
==== Front
Oncologist
Oncologist
oncolo
The Oncologist
1083-7159
1549-490X
Oxford University Press US

38856325
10.1093/oncolo/oyae114
oyae114
Health Outcomes and Economics of Cancer Care
AcademicSubjects/MED00010
Oncolo/11
Synchronous or metachronous breast and colorectal cancers in younger-than-average-age patients: a case series
https://orcid.org/0000-0002-8573-7145
Silverstein Jordyn Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA 94143, United States

Wright Francis School of Medicine, University of California, San Francisco, San Francisco, CA 94143, United States

Stanfield Dalila UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, United States

Chien Amy Jo Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA 94143, United States
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, United States

Wong Jasmine M Department of Surgery, UCSF, San Francisco, CA 94143, United States

Park John W Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA 94143, United States
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, United States

Blanco Amie UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, United States
Cancer Genetics and Prevention Program, UCSF, San Francisco, CA 94143, United States

https://orcid.org/0000-0002-9705-4114
Van Loon Katherine Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA 94143, United States
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, United States

Atreya Chloe E Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA 94143, United States
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, United States

Corresponding author: Jordyn Silverstein, MD, Division of Hematology and Oncology, 550 16th Street, 6th Floor, Box 3211, San Francisco, CA 94158, USA (JSilverstein@mednet.ucla.edu)
Corresponding author: Chloe E. Atreya, MD, PHD, UCSF Helen Diller Family Comprehensive Cancer Center, 550 16th Street, 6th Floor, San Francisco, CA 94158, USA (Chloe.atreya@ucsf.edu).
9 2024
10 6 2024
10 6 2024
29 9 e1159e1168
11 10 2023
23 4 2024
© The Author(s) 2024. Published by Oxford University Press.
2024
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies.

Materials and Methods

This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60.

Results

Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative.

Conclusion

Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.

Little is known about the proportion of young patients affected by dual diagnoses of breast cancer and colorectal cancer. This is the largest study to date on patients with both cancers who are younger than 60 years.

young
colorectal
breast cancer
genetic
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pmcImplications for Practice

This is the largest case series on younger patients with both breast and colon cancer. It characterizes the demographics, risk factors, and genetic features to help understand this cohort. Additionally, the study describes management nuances of treating both cancers that could help guide the treatment of patients in the future faced with this dual diagnosis.

Introduction

Breast cancer and colorectal cancer (CRC) are 2 of the 3 most common cancers. In the United States, these cancers account for approximately 30% and 8% of new cancer cases in women each year, respectively.1 The median age at diagnosis is 63 years old for breast cancer and 67 years old for CRC.2,3 However, approximately 32% of breast cancer cases and 10% of CRC cases are considered young-onset, with a diagnosis before the age of 50.4,5 Among early-onset cancers, breast has the highest number of incident cases and gastrointestinal cancers have the fastest-growing incidence rates.4-8 Overlapping risk factors for both breast cancer and CRC include physical inactivity, central obesity, and alcohol consumption.7 Limited information is known about what proportion of young patients are impacted with dual diagnoses of breast cancer and CRC.

The frequency of multiple primaries in a cancer population is estimated to be around 2%-17%.9 The largest study of patients with both breast cancer and CRC used Surveillance, Epidemiology, and End Results (SEER) data from 1988 to 2007 to describe outcomes for 4835 patients; among this group, 75% were diagnosed with either cancer after age 65.10 This study did not investigate genetic risk factors, family history, behavioral risk factors, or treatment-related factors. To date, the literature is mostly comprised of case series (105 and 299 patients) and case reports of colon and breast cancer in individual patients, all of which have an average age around 65.11-18 Only a few case reports exist for young patients and only 5 case reports on patients less than 60 years old were identified.15,19 Additionally, only one case demonstrated a genetic mutation (CHEK2*1100delC) to explain both a hereditary breast and CRC phenotype.20

In light of the absence of data on patients less than 60 years old with a dual diagnosis of breast cancer and CRC, our aims were to describe: (1) demographic and known cancer risk factors, (2) clinicopathologic features and somatic and germline mutational profiles, and (3) clinical management and outcomes of younger-than-average patients with both breast cancer and CRC. We hypothesized that systematic characterization of these patients would inform understanding of the unique diagnostic and nuanced therapeutic implications for this population.

Materials and methods

Study design and study population

This study is a retrospective medical records review of patients at the UCSF Helen Diller Family Comprehensive Cancer Center. The study was approved by the University of California, San Francisco (UCSF) Human Research Protection Program (number 22-36184).

Following approval, patients were identified by physician recall as well as computational data extraction to find patients within UCSF’s Cancer Registry as well as the Cancer Genetics Registry who were diagnosed with histologically confirmed colorectal adenocarcinoma and any breast lesions that would require treatment (including ductal carcinoma in situ [DCIS] and growing lesions) before age 60 at UCSF during 2001-2022. The age threshold of 60 was chosen to maximize the number of patients included in this study with the rationale that it is below the average age of diagnosis of either cancer and, using this age cutoff, the first cancer was diagnosed at age <50 in the majority of patients. Additionally, prior research on this population included only rare patients who are under 60 years old, so younger-than-average patients are understudied.

Data collection

Data were abstracted from patient charts by a single reviewer (J.S.) and discussed with a board-certified oncologist (C.E.A.). The data cutoff was December 19, 2022. The variables that were abstracted included age, self-reported gender identity, race/ethnicity, birthplace, smoking and alcohol history, occupation, body mass index (BMI) at diagnosis of first cancer or earliest BMI in the medical record, past medical history, order of cancer diagnosis and whether metachronous or synchronous, date/age of diagnosis, cancer stage at diagnosis, hormone receptor status at diagnosis, histology, grade, tumor location, known germline mutation, family history in a first-degree relative, MMR status, MSI status, BRCA status, and date of last contact or death, and whether they are deceased or alive. During chart review, additional treatment details were collected for patients where there was clinical decision-making related to a patient receiving treatment for both primary tumors simultaneously. The variables list was approved by both a CRC oncologist (C.A.) as well as breast oncologists (A.J.C., J.C., J.W.) for completeness. Patients with synchronous cancers were defined as diagnosed of both primary tumors within 6 months of each other. Patients with metachronous cancers were defined as having a diagnosis of each cancer more than 6 months apart.

Statistical variables and analysis

Descriptive statistics were used to summarize demographic, clinical, pathologic, and genetic data, as well as the prevalence of various lifestyle factors. All data analyses were performed using Excel and STATA.

Results

Demographic information

A total of 51 patients were identified with both breast and CRC diagnosed before the age of 60, and detailed information was available for 41 of these patients. Nine were identified by physician recall, 17 from the UCSF Cancer Registry, and 30 from the Cancer Genetics Registry; of the 41 patients, 5 overlapped between physician recall and the UCSF Cancer Registry. The majority of breast cancers were diagnosed before 2010 (n = 27, 65.8%) while the majority of CRC cases were diagnosed after 2010 (27, 65.8%).

Only one patient included in this cohort self-identified as a man (1.9%), and all other patients self-identified as a woman (Table 1). The median age of breast cancer diagnosis was 43 (range 27-59), and the median age of CRC diagnosis was 50 (range 28-59). Out of 51 total patients, 10 patients (19.6%) had both cancers diagnosed before age 50, and 41 (80.4%) had the first cancer diagnosed before age 50. Only 10 patients (19.6%) had both cancers diagnosed between age 50 and 60. Most patients were Caucasian (38, 74.5%) and never smokers (23, 56.1%). Nearly half were current alcohol consumers (20, 48.8%). The average BMI was 25.8 (range: 14-49), and 46% (19) were overweight or obese at diagnosis of the first cancer or the earliest BMI recorded after the first cancer. Ten patients (24.3%) were known to be born outside of the United States, originating from Pakistan (n = 2), Japan, the Philippines, France, Israel, Ghana, Vietnam, Burma, and Mexico.

Table 1. Baseline demographic and clinical information.

Younger-onset breast and CRC (n = 51)	
Gender (%)	
 Men	1 (2.0)	
 Women	50 (98.0)	
Age at breast cancer diagnosis	
 Median, years (IQR)	43 (39-49)	
 Missing	1 (2.0)	
Age at CRC diagnosis	
 Median, years (IQR)	50 (44-55)	
Race/ethnicity (%)	
 Caucasian/non-Hispanic	38 (74.5)	
 Caucasian/Hispanic	2 (3.9)	
 Asian	9 (17.6)	
 Othera	1 (2.0)	
 Missing	1 (2.0)	
Cancer first diagnosed	
 Breast	36 (70.6)	
 Colorectal	13 (25.5)	
 Missing	2 (3.9)	
Metachronous or synchronous	
 Metachronous	44 (86.3)	
 Synchronous	7 (13.7)	
Younger-onset breast and CRC with detailed medical records (n = 41b)	
BMI	
 Median (IQR)	25 (22-28)	
 Missing (%)	6 (14.6)	
Birthplace (%)	
 United States	10 (24.3)	
 Outside United States	10 (24.3)	
 Missing	21 (51.2)	
Alcohol use (%)	
 Current consumer	20 (48.8)	
 Prior consumer	4 (9.8)	
 Never consumer	14 (34.1)	
 Missing	3 (7.3)	
Tobacco use (%)	
 Current smoker	4 (9.8)	
 Prior smoker	11 (26.8)	
 Never smoker	23 (56.1)	
 Missing	3 (7.3)	
Breast cancer	
 Stage at diagnosis	
  0	11 (26.7)	
  1	12 (30.3)	
  2	9 (21.9)	
  Missing	9 (21.9)	
 Histology	
  DCIS	13 (31.7)	
  LCIS	1 (2.4)	
  IDC	17 (41.5)	
  ILC	1 (2.4)	
  Fibroepithelial lesionc	1 (2.4)	
  Missing	8 (19.5)	
 Location of tumor	
  Left breast	17 (41.5)	
  Right breast	18 (43.9)	
  Both breasts	1 (2.4)	
  Missing	5 (12.2)	
CRC	
 Stage at diagnosis	
  1	8 (19.5)	
  2	6 (14.6)	
  3	9 (21.9)	
  4	10 (24.4)	
  Missing	8 (19.5)	
 Graded	
  Poorly differentiated	4 (9.8)	
  Moderately differentiated	19 (46.3)	
  Well differentiated	6 (14.6)	
  Missing	12 (31.3)	
 Location of tumor	
  Right colon (ascending, cecum)	9 (21.9)	
  Transverse colon	5 (12.2)	
  L colon (descending, sigmoid)e	7 (17.1)	
  Colon NOS	6 (14.6)	
  Rectum	13 (31.7)	
  Missing	1 (2.4)	
aOther race/ethnicity was Lebanese.

bForty-one out of the 51 patients had detailed information in the medical record.

cFibroepithelial lesion was included since it was an actively growing lesion that impacted decision-making.

dWell to moderately differentiated was considered well differentiated, poorly to moderately differentiated was considered poorly differentiated.

eIf a patient had a rectosigmoid tumor that was treated with a hemicolectomy then it was considered a sigmoid rather than a rectal primary.

Abbreviations: IQR, inter-quartile range; BMI, body mass index; DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; NOS, not otherwise specified.

Breast cancer clinicopathologic information

Breast cancer was the first cancer diagnosed in 36 patients (70.6%), and 44 out of the 51 (86.3%) had a metachronous diagnosis with CRC. There were 7 (13.7%) cases of synchronous breast and CRC. The breast cancers were predominantly early stage 0 (11, 26.7%), stage 1 (12, 30.3%), and 2 (9, 21.9%). The most common breast cancer types were invasive ductal carcinoma (17, 41.5%) and DCIS (13, 31.7%), and they were split between the right (43.9%, 18) and left breast (41.5%, 17). One patient had cancer in both breasts and 5 (12.2%) were missing location.

Colorectal cancer clinicopathologic information

The CRC cases were evenly distributed across all stages at the time of diagnosis, stage 1 (8, 19.5%), stage 2 (6, 14.6%), stage 3 (9, 21.9%), and stage 4 (10, 24.4%). All CRC cases were adenocarcinoma (34 confirmed patients, 7 with missing data from the chart) and mostly moderately differentiated (19, 46.3%). The tumors occurred in the right colon (9, 21.9%), transverse colon (5, 12.2%), left colon (7, 17.1%), and rectum (13, 31.7%). Only one patient had a known history of inflammatory bowel disease. Fourteen patients (34.1%) had sedentary jobs including advertising, consulting, designers, and office workers; and 2 (4.9%) were restaurant workers.

Genetic information

Twenty-three patients (56.1%) had a family history of cancer in a first-degree relative, and 16 (39.0%) had a first-degree family member with breast, CRC, or both (Table 2). One patient was adopted with an unknown family history and 13 (31.7%) had documentation of no family history in a first-degree relative. Ten patients (24.3%) had a known germline mutation, and all of these were patients who had a known family history of cancer in a first-degree relative (8) or a missing family history (2). Germline mutation data were missing from the charts of 12 patients (29.3%). The known germline mutations were Lynch syndrome (5, 12.2%) and BRCA mutation (5, 12.2%). Of the patients with Lynch syndrome, there were mutations in MSH2 (2), MSH6 (2), and PSM2 (1). Two patients had BRCA1 and 3 had BRCA2 mutations. Nineteen patients (46.3%) had no identifiable germline mutations after testing.

Table 2. Genetic risk factors.

Younger-onset breast cancer and CRC (n = 41)	
Family history of cancer in a first-degree relative (%)	
 Yes	23 (56.1)	
 No	13 (31.7)	
 Missing or unknown	5 (12.2)	
Type of cancer in first-degree relative (n = 23)	
 Breast	9 (39.1)	
 Colorectal	6 (26.0)	
 Both breast and CRC	1 (43.4)	
Known germline mutation (%)	
 Yes	10 (24.3)	
 No	19 (46.3)	
 Missing	12 (29.3)	
Type of germline mutation (n = 10)	
 Lynch	5 (50.0)	
 BRCAb	5 (50.0)	
aLynch Syndrome consisted of mutations in MSH2, MSH6, and PMS2.

bBRCA mutations: BRCA-1 (n = 2) and BRCA-2 (n = 3).

Seven patients (17.1%) had an additional cancer other than breast and CRC including endometrial cancer (4), lung cancer (1), follicular lymphoma (1), and uterine cancer (1). Six patients (14.6%) had no known family history of cancer in a first-degree relative and no known germline mutation.

Therapeutic dilemmas and management strategies

A subgroup of patients (7 out of 41, 17.1%) had either synchronous diagnoses or simultaneous treatment of both cancers due to either a new cancer diagnosis or new recurrence while undergoing active management of the other cancer (Table 3). None of these patients had a known germline mutation. In all cases, the sequence of diagnosis, the stage of each cancer at diagnosis, and the overall prognosis of each cancer impacted clinical decision-making. Figure 1 summarizes key takeaways and general management workflow for these difficult cases. In general, the cancer that was most life limiting was prioritized while maximizing concurrent treatment. For example, for patient 3, FOLFOXIRI was given for metastatic CRC in addition to trastuzumab for stage 1 HER2+ breast cancer. A common therapeutic dilemma encountered was whether to continue hormonal therapy during fluorouracil (5-FU) containing chemotherapy for CRC, with observation of a range of practice variations. Multiple patients discontinued hormonal therapy during FOLFOX or FOLFIRI treatment since 5-FU is also active against breast cancer. Although neuropathy is a dose-limiting side effect of both docetaxel and cyclophosphamide for breast cancer and oxaliplatin for CRC, 2 patients tolerated full treatment with both regimens.

Figure 1. Workflow of clinical decision-making with breast and colorectal cancers diagnosed metachronously or synchronously. Abbreviations: CRC, colorectal cancer; tx, treatment.

Table 3. Management nuances of patients with both breast cancer and CRC.

Number	Malignancy 1 (age at diagnosis)	Malignancy 2 (age at diagnosis)	Therapeutic dilemma	Management strategy	Outcomea	
1	Breast cancer (47)
2009: dx with stage 2a ER+/PR+/HER2− IDC, underwent mastectomy with adjuvant TC + anastrazole
2014: recurrence to LNs started on exemestane
2016: (after CRC diagnosis) recurrence to supraclavicular LN started radiation and fulvestrant
2021: recurrence in axillary LN s/p excision and put on letrozole	Colorectal cancer (53)
2016: dx with stage 3 transverse colon cancer treated with resection and adjuvant CapeOx	What to do with hormonal therapy for breast cancer while receiving CapeOx for colon cancer?	Held fulvestrant while on CapeOx since capecitabine is an effective tx for metastatic breast cancer	Alive without evidence of breast cancer after 2021 recurrence and without colon cancer recurrence after 5 years of surveillance	
2	Breast cancer (41)
2007: dx with stage 2 ER+/PR+/HER2− IDC tx with mastectomy followed by adjuvant TC, followed by goserelin/tamoxifen, then maintenance tamoxifen for 5 years, followed by letrozole	Colorectal cancer (46)
2013: dx with stage 4 (BRAF mutant) transverse colon cancer with metastases to the liver treated with colectomy, hepatectomy, and FOLFOX + bevacizumab	What to do with maintenance hormonal therapy while receiving FOLFOX?
How does prior chemotherapy for breast cancer treatment impact choice of chemotherapy for CRC?	Continued hormonal therapy while receiving FOLFOX
Considered the side effects from prior breast cancer tx: although both taxotere and oxaliplatin cause neuropathy, oxaliplatin was tolerated for all 13 cycles	Alive without breast recurrence, and 8 years without evidence of recurrent or metastatic colon cancer	
3	Colorectal cancer (35)
December 2018: dx with stage 4 ascending colon cancer with liver metastases (ERBB2 negative, RAS mutated; staging scans reveal synchronous breast cancer)
Treated with FOLFOXIRI (+trastuzumab), then hepatectomy (with concurrent mastectomy), followed by FOLFOXIRI (+trastuzumab and tamoxifen)
October 2019: recurrence to lung and liver with subsequent progression on all further lines of therapy	Breast cancer (35)
January 2019: dx with stage 1a ER+/PR+/HER2+ IDC, treated with trastuzumab initially then mastectomy while undergoing surgery for colon cancer, then continued trastuzumab and tamoxifen
October 2019: tamoxifen and trastuzumab stopped due to the aggressive nature of colon cancer	With synchronous breast and colon cancer, which cancer should be treated first or how to treat both at the same time?
When to discontinue hormonal and trastuzumab therapy for early-stage breast cancer given alongside chemotherapy for mCRC?	Since the colon cancer was more advanced it was treated first
Since the breast cancer was HER2+ and hormone receptor positive, HER2 and hormonal therapy were added to the colon cancer chemotherapy regimen
When surgery was done for the colon cancer, concurrent mastectomy was performed
Since the breast cancer had low risk for recurrence, hormonal therapy and trastuzumab were stopped when colon cancer was progressing and life limiting	Deceased at age 38 from metastatic colon cancer	
4	Colorectal cancer (39)
July 2019: dx with rectal cancer (KRAS mutated) metastatic to the liver, LN including L axillary, vaginal cuff, peritoneum, and with suspicious breast uptake, tx with neoadjuvant FOLFOX followed by LAR with TAH/BSO; peritoneal implants found
January 2020: started adjuvant FOLFOX + bevacizumab (+hormonal therapy) with progression
November 2020: started FOLFIRI + bevacizumab
February 2021: progression of both CRC and breast cancer; restarted on FOLFIRI + bevacizumab with response (then held for breast surgery), with subsequent rapid progression off therapy so restarted FOLFIRI + bevacizumab (+exemestane) followed by progression on all further therapies	Breast cancer (39)
August 2019: breast biopsy for suspicious uptake on PET/CT for CRC: dx with ER+/PR+/HER2− IDC with axillary LN involvement
November 2019: started tamoxifen after neoadjuvant FOLFOX and then switched to anastrazole after TAH/BSO
February 2021: progression of breast cancer, anastrazole stopped, surgery deferred while receiving FOLFIRI for CRC
October 2021: lumpectomy with residual disease and matted nodes, deferred XRT and started exemestane	When there is a progression of both metastatic rectal cancer and locally advanced breast cancer what to treat first?
Should anastrazole be continued when starting FOLFIRI?
What to do about postoperative radiation therapy for residual breast cancer while undergoing tx for mCRC?	Since metastatic rectal cancer had a worse prognosis, chemotherapy was started first and only after achieving rectal cancer control was chemotherapy paused and surgery intended to cure the breast cancer undertaken to increase her candidacy for CRC clinical trials
Given her breast cancer progressed while on anastrazole it was stopped during FOLFIRI given 5-FU has activity against breast cancer
Even though her breast cancer qualified for radiation treatment since she had residual disease, radiation was deferred given the urgency to restart mCRC tx	Deceased at age 42 from metastatic rectal cancer	
5	Colorectal cancer (53)
June 2009: dx with stage 1 sigmoid colon cancer detected on routine colonoscopy; treated with sigmoidectomy	Breast cancer (53)
September 2009: dx with stage 1 ER+/PR−/HER2− IDC treated with lumpectomy, adjuvant TC and radiation therapy	Does surgery for colon cancer (stage 1) <2 months prior change the tx for a new diagnosis of breast cancer?	The tx of her stage 1 breast cancer was not impacted by her colon cancer since it was stage 1 (resected) and no adjuvant treatment was indicated for CRC	Alive with no evidence of colon or breast cancer recurrence 10 years after diagnosis	
6	Colorectal cancer (38)
2018: dx with stage 3 rectosigmoid cancer s/p resection and adjuvant FOLFOX
2020: developed pulmonary metastatic disease and lymphadenopathy; started on FOLFIRI + bevacizumab	Breast tumor (40)
2020: new breast nodule identified at the time of mCRC recurrence
2020: elected to get a biopsy which showed a fibroepithelial lesion
6 months later, a mammogram showed growth of the lesion	What to do with a new growing breast lesion while undergoing tx for mCRC?
How to address pulmonary metastasis with 2 possible cancers as the primary?	Despite growth, the decision was made not to resect the breast lesion since that would have required holding CRC tx, which was a more life-limiting diagnosis
Biopsy of pulmonary metastases was considered but ultimately not recommended given known mCRC and most fibroepithelial lesions are benign	Deceased at age 43 from metastatic rectal cancer	
7	Breast cancer (48)
2018: (perimenopausal) dx with high-grade DCIS s/p breast lumpectomy and adjuvant radiation and started on tamoxifen	Colorectal cancer (51)
2021: dx with stage 3B colon cancer abutting the appendiceal orifice; underwent surgical resection and started on adjuvant FOLFOX × 6 months	What to do with tamoxifen therapy for high-grade DCIS while on adjuvant FOLFOX for CRC?	Tamoxifen for DCIS was held during FOLFOX to reduce risk of thrombotic complications	Alive without breast cancer recurrence and no evidence of colon cancer; in surveillance	
aData cutoff was December 19, 2022.

Abbreviations: dx, diagnosed; tx, treatment; ER, estrogen receptor; PR, progesterone receptor; IDC, invasive ductal carcinoma; TC, taxotere Cytoxan; LN, lymph; node; CapeOx, capecitabine oxaliplatin; FOLFOX, leucovorin calcium (folinic acid), fluorouracil, oxaliplatin; LAR, low anterior resection; TAH/BSO, total abdominal hysterectomy, bilateral salpingoophorectomy; mCRC, metastatic colorectal cancer; s/p, status post; FOLFIRI, leucovorin calcium (folinic acid), fluorouracil, and irinotecan hydrochloride; XRT, radiation therapy; DCIS, ductal carcinoma in situ.

Discussion

This is the first study to characterize the demographic, clinical, and genetic features of younger patients diagnosed with both breast cancer and CRC. In addition, this study describes therapeutic dilemmas and management nuances that could help guide future physicians in the treatment of this complex group of patients.

We found that the age and stage of younger patients with both breast cancer and CRC followed the trends from previous reports of young-onset patients with either cancer.2-5 Specifically, the median age of diagnosis of breast cancer was 43 and colon cancer was 50 in our study, compared to reported median ages of 63 (28% diagnosed before age 55) and 66 (13% diagnosed before age 55), respectively.2-5 As expected, breast cancer was more commonly diagnosed before CRC in this cohort. Additionally, a SEER study of patients of all ages with both breast cancer and CRC also showed breast cancer was more often diagnosed first.10 Most patients in this study had early-stage breast and later-stage CRC. Young patients diagnosed with breast cancer mostly have local or regional disease, while early-onset colorectal cancer is characterized by advanced stage at diagnosis.2,21

We conducted a comprehensive review of medical records in an effort to identify risk factors within this cohort and found alcohol consumption and sedentary jobs were the most common. The majority of patients in this study had a risk factor for at least one of the cancers. Almost 50% of patients in this study were current alcohol consumers, although the amount of alcohol was not recorded. Studies have shown that even modest amounts of alcohol can increase the risk of both breast and CRC and therefore could contribute to increased risk in this population.7,22-25 A substantial group of patients in this study (34%) had sedentary jobs which may also confer an increased risk of CRC and breast cancer.26-30 Research shows that, in the United States, less than 20% of occupations require moderate-intensity physical activity, therefore the majority of employed individuals have sedentary jobs and this is not unique to our study population.31 There are many potential confounders, including the association between sedentary jobs and health care access, which make the correlation between sedentary jobs and cancer risk difficult to interpret. Only a small subset of patients in this study were obese. While obesity has been shown to almost double the risk of early-onset CRC, higher BMI has been associated with lower breast cancer incidence in premenopausal women and increased risk in postmenopausal women.25,32-36 Although inflammatory bowel disease is a clear risk factor for CRC, a large meta-analysis showed that IBD had no influence on breast cancer risk.37-39 Further studies are needed to understand what role these risk factors are playing in the development of both cancers in this young population.

Due to the retrospective nature of this study, there were variable rates and types of genetic testing done for patients in this study. Acknowledging this limitation, 24% of patients in this study had germline mutations in either BRCA (12%) or Lynch syndrome (12%). In the literature, BRCA1 and BRCA2 are found in approximately 10%-20% of patients with early-onset breast cancer and approximately 13% of patients with early-onset CRC have a hereditary cancer (most commonly Lynch syndrome: 8%).40,41 Additionally, although not seen in the current study, germline mutation of CHEK2 has been associated with both breast and CRC.20,42 In clinical practice, early-onset of either disease should lead to genetic testing. In this study, 37% of patients had a first-degree relative with either breast (22%) or CRC (15%). This is compared to reports of 13% of people with breast cancer have a family history of breast cancer in a first-degree relative and approximately 7%-26% of early-onset CRC have a first-degree relative with CRC.43-46 Understanding the family history patterns of young patients with both cancers could help inform screening for both cancers in the future.

This study provides key insights about some of the management dilemmas that physicians face when treating a patient with both breast cancer and CRC. In general, the treatment strategy is highly individualized and depends on several factors including (1) order of diagnosis, (2) stage of each cancer, and (3) overall prognosis. In general, the cancer that was more life limiting was often treated first, but when possible, concurrent treatments were given. This study had more early-stage breast cancer and later-stage CRC. Therefore, although the survival outcomes with metastatic breast cancer and mCRC are similar, ie, median overall survival of ~3 years and 5-year survival ~30%, the late-stage CRC was often the priority cancer to treat in this cohort.47-49 Occasionally, the early-stage cancer was treated with curative intent to increase the eligibility for clinical trials, since clinical trials typically exclude patients with a concurrent active cancer; however, 41% of trials exclude prior cancer within 5 years.50 When possible, combined surgeries were planned to address both the breast and CRC.

The fluoropyrimidine class of chemotherapy has shown efficacy in both breast and CRC, and thus was a frequently selected treatment in this study with the goal to treat both cancers.51 Attention was given to overlapping toxicities of CRC and breast cancer treatment, particularly neuropathy from both platinum chemotherapies and taxanes.52-54 However, the patients in this study were able to complete all cycles of oxaliplatin after prior taxane therapy without dose-limiting toxicities. Patients should be monitored for overlapping toxicities if treating a second primary cancer with additional chemotherapy.

A common dilemma encountered was whether to continue hormonal therapy for breast cancer maintenance therapy during chemotherapy treatment for CRC. According to the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group, patients with early hormone-positive breast cancer should continue hormonal therapy for up to 10 years.55 Therefore, most younger patients with either synchronous or metachronous CRC and breast cancer face this dilemma. In this study some oncologists held hormonal therapy during CRC-directed chemotherapy, due to the fact that the fluoropyrimidines (especially 5-fluorouracil and capecitabine) have been shown to have activity against breast cancers, while others continued hormonal therapy even during these treatments.51 In general, when treating patients with breast cancer with cytotoxic chemotherapy, hormonal therapy is withheld due to the theoretical risk that endocrine therapy which is cytostatic and prevents cells from dividing could decrease the efficacy of chemotherapy which targets actively dividing cells, although this has not been proven.56 Since the chemotherapy agents are targeting CRC and the endocrine therapy is targeting the breast cancer, it is unclear whether the same principal applies. One oncologist held tamoxifen during FOLFOX therapy due to the theoretical increased risk of venous thromboembolism (VTE) from chemotherapy and tamoxifen therapy together. While there are no guidelines in this space, one study showed a higher risk of VTE in patients with breast cancer after tamoxifen and chemotherapy, however, not after aromatase inhibitor therapies.57

Another consideration for patients with synchronous mCRC and breast cancer is to determine the HER2 (ERBB2) status of the mCRC, as approximately 3% of mCRC are HER2 positive, and 5% of KRAS and NRAS wild-type tumors.58 Similar to breast cancer, HER2 amplified mCRC can indicate more aggressive disease. Although studies of HER2-targeted therapy for mCRC have encouraging signal, they are limited due to the low rate of ERBB2 overexpression. However, if the patient has HER2 positive breast cancer, the utilization of ERBB targeted therapy may offer therapeutic benefit for both cancers.59 This study was conducted prior to the approval of tucatinib for mCRC and therefore was not used for patients in this study.60 The optimal choice of HER2 targeted therapy with a dual diagnosis of breast and CRC has not yet been determined.

This study has several limitations that must be acknowledged. Particularly given the modest sample size and retrospective design this study is purely exploratory in nature, although it is one of the biggest sample sizes of this rare population. Since some of the patients were identified through the UCSF Cancer Genetics and Prevention Program Registry, selection bias could contribute to the high number of germline mutations among this population. Additionally, the number of genes tested over the study period was variable, so this study could underestimate the true number of hereditary cancers among this population. No conclusions about the causality of the risk factors or germline mutations could be made since there was no control group for comparison. The medical records had a high degree of missing data, particularly for hormone receptor status of breast cancers, a limitation of retrospective data collection. We also lacked detailed information about the amount of alcohol or tobacco use. Additionally, there have been significant changes to the standard of care over the course of this study to the treatment of each cancer, which could change comanagement decisions of these patients in the future.

Conclusion

Younger patients with both breast cancer and CRC are a unique cohort, many without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors identified among patients without a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care. As the incidence of both cancers is increasing in adults under the age of 50, future studies are needed to fully characterize this growing group of patients.

Acknowledgments

We would like to acknowledge the patients of the current study and of the future who face a diagnosis of both CRC and breast cancer at young ages. We hope to continue to aid in understanding this population for them and their loved ones.

Author contributions

Conception/design: Jordyn Silverstein, Francis Wright, Chloe E. Atreya, Katherine Van Loon, John W. Park, Amie Blanco, Amy Jo Chien. Collection and/or assembly of data: Jordyn Silverstein, Chloe E. Atreya, Dalila Stanfield. Data analysis and interpretation: Jordyn Silverstein, Chloe E. Atreya. Manuscript writing: Jordyn Silverstein, Chloe E. Atreya, Katherine Van Loon, John W. Park, Amie Blanco, Amy Jo Chien. Final approval of manuscript: all authors.

Funding

None declared.

Conflicts of Interest

No relevant conflicts of interest exist for the authors.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.
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References

1. Siegel RL , MillerKD, FuchsHE, JemalA. Cancer statistics, 2022. CA Cancer J Clin. 2022;72 (1 ):7-33. 10.3322/caac.21708 35020204
2. Cancer of the breast (female) - Cancer Stat Facts. SEER. Accessed February 24, 2022. https://seer.cancer.gov/statfacts/html/breast.html
3. Cancer of the colon and rectum - Cancer Stat Facts. SEER. Accessed February 24, 2022. https://seer.cancer.gov/statfacts/html/colorect.html
4. Shah RR , MillienVO, da CostaWL, et al . Trends in the incidence of early-onset colorectal cancer in all 50 United States from 2001 through 2017. Cancer. 2022;128 (2 ):299-310. 10.1002/cncr.33916 34529823
5. Heer E , HarperA, EscandorN, et al . Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study. Lancet Glob Health. 2020;8 (8 ): e1027-e1037. 10.1016/S2214-109X(20)30215-1 32710860
6. Done JZ , FangSH. Young-onset colorectal cancer: a review. World J Gastrointest Oncol. 2021;13 (8 ):856-866. 10.4251/wjgo.v13.i8.856 34457191
7. Ugai T , SasamotoN, LeeHY, et al . Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat Rev Clin Oncol. 2022;19 (10 ):656-673. 10.1038/s41571-022-00672-8 36068272
8. Koh B , TanDJH, NgCH, et al . Patterns in cancer incidence among people younger than 50 years in the US, 2010 to 2019. JAMA Netw Open. 2023;6 (8 ):e2328171. 10.1001/jamanetworkopen.2023.28171 37585204
9. Vogt A , SchmidS, HeinimannK, et al . Multiple primary tumours: challenges and approaches, a review. ESMO Open. 2017;2 (2 ):e000172. 10.1136/esmoopen-2017-000172 28761745
10. Fisher CS , WachtelMS, MargenthalerJA. Outcomes for patients who develop both breast and colorectal cancer. Ann Surg Oncol. 2012;19 (1 ):242-248. 10.1245/s10434-011-1843-8 21701928
11. Abdulla HA , AlmarzooqR, AlrayesA. Synchronous breast and colon cancer: the importance of multidisciplinary team cancer meetings. BMJ Case Rep. 2019;12 (12 ):e232680. 10.1136/bcr-2019-232680
12. Asaad A , BarronM, RasheedN, IdaeworP, Saad Abdalla Al-ZawiA. The rare diagnosis of synchronous breast and colonic cancers: a case report and review of literature. Cureus. 3314;13 (2 ):e1. 10.7759/cureus.13314
13. Yetkin G , CelayirF, AkgunIE, UcakR. Synchronous occurrence of primary breast carcinoma and primary colon adenocarcinoma. Case Rep Surg. 2017;2017 (2 ):1-3. 10.1155/2017/7048149
14. Higgins L , RobertsonI, KhanW, BarryK. Synchronous breast and colon cancer: factors determining treatment strategy. Case reports. BMJ Case Rep. 2013;2013 (12 ):bcr2013009450. 10.1136/bcr-2013-009450
15. Tripodi D , Cannistra’C, GagliardiF, et al . Coincidental or causal? Concurrence of colorectal carcinoma with primary breast cancer. Dig Dis Sci. 2021;67 (2 ):437-444. 10.1007/s10620-021-07296-5 34731362
16. Anania G , SantiniM, MarzettiA, et al . Synchronous primary malignant tumors of the breast, caecum and sigma. Case report. G Chir. 2012;33 (11-12 ):409-410.23140927
17. Lee H , LeeHW, ParkEJ, KangJ, BaikSH. Clinicopathologic characteristics and survival of patients with double primary malignancies: breast and colorectal cancer. Ann Coloproctol. 2021;38 (3 ):197-206. 10.3393/ac.2021.00640.0091 34657410
18. Lu Y , SegelmanJ, NordgrenA, et al . Increased risk of colorectal cancer in patients diagnosed with breast cancer in women. Cancer Epidemiol. 2016;41 :57-62. 10.1016/j.canep.2016.01.006 26826682
19. Abushwemeh MA , JabeenN, QaseerAA, et al . Synchronous breast and colon cancer in a young female: a single stage surgery. Int Surg J. 2021;8 (4 ):1309-1311. 10.18203/2349-2902.isj20211317
20. Meijers-Heijboer H , WijnenJ, VasenH, et al . The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet. 2003;72 (5 ):1308-1314. 10.1086/375121 12690581
21. Mauri G , Sartore-BianchiA, RussoAG, et al . Early-onset colorectal cancer in young individuals. Mol Oncol. 2019;13 (2 ):109-131. 10.1002/1878-0261.12417 30520562
22. Shield KD , SoerjomataramI, RehmJ. Alcohol use and breast cancer: a critical review. Alcohol Clin Exp Res. 2016;40 (6 ):1166-1181. 10.1111/acer.13071 27130687
23. Fedirko V , TramacereI, BagnardiV, et al . Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol. 2011;22 (9 ):1958-1972. 10.1093/annonc/mdq653 21307158
24. Chen WY , RosnerB, HankinsonSE, ColditzGA, WillettWC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306 (17 ):1884-1890. 10.1001/jama.2011.1590 22045766
25. Breau G , EllisU. Risk factors associated with young-onset colorectal adenomas and cancer: a systematic review and meta-analysis of observational research. Cancer Control. 2020;27 (1 ):1073274820976670. 10.1177/1073274820976670 33274652
26. Boyle T , FritschiL, HeyworthJ, BullF. Long-term sedentary work and the risk of subsite-specific colorectal cancer. Am J Epidemiol. 2011;173 (10 ):1183-1191. 10.1093/aje/kwq513 21421743
27. Lee J , LeeJ, LeeD, KimH, KangM. Sedentary work and breast cancer risk: a systematic review and meta‐analysis. J Occup Health. 2021;63 (1 ):e12239. 10.1002/1348-9585.12239 34161650
28. O'Sullivan DE , SutherlandRL, TownS, et al . Risk factors for early-onset colorectal cancer: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20 (6 ):1229-1240. 10.1016/j.cgh.2021.01.037 33524598
29. Nguyen LH , LiuPH, ZhengX, et al . Sedentary behaviors, TV viewing time, and risk of young-onset colorectal cancer. JNCI Cancer Spectr. 2018;2 (4 ):pky073. 10.1093/jncics/pky073 30740587
30. Chan DSM , AbarL, CariolouM, et al . World cancer research fund international: continuous update project-systematic literature review and meta-analysis of observational cohort studies on physical activity, sedentary behavior, adiposity, and weight change and breast cancer risk. Cancer Causes Control. 2019;30 (11 ):1183-1200. 10.1007/s10552-019-01223-w 31471762
31. Church TS , ThomasDM, Tudor-LockeC, et al . Trends over 5 decades in U.S. occupation-related physical activity and their associations with obesity. PLoS One. 2011;6 (5 ):e19657. 10.1371/journal.pone.0019657 21647427
32. Liu PH , WuK, NgK, et al . Association of obesity with risk of early-onset colorectal cancer among women. JAMA Oncol. 2019;5 (1 ):37-44. 10.1001/jamaoncol.2018.4280 30326010
33. Huang Z , HankinsonSE, ColditzGA, et al . Dual effects of weight and weight gain on breast cancer risk. JAMA. 1997;278 (17 ):1407-1411.9355998
34. Hopper JL , DiteGS, MacInnisRJ, et al. ; kConFab Investigators. Age-specific breast cancer risk by body mass index and familial risk: prospective family study cohort (ProF-SC). Breast Cancer Res. 2018;20 (1 ):132. 10.1186/s13058-018-1056-1 30390716
35. Continuous update project report summary. Diet, nutrition, physical activity, and breast cancer. World Cancer Research Fund International/American Institute for Cancer Research. Published online 2017. https://jamanetwork-com.ucsf.idm.oclc.org/journals/jamaoncology/fullarticle/2677294
36. Bandera EV , JohnEM. Obesity, Body composition, and breast cancer: An evolving science. JAMA Oncol. 2018;4 (6 ):804-805. 10.1001/jamaoncol.2018.0125 29621383
37. Gong C , XuR, ZouP, ZhangY, WangX. Inflammatory bowel disease and risk of breast cancer: a meta-analysis of cohort studies. Eur J Cancer Prev. 2022;31 (1 ):54-63. 10.1097/CEJ.0000000000000667 34871199
38. Olén O , ErichsenR, SachsMC, et al . Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet. 2020;395 (10218 ):123-131. 10.1016/S0140-6736(19)32545-0 31929014
39. Olén O , ErichsenR, SachsMC, et al . Colorectal cancer in Crohn’s disease: a Scandinavian population-based cohort study. Lancet Gastroenterol Hepatol. 2020;5 (5 ):475-484. 10.1016/S2468-1253(20)30005-4 32066530
40. Siddig A , Tengku DinTADAA, Mohd NafiSN, et al . The unique biology behind the early onset of breast cancer. Genes (Basel). 2021;12 (3 ):372. 10.3390/genes12030372 33807872
41. Maxwell KN , WubbenhorstB, D’AndreaK, et al . Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015;17 (8 ):630-638. 10.1038/gim.2014.176 25503501
42. Lu HM , LiS, BlackMH, et al . Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncol. 2019;5 (1 ):51-57. 10.1001/jamaoncol.2018.2956 30128536
43. Daca Alvarez M , QuintanaI, TerradasM, et al . The inherited and familial component of early-onset colorectal cancer. Cells. 2021;10 (3 ):710. 10.3390/cells10030710 33806975
44. Chen FW , SundaramV, ChewTA, LadabaumU. Low prevalence of criteria for early screening in young-onset colorectal cancer. Am J Prev Med. 2017;53 (6 ):933-934. 10.1016/j.amepre.2017.07.016 29051017
45. Stoffel EM , KoeppeE, EverettJ, et al . Germline genetic features of young individuals with colorectal cancer. Gastroenterology. 2018;154 (4 ):897-905.e1. 10.1053/j.gastro.2017.11.004 29146522
46. Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101 986 women without the disease. Lancet. 2001;358 (9291 ):1389-1399. 10.1016/S0140-6736(01)06524-2 11705483
47. Zeineddine FA , ZeineddineMA, YousefA, et al . Survival improvement for patients with metastatic colorectal cancer over twenty years. NPJ Precis Onc. 2023;7 (1 ):1-9. 10.1038/s41698-023-00353-4
48. Meegdes M , GeurtsSME, ErdkampFLG, et al . Real-world time trends in overall survival, treatments and patient characteristics in HR+/HER2− metastatic breast cancer: an observational study of the SONABRE Registry. Lancet Reg Health Eur. 2023;26 (100573 ). 10.1016/j.lanepe.2022.100573
49. Breast cancer - metastatic - statistics. Cancer.Net. Published May 19, 2017. Accessed April 26, 2023. https://www.cancer.net/cancer-types/breast-cancer/statistics
50. Patel RR , ParisiR, VermaV, et al . Association between prior malignancy exclusion criteria and age disparities in cancer clinical trials. Cancers (Basel). 2022;14 (4 ):1048. 10.3390/cancers14041048 35205795
51. Leonard RCF. Oral fluoropyrimidines among the new drugs for patients with metastatic breast cancer. Br J Cancer. 2001;84 (11 ):1437-1442. 10.1054/bjoc.2001.1819 11384089
52. Park SB , GoldsteinD, KrishnanAV, et al . Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin. 2013;63 (6 ):419-437. 10.3322/caac.21204 24590861
53. Mizrahi D , ParkSB, LiT, et al . Hemoglobin, body mass index, and age as risk factors for paclitaxel- and oxaliplatin-induced peripheral neuropathy. JAMA Netw Open. 2021;4 (2 ):e2036695. 10.1001/jamanetworkopen.2020.36695 33587134
54. Windebank AJ , GrisoldW. Chemotherapy-induced neuropathy. J Peripher Nerv Syst. 2008;13 (1 ):27-46. 10.1111/j.1529-8027.2008.00156.x 18346229
55. Davies C , PanH, GodwinJ, et al. ; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381 (9869 ):805-816. 10.1016/S0140-6736(12)61963-1 23219286
56. Pritchard KI. Combining endocrine agents with chemotherapy: Which patients and what sequence? Cancer. 2008;112 (3 Suppl ):718-722. 10.1002/cncr.23189 18072257
57. Walker AJ , WestJ, CardTR, et al . When are breast cancer patients at highest risk of venous thromboembolism? A cohort study using English health care data. Blood. 2016;127 (7 ): 849-57; quiz 953. 10.1182/blood-2015-01-625582 26574606
58. Strickler JH , YoshinoT, GrahamRP, SienaS, Bekaii-SaabT. Diagnosis and treatment of ERBB2-positive metastatic colorectal cancer: a review. JAMA Oncol. 2022;8 (5 ):760-769. 10.1001/jamaoncol.2021.8196 35238866
59. Ramanathan RK , HwangJJ, ZamboniWC, et al . Low overexpression of HER-2/Neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin®) and irinotecan as therapy. a phase II trial. Cancer Invest. 2004;22 (6 ):858-865. 10.1081/cnv-200039645 15641483
60. Research C for DE and. FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. FDA. 2023. Accessed May 4, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer
