2 is measured primarily by either IHC to assess expression of the HER2 protein or by in situ hybridization (ISH) to assess gene copy number. The American Society of Clinical Oncology/College of American Pathologists consensus panel has published guidelines for cases when either IHC or ISH testing is equivocal.

IHC:

• Negative: 0 or 1+ staining

• Equivocal: 2+ staining

• Positive: 3+ staining

ISH (dual probe):

• Possible negative results:

o HER2/chromosome enumeration probe (CEP17) ratio <2.0 AND

HER2 copy number <4

• Possible equivocal results: (requires performing alternative ISH test to confirm equivocal or IHC if not previously performed) o HER2/CEP17 ratio <2.0 AND HER2 copy number ≥4 but <6

• Possible positive results:

o HER2/CEP17 ratio ≥2.0 by ISH o HER2 copy number ≥6 regardless of ratio by ISH

ISH (single probe):

• Negative: <4 HER2 copies

• Equivocal: ≥4 HER2 copies but <6 HER2 copies

• Positive: ≥6 HER2 copies

TNM Definitions and AJCC Stage Groupings

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define breast cancer. The grade of the tumor is determined by its morphologic features, such as tubule formation, nuclear pleomorphism, and mitotic count.

Tables presenting AJCC definitions for T, N, and M classification; histologic grade;

DCIS nuclear grade and AJCC Anatomic and Prognostic Stage Groups are available at https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. In the United States, cancer registries and clinicians must use the Clinical and Pathological Prognostic Stage Group tables for reporting. It is expected that testing is performed for grade, HER2, ER, and PR status and that results are reported for all cases of invasive cancer in the United States.

Treatment

Treatment Option Overview for Early/Localized/Operable Breast Cancer

Standard treatment options for early, localized, or operable breast cancer may include the following:

Surgery:

https://www.cancer.gov/types/breast/hp/breast-treatment-pdq

I-7 POC Data Acquisition Manual: Introduction

1. Breast-conserving surgery (lumpectomy) and sentinel lymph node (SLN) biopsy with or without axillary lymph node dissection for positive SLNs.

2. Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction and sentinel node biopsy with or without axillary lymph node dissection for positive SLNs.

Postoperative radiation therapy:

1. Axillary node–negative breast cancer (postmastectomy):

• No additional therapy.

• Radiation therapy.

2. Axillary node–positive breast cancer (postmastectomy):

• For one to three nodes, the role of regional radiation therapy to the infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall is unclear.

• For four or more nodes or extranodal involvement, regional radiation therapy is advised.

3. Axillary node–negative or positive breast cancer (post–breast-conserving therapy):

• Whole-breast radiation therapy.

Postoperative systemic therapy:

1. Therapy depends on many factors including stage, grade, molecular status of the tumor (e.g., estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2/neu], or triple-negative [ER-negative, PR-negative, and HER2/neu-negative] status). Adjuvant treatment options may include the following:

• Tamoxifen.

• Aromatase inhibitor (AI) therapy.

• Ovarian function suppression.

• Chemotherapy.

Preoperative systemic therapy:

1. Chemotherapy.

2. HER2-targeted therapy.

3. Endocrine therapy.

Surgery

Stages I, II, IIIA, and operable IIIC breast cancer often require a multimodal approach to treatment. The diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures:

• Biopsy. In many cases, the diagnosis of breast carcinoma is made by core needle biopsy.

• Surgical procedure. After the presence of a malignancy is confirmed by biopsy, the following surgical treatment options can be discussed with the patient before a therapeutic procedure is selected:

• Breast-conserving surgery.

• Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II)

I-8 POC Data Acquisition Manual: Introduction with or without breast reconstruction.

To guide the selection of adjuvant therapy, many factors including stage, grade, and molecular status of the tumor (e.g., ER, PR, HER2/neu, or triple-negative status) are considered.

Locoregional treatment Selection of a local therapeutic approach depends on the following:

• Location and size of the lesion.

• Analysis of the mammogram.

• Breast size.

• Patient’s desire to preserve the breast.

Options for surgical management of the primary tumor include the following:

• Breast-conserving surgery plus radiation therapy. All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy. However, the presence of inflammatory breast cancer, regardless of histologic subtype, is a contraindication to breast-conserving therapy. The presence of multifocal disease in the breast and a history of collagen vascular disease are relative contraindications to breast-conserving therapy.

• Mastectomy with or without breast reconstruction.

Surgical staging of the axilla should also be performed.

Survival is equivalent with any of these options, as documented in the trial of the European Organization for Research and Treatment of Cancer (EORTC) (EORTC-10801) and other prospective randomized trials.

The rate of local recurrence in the breast after conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary has been debated. For patients undergoing partial mastectomy, margins may be positive after primary surgery, often leading to re- excision.

Axillary lymph node management Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%. Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.

The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium Tc 99m-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients. These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.

Because of the following body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy.

I-9 POC Data Acquisition Manual: Introduction

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., at least 6–10), while reducing morbidity from the procedure.

Breast reconstruction For patients who opt for a total mastectomy, reconstructive surgery may be performed at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction).[36-39]

Breast contour can be restored by the following:

• Submuscular insertion of an artificial implant (silicone or saline filled). If an immediate implant cannot technically be performed, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained.

The tissue expander is then replaced by a permanent implant.

• Rectus muscle or other lap. Muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

After breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes in either the adjuvant or local recurrent disease setting. Radiation therapy after reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.]

Postoperative Radiation Therapy Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy is also indicated for high-risk postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence

Post–breast-conserving surgery For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women.

Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death. Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.

Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.

Regional nodal irradiation Regional nodal irradiation is routinely given postmastectomy to patients with involved lymph nodes;

however, its role in patients who have breast-conserving surgery and whole-breast irradiation has been less clear.

Postmastectomy Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk of locoregional failure after mastectomy. Patients at highest risk of local recurrence have one or more of the following:

• Four or more positive axillary nodes.

• Grossly evident extracapsular nodal extension.

• Large primary tumors.

I-10 POC Data Acquisition Manual: Introduction

• Very close or positive deep margins of resection of the primary tumor.

In this high-risk group, radiation therapy can decrease locoregional recurrence, even among those patients who receive adjuvant chemotherapy.

Patients with one to three involved nodes without any of the high-risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting is unclear.

Timing of postoperative radiation therapy The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery has been studied. Based on the following studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving surgery may be preferable for patients at high risk of distant dissemination.

Late toxic effects of radiation Late toxic effects of radiation therapy are uncommon and can be minimized with current radiation delivery techniques and with careful delineation of the target volume.

Postoperative Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. The selection of therapy is most appropriately based on knowledge of an individual’s risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach allows clinicians to help individuals determine if the gains anticipated from treatment are reasonable for their situation.

Many of the studies that support the use of chemotherapy after surgery were conducted before the widespread practice of testing for HER2. In general, their results are still applicable to the management of patients with all three subtypes of breast cancer.

Pertuzumab Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Its use, in combination with trastuzumab, has been evaluated in a randomized trial in the postoperative setting.

Endocrine therapy for hormone receptor–positive breast cancer Much of the evidence presented in the following sections on therapy for women with hormone receptor– positive disease has been considered in an American Society of Clinical Oncology guideline that describes several options for the management of these patients. Five years of adjuvant endocrine therapy has been shown to substantially reduce the risks of locoregional and distant recurrence, contralateral breast cancer, and death from breast cancer.

The optimal duration of endocrine therapy is unclear, with the preponderance of evidence supporting at least 5 years of endocrine therapy.

Tamoxifen Tamoxifen has been shown to be of benefit to women with hormone receptor–positive breast cancer.

Ovarian ablation, tamoxifen, and chemotherapy Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies. Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes

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Aromatase inhibitors (AIs)

Premenopausal women AIs have been compared with tamoxifen in premenopausal women in whom ovarian function was suppressed or ablated. The results of these studies have been conflicting.

Postmenopausal women In postmenopausal women, the use of AIs in sequence with or as a substitute for tamoxifen has been the subject of multiple studies, the results of which have been summarized in an individual patient-level meta-analysis.

Duration of AI therapy The optimal duration of AI therapy is uncertain, and multiple trials have evaluated courses longer than 5 years.

Endocrine therapy and cyclin-dependent kinase (CDK) inhibitor therapy CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor–positive breast cancer that is resistant to endocrine therapy. CDK inhibitors, in combination with endocrine therapy, have been approved by the FDA in both first-line and later-line treatment of patients with advanced hormone receptor– positive HER2-negative breast cancer and are now being studied in the adjuvant setting.

Bone-modifying therapy Both bisphosphonates and denosumab have been evaluated as adjuvant therapies for early-stage breast cancer; however, the role of these agents as adjuvant therapy for early-stage breast cancer is unclear.

Compared with denosumab, the amount of evidence supporting bisphosphonates is greater, and there is evidence supporting breast cancer mortality—an endpoint that is more clinically relevant.

Neoadjuvant therapy is particularly favored in patients with triple-negative or HER2-positive disease, when pathologic response is used as a guide in choosing the optimal adjuvant therapy after surgery.

Omission of postoperative radiation therapy to the regional nodes in patients who initially present as node positive and become node negative after neoadjuvant therapy is currently being evaluated.

Patient selection, staging, treatment, and follow-up Multidisciplinary management of patients undergoing preoperative therapy by an experienced team is essential to optimize the following:

• Patient selection.

• Choice of systemic therapy.

• Management of the axilla and surgical approach.

• Decision to administer adjuvant radiation therapy.

The tumor histology, grade, and receptor status are carefully evaluated before preoperative therapy is initiated. Patients whose tumors have a pure lobular histology, low grade, or high hormone-receptor expression and HER2-negative status are less likely to respond to chemotherapy and should be considered for primary surgery, especially when the nodes are clinically negative. Even if adjuvant chemotherapy is administered after surgery in these cases, a third-generation regimen (anthracycline/taxane based) may be avoided.

Before beginning preoperative therapy, the extent of the disease within the breast and regional lymph nodes should be assessed. Staging of systemic disease may include the following:

• CT scan of the chest and abdomen and a bone scan.

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• Positron-emission tomography.

Baseline breast imaging is performed when breast-conserving therapy is desired to identify the tumor location and exclude multicentric disease. Suspicious abnormalities are usually biopsied before beginning treatment and a marker placed at the center of the breast tumor(s). When possible, suspicious axillary nodes should be biopsied before initiation of systemic treatment.

In patients with clinically negative nodes who receive neoadjuvant chemotherapy, an SLN biopsy is typically performed at the time of surgery. In patients presenting with positive lymph nodes, detected by either clinical examination or imaging, SLN biopsy may be performed in a patient who becomes clinically node negative after preoperative therapy. The use of dual mapping with both radiocolloid and blue dye and retrieval of at least three negative lymph nodes was associated with a lower false-negative rate and ALND may be omitted in these patients.

When considering preoperative therapy, treatment options include the following:

• For HER2-negative breast tumors, an anthracycline/taxane-based chemotherapy regimen.

• For HER2-positive disease, chemotherapy and HER2-targeted therapy.

• Ideally, the entire treatment regimen is administered before surgery.

• For postmenopausal women with hormone receptor–positive breast cancer, chemotherapy is an option. For those who cannot be given chemotherapy, preoperative endocrine therapy may be an option.

• For premenopausal women with hormone-responsive cancer, the use of preoperative endocrine therapy is under investigation.

Regular clinical assessment of response to therapy is necessary after beginning preoperative therapy. Repeat radiographic assessment is also required if breast conservation is the surgical goal. Patients with progressive disease during preoperative therapy may either transition to a non–cross-resistant regimen or proceed to surgery, if feasible. Although switching to a non–cross-resistant regimen results in a higher pCR rate than continuing the same therapy, there is no clear evidence that other breast cancer outcomes are improved with this approach.

HER2/neu-negative breast cancer Early trials examined whether anthracycline-based regimens used in the adjuvant setting would prolong DFS and OS when used in the preoperative setting. The evidence supports higher rates of breast-conserving therapy with the use of a preoperative anthracycline chemotherapy regimen than with postoperative use, but no improvement in survival was noted with the preoperative strategy.

Typically, an anthracycline-and-taxane–based regimen is used if chemotherapy is administered in the neoadjuvant setting for patients with HER2/neu-negative breast cancer.

Triple-negative breast cancer Promising results have been observed with the addition of carboplatin to anthracycline/taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival endpoints and the identification of biomarkers of response or resistance are necessary before the addition of carboplatin to standard preoperative chemotherapy can be considered a new standard of care.

Longer term follow-up with regard to survival outcomes and toxicity will inform the use of immunotherapy in the neoadjuvant treatment of TNBC. Key issues that remain to be clarified include identification of a predictive biomarker, the optimal chemotherapy backbone, and the role of adjuvant immunotherapy after neoadjuvant chemotherapy plus immunotherapy.

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HER2/neu-positive breast cancer After the success in the adjuvant setting, initial reports from phase II studies indicated improved pCR rates when trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, was added to preoperative anthracycline/taxane–based regimens. This has been confirmed in phase III studies.

Trastuzumab Newer HER2-targeted therapies (lapatinib, pertuzumab) have also been investigated. It appears that dual targeting of the HER2 receptor results in an increase in pCR rate; however, no survival advantage has been demonstrated to date with this approach.

Pertuzumab Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two preoperative clinical trials to improve on the pCR rates observed with trastuzumab and chemotherapy.

Lapatinib Lapatinib is a small-molecule kinase inhibitor that is capable of dual receptor inhibition of both epidermal growth factor receptor and HER2. Study results do not support the use of lapatinib in the preoperative setting.

Preoperative endocrine therapy Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptor-positive breast cancer when chemotherapy is not a suitable option because of comorbidities or performance status.

Although the toxicity profile of preoperative hormonal therapy over the course of 3 to 6 months is favorable, the pCR rates obtained (1%–8%) are far lower than have been reported with chemotherapy in unselected populations.

The use of preoperative endocrine therapy in premenopausal women with hormone-responsive breast cancer remains investigational.

Postoperative therapy

Capecitabine One clinical trial suggested that there is a benefit to using capecitabine as adjuvant therapy in patients who did not obtain a pCR after preoperative chemotherapy.

Trastuzumab emtansine (T-DM1)

Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of locoregional recurrence. Baseline clinical and subsequent pathologic staging should be considered in deciding whether to administer postmastectomy radiation.

Other adjuvant systemic treatments may be administered either postoperatively, during, or after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with hormone receptor-positive disease and adjuvant trastuzumab for those with HER2-positive disease.

Posttherapy Surveillance The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I, stage II, or stage III breast cancer remain controversial.

Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x- rays, and blood tests of liver function does not improve survival or quality of life when compared with

I-14 POC Data Acquisition Manual: Introduction routine physical examinations. Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected. On the basis of these data, acceptable follow-up can be limited to the following for asymptomatic patients who complete treatment for stages I to III breast cancer:

• Physical examination.

• Annual mammography.

Locally Advanced or Inflammatory Breast Cancer

Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer On the basis of the available evidence, multimodality therapy delivered with curative intent is the standard of care for patients with locally advanced or inflammatory breast cancer.

The standard treatment options for locally advanced or inflammatory breast cancer may include the following:

1. Breast-conserving surgery or total mastectomy with axillary lymph node dissection.

2. Chemotherapy.

3. Radiation therapy.

4. Hormone therapy.

Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen receptor (ER) and progesterone receptor levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression.

The standard chemotherapy regimen for initial treatment is the same as that used in the adjuvant setting, although trials done solely in patients with locally advanced disease have not shown a statistically significant advantage to dose- dense chemotherapy.

For patients who respond to preoperative chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered for patients with a good partial or complete response to preoperative chemotherapy. Subsequent systemic therapy may consist of further chemotherapy.

Hormone therapy is administered to patients with ER-positive or ER-unknown tumors.

Although the evidence described below has not been replicated, it suggests patients with locally advanced or inflammatory breast cancer should be treated with curative intent.

All patients are considered candidates for clinical trials to evaluate the most appropriate way to administer the various components of new multimodality regimens.

Locoregional Recurrent Breast Cancer Recurrent breast cancer is often responsive to therapy, although treatment is rarely curative at this stage of disease. Patients with locoregional breast cancer recurrence may become long-term survivors with appropriate therapy.

The rates of locoregional recurrence have been reduced over time, and a meta-analysis suggests a recurrence rate of less than 3% in patients treated with breast-conserving surgery and radiation therapy. The rates are somewhat higher (up to 10%) for those treated with mastectomy. Nine percent to 25% of patients with locoregional recurrence will have distant metastases or locally extensive disease at the time of recurrence.

Before treatment for recurrent breast cancer, restaging to evaluate the extent of disease is indicated.

Cytologic or histologic documentation of recurrent disease is obtained whenever possible. When therapy is selected, the estrogen-receptor (ER) status, progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2/neu) status at the time of recurrence and previous treatment are considered, if

I-15 POC Data Acquisition Manual: Introduction known.

ER status may change at the time of recurrence. Treatment options for locoregional recurrent breast cancer include the following:

1. Chemotherapy.

2. Hormone…