Synchronous or metachronous breast and colorectal cancers in younger-than-average-age patients: a case series

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.


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. 2,3However, approximately 32% of breast cancer cases and 10% of CRC cases are considered young-onset, with a diagnosis before the age of 50. 4,55][6][7][8] Overlapping risk factors for both breast cancer and CRC include physical inactivity, central obesity, and alcohol consumption. 7Limited 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 e1160 The Oncologist, 2024, Vol. 29, No. 9 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][12][13][14][15][16][17][18] Only a few case reports exist for young patients and only 5 case reports on patients less than 60 years old were identified. 15,19Additionally, only one case demonstrated a genetic mutation (CHEK2*1100delC) to explain both a hereditary breast and CRC phenotype. 20n 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.

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

CRC
Treat the more advanced, life-threatening cancer first Administer breast cancer directed therapy as indicated

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.

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
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  (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.

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.
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.

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.3][4][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. 10Most 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. 2,21e 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.7][28][29][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. 31There 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.8][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%). 40,41Additionally, although not seen in the current study, germline mutation of CHEK2 has been associated with both breast and CRC. 20,42In 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%).4][45][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.8][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. 50When 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. 513][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. 55Therefore, 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. 51In 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. 56Since 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. 57nother 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 e1166 The Oncologist, 2024, Vol. 29, No. 9 HER2 positive, and 5% of KRAS and NRAS wild-type tumors. 58Similar 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. 59This study was conducted prior to the approval of tucatinib for mCRC and therefore was not used for patients in this study. 60The 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.

•
If CRC is more advanced and breast cancer is HER2+, can add HER2-directed therapy to the CRC regimen • Consider concurrent CRC and breast cancer surgery if indicated • Defer surgery for the less advanced cancer if it will require holding treatment for more advanced cancer • If eliminating the less advanced cancer can increase candidacy for a clinical trial, consider pausing therapy for the advanced cancer to pursue curative intent treatment of the less advanced cancer • If new pulmonary or hepatic metastasis develop, consider biopsy to determine the site of origin since both breast cancer and CRC have a propensity to metastasize to lungs and liver.

principles above Administer CRC-directed therapy with concurrent maintenance therapy for breast cancer
(endocrine +/-anti-HER2) • If capecitabine or 5-FU containing chemotherapy is being given for CRC, consider holding hormonal therapy since both treatments have breast cancer activity • Breast cancer screening should continue as clinically indicated • If breast cancer recurs and treatment overlaps with CRC, abide by principles below • CRC screening as clinically indicated during breast cancer treatment • If CRC treatment overlaps with breast cancer treatment abide by

Table 1 .
Baseline demographic and clinical information.

Table 1 . Continued Younger-onset breast and CRC (n = 51)
a Other 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.

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