Part XIV · Special populations and uncommon presentations · Chapter 81

Young adults, fertility, and pregnancy

Decisions taken in weeks that a patient lives with for forty years.

1 · Breast cancer in adolescents and young adults

The adolescent and young adult boundary is administrative. Registries draw it at 15 to 39 years, and nothing in the biology changes at either edge. The category is useful because the consequences of treatment run for decades rather than because the tumours are a class.

Young-onset disease is enriched for higher stage at presentation, higher grade, and for triple-negative and HER2-positive phenotypes. The incidence trend and its interpretation are set out in The rise of young-onset disease. What is less often quoted is where the survival deficit actually sits.

One multicentre cohort examined 17,575 women with stage I to III disease, of whom 1,916 were aged 40 years or younger. Median follow-up was 6.4 years. After adjustment, breast cancer mortality was higher in the younger group, with a hazard ratio of 1.4 and a 95% confidence interval of 1.2 to 1.7. Stratified by subtype, the excess was significant in luminal A disease. The hazard ratio there was 2.1, with an interval of 1.4 to 3.2. It was also significant in luminal B disease, with a hazard ratio of 1.4 and an interval of 1.1 to 1.9. It was borderline in triple-negative disease and absent in HER2-positive disease1.

Caution

The intuitive account is that young women do badly because they get aggressive subtypes. This dataset says the opposite. Once subtype is held constant, the age effect concentrates in the luminal tumours, which are the ones with the best average prognosis. Age is doing something inside hormone receptor positive disease that subtype assignment does not capture.

Young women describe their experience in terms the tumour registry does not record. Definitions of young vary, and the concerns cluster around fertility, partners, children and work2,3. Quality of life in survivors is generally good, with more emotional disruption among the youngest, much of it tied to an abrupt treatment-induced menopause4. A systematic review found distinct psychosocial and menopause-related concerns, weight gain and physical inactivity5. Interventions that treat the woman without her partner may not be the best design, and couple-based approaches have early support6. The reproductive consequences are reviewed for gynaecologists in7.

Three tasks belong at diagnosis and are time-critical. Germline testing changes surgical and systemic decisions, and the indications are in Inherited susceptibility and familial breast cancer. Fertility referral must precede the first dose, which is the subject of Fertility preservation before treatment. And the conversation about pregnancy after treatment starts now, because it constrains the endocrine plan described in Adjuvant chemotherapy and the genomic assay decision.

2 · Fertility preservation before treatment

Two different problems hide under one heading. One is banking gametes or embryos, which preserves the material. The other is protecting the ovary during chemotherapy, which preserves function. They are not substitutes for each other, and a patient offered only the second has been offered half of what exists8.

Cryopreservation of mature oocytes or embryos after controlled ovarian stimulation is the established method, and guidelines treat embryo and oocyte cryopreservation as standard practice9. Stimulation with concurrent letrozole keeps oestradiol low, and pregnancy rates with the resulting embryos were comparable to those expected in women without cancer10. The options and their evidence are reviewed in11,12,13,14. Ovarian tissue cryopreservation is now an option rather than an experimental procedure. Random-start protocols allow stimulation to begin at any point in the cycle, which removes most of the scheduling delay that used to make referral feel incompatible with starting treatment. Referral before surgery rather than after it shortened the interval to chemotherapy and allowed more stimulation cycles15.

Ovarian protection with a gonadotropin-releasing hormone agonist has been tested directly. In POEMS/SWOG S0230, premenopausal women with operable hormone receptor negative disease received standard chemotherapy with or without goserelin. Among 135 patients with complete primary endpoint data, ovarian failure at 2 years occurred in 8% of the goserelin group and 22% of the chemotherapy-alone group. The odds ratio was 0.30, with a 95% confidence interval of 0.09 to 0.9716. An individual patient level meta-analysis of five trials and 873 patients found premature ovarian insufficiency in 14.1% with the agonist and 30.9% without it. The adjusted odds ratio was 0.38, with an interval of 0.26 to 0.57. Post-treatment pregnancy occurred in 10.3% and 5.5% respectively17. The earlier literature was less settled, and a systematic review found insufficient evidence either way18. The debate that followed is visible in the correspondence between investigators19,20,21. Amenorrhoea itself is a poor proxy for lasting ovarian failure. About half of women with six months of chemotherapy-induced amenorrhoea resumed bleeding within three years22.

Caution

Most of this evidence uses amenorrhoea or a postmenopausal follicle-stimulating hormone level as the endpoint. Those are measurements of menstrual and hormonal status. They are not measurements of the capacity to conceive. Anti-Mullerian hormone and antral follicle count measure reserve, which is a third quantity again. A patient told that her ovarian function was protected has been told something narrower than she will hear.

In practice

Refer before the first dose, not after the first cycle. The window is the interval between diagnosis and treatment, and it closes.

Offer cryopreservation and ovarian suppression as separate decisions. A patient may reasonably take one, both, or neither.

Ask what the patient wants, not what her age predicts. Uptake is poor and the commonest reason is that the conversation did not happen. At four cancer centres, infertility risk was documented in 26% of records and referral in 13%23. Patients report that they raised the subject themselves, and that they were dissatisfied with how it was discussed24,25,26.

3 · Pregnancy-associated and postpartum breast cancer

Cancer complicates a small fraction of deliveries. Among 3,168,911 deliveries in California, breast cancer was the most frequently associated malignancy, at 0.13 per 1,000, and maternal and neonatal morbidity were increased27. Reviews of breast cancer during pregnancy set out the clinical problem28. The tumours share histological and prognostic features with those of other young women29.

Pregnancy-associated breast cancer is a phrase that collapses two different situations. One is diagnosis during gestation. The other is diagnosis in the years after delivery. Only the first is a treatment problem in the obstetric sense. The second is a biological problem, and it is the more consequential of the two.

Parity confers long-term protection and short-term risk. A pooled analysis of 15 prospective studies found that risk in parous women remained above that of nulliparous women for more than 20 years after childbirth. Crossover to reduced risk was observed for oestrogen receptor positive disease and not for receptor negative disease. The pattern was more pronounced with a family history, with older age at first birth, and with more births. Breastfeeding did not modify it30.

The mechanism is postpartum involution, developed in Pregnancy, lactation, and postpartum involution and Pregnancy, postpartum involution, and tissue remodeling. Involution is a programmed tissue remodelling event with the features of wound healing, including collagen deposition and COX-2 dependent inflammation, and it promotes progression of ductal carcinoma in situ in model systems31. The tumour is not more aggressive by grade. The tissue it grows in is transiently permissive.

The clinical correlate is a stage-independent excess of metastasis. In a cohort study, diagnosis within 10 years post partum was associated with increased risk of metastasis. The excess was greatest in stage I and stage II disease, was present in both receptor positive and receptor negative cancers, and persisted in receptor positive cases for up to 15 years after diagnosis. Postpartum cases showed more lymphovascular invasion and more nodal involvement, and no increase in Ki67 index32.

The measurement caveat matters here more than usual. The window chosen to define postpartum disease determines the answer. Five years and ten years are different definitions, and studies using them are not directly comparable. Neither is a biological boundary.

Interplay

Postpartum disease is the cleanest available demonstration that host tissue state, rather than tumour genotype, can carry prognostic weight. The tumours are not separated from others by the receptor and grade measurements of Receptor assessment and the measurement problem. The stroma they arose in is different. This is the microenvironment argument of Functional states of the microenvironment arriving through an obstetric history.

See Host and tumor interactions

4 · Treatment during pregnancy and lactation

The governing principle is that the pregnancy is usually continued and the cancer usually treated. Termination has not been shown to improve oncologic outcome, and the decision belongs to the patient rather than to the algorithm.

Diagnosis is delayed by the pregnant breast. Ultrasound is the first imaging test, mammography with abdominal shielding is acceptable, and core biopsy is unaffected by gestation. In one series, cancers diagnosed during pregnancy were mammographically evident despite dense parenchyma, and ultrasound showed every mass and tracked the response to chemotherapy33. Staging avoids computed tomography and isotope bone scan where alternatives exist.

Surgery is safe in any trimester, and breast conservation is possible when radiation can wait34,35. Sentinel node mapping with technetium radiocolloid is acceptable, and blue dye is avoided. Dosimetry puts the fetal dose far below the threshold for harm36,37,38. Small clinical series found mapping feasible during pregnancy39,40, and a review of contraindications did not list pregnancy as absolute41. Radiotherapy is deferred until after delivery in almost all cases.

Chemotherapy is contraindicated in the first trimester because organogenesis is occurring. Anthracycline and taxane regimens are given in the second and third trimesters. The evidence is cumulative rather than randomised. Reviews of cytotoxic exposure in pregnancy found the first trimester to be the period of risk42,43. Among 160 pregnancies exposed to anthracyclines, fetal outcome was normal in 73%, complications were commoner in the first trimester, and doxorubicin doses above 70 mg/m2 per cycle raised the risk44. A prospective protocol of FAC in the second and third trimesters, in 57 women, found the children healthy at follow-up45, and a smaller series agreed46. Taxanes and vinorelbine appeared feasible after the first trimester in a review of 24 pregnancies47, supported by case reports48,49. Delivery is planned with an interval after the last cycle sufficient for maternal and fetal marrow recovery. Chemotherapy is withheld beyond about 35 weeks so that spontaneous labour does not occur at the neutrophil nadir.

Three drug classes are contraindicated throughout. Endocrine therapy is teratogenic. HER2-directed antibodies cause oligohydramnios through their effect on fetal renal epithelium. That warning rests on case reports, several describing reversible anhydramnios and one a poor fetal outcome50,51,52,53. Others describe uneventful pregnancies54,55,56,57, including one after first-trimester exposure to lapatinib58. Checkpoint inhibitors have no safety data in pregnancy and a mechanism that predicts harm.

The outcome data are more reassuring than the mechanism suggests, and the reason is instructive. A multicentre case-control study compared 129 children whose mothers had cancer during pregnancy with matched controls. Of the exposed children, 96 had received chemotherapy in utero. There was no significant between-group difference in cognitive development on the Bayley scales, and cardiac evaluation at 36 months was normal. Gestational age at birth correlated with cognitive outcome in both groups. Prematurity predicted worse cognition, and that effect was independent of cancer treatment59.

Caution

The clinical instinct is to deliver early and then treat freely. This dataset says that iatrogenic prematurity, not cytotoxic exposure, is the measurable harm to the child. Elective early delivery to start treatment is a decision that trades a documented risk for a hypothetical one.

Lactation is not compatible with cytotoxic therapy, endocrine therapy, or HER2-directed antibodies. Breastfeeding from a previously irradiated breast is often unsuccessful for mechanical reasons, and the contralateral breast is usually adequate. After breast-conserving therapy, lactation from the treated breast was possible but diminished in most women60.

5 · Pregnancy after breast cancer and interrupting endocrine therapy

The clinical conflict is arithmetic. Adjuvant endocrine therapy runs for 5 to 10 years, and the patients who most want a pregnancy are the ones for whom that interval consumes the remaining fertile years.

POSITIVE addressed the question directly. Women aged 42 years or younger with stage I to III hormone receptor positive disease, who had received 18 to 30 months of adjuvant endocrine therapy, interrupted treatment to attempt pregnancy. Among 516 women the median age was 37 years and 93.4% had stage I or stage II disease. Of 497 followed for pregnancy status, 368 had at least one pregnancy and 317 had at least one live birth. At 1638 patient-years of follow-up there had been 44 breast cancer events against a prespecified safety threshold of 46. The 3-year incidence of breast cancer events was 8.9% in the interruption group and 9.2% in an external control cohort61.

The follow-up duration must be stated every time this result is quoted. Median follow-up was 41 months. Hormone receptor positive disease recurs on a hazard curve that stays meaningfully above zero for two decades, which is the argument in Annual hazard of recurrence and the long tail of hormone receptor-positive disease. A 41-month result addresses the fear that interruption causes an early relapse. It cannot address whether interruption shifts risk into years 10 to 20, because the trial has not been running that long.

Three further limits belong with the number. The design was a single group with an external control rather than a randomised comparison. The population was selected, both by stage and by having already completed 18 to 30 months of therapy without recurrence. And the protocol resumed endocrine therapy after the pregnancy attempt, so the result describes an interruption rather than an abandonment.

Observational data on pregnancy after breast cancer are consistent and must be read carefully. An early matched cohort of 107 women with a later pregnancy found no adverse effect on long-term prognosis, with a small non-significant excess among those who conceived within 12 months62. A systematic review and meta-analysis found that survivors were less likely to conceive than the general population, with a relative risk of 0.40 and a 95% confidence interval of 0.32 to 0.49. Caesarean section, low birth weight, preterm birth, and small for gestational age were all more frequent, particularly after chemotherapy. Congenital abnormality was not increased. Compared with survivors who did not conceive, those who did had better disease-free survival, with a hazard ratio of 0.66, and better overall survival, with a hazard ratio of 0.5663. A later analysis restricted to hormone receptor positive disease found no disease-free survival difference, with a hazard ratio of 0.96 and an interval of 0.75 to 1.24. Overall survival in that analysis favoured the pregnancy group, with a hazard ratio of 0.4664.

Caution

The apparent survival advantage of pregnancy is almost certainly selection. Women conceive when they are well, are still well at the point of conception, and have already survived the interval in which early recurrence occurs. Presenting that hazard ratio to a patient as a benefit of pregnancy misrepresents it. The defensible statement is that pregnancy has not been shown to be harmful, and that is a different sentence.

In practice

Raise this before the first prescription, not at the two-year review. The plan for interruption shapes which endocrine regimen is chosen and whether ovarian suppression is used.

Quote the follow-up. Say that the reassurance covers roughly three years and that the trial continues.

Resume endocrine therapy afterwards. That was the protocol, and the result does not license stopping.

Fertility does not return because treatment stopped. Reassess reserve rather than assume it.

6 · Parenting, relationships, and long-horizon survivorship

A woman treated at 34 has a survivorship horizon measured in decades, and every late effect in Rehabilitation and survivorship applies to her for longer than it applies to anyone else.

Premature menopause is the dominant late effect and it arrives abruptly. Chemotherapy-induced ovarian failure and ovarian suppression produce in months what normally takes years. The consequences are bone loss, vasomotor symptoms, genitourinary atrophy, sexual dysfunction, and a cardiovascular risk profile shifted forward by decades. The management belongs to Sexual health and menopausal symptoms and Bone health and cardiovascular risk after treatment, with one modification. Systemic hormone replacement, which is the standard answer in the general population, is not available here.

Adherence is the quiet failure. In a cohort of 8,769 women, 32% had discontinued adjuvant endocrine therapy by 4.5 years, and only 72% of those who continued were fully adherent. Women under 40 years had the highest risk of discontinuation, with a hazard ratio of 1.51 and a 95% confidence interval of 1.23 to 1.8565. The population with the most to gain from prolonged therapy is the population least likely to complete it. Poor adherence to long-term medication is a problem across medicine, not a peculiarity of oncology66.

Second primary risk is also age-weighted. In a population cohort of women with early invasive breast cancer, contralateral breast cancer by 20 years was 3.1 percentage points more common than expected. The absolute excess was greater in younger women than in older ones67. That shapes the surveillance argument in Second primaries and long-term health maintenance.

The non-medical load is not a soft topic. Young patients carry dependent children, active careers, mortgages, and partners who become caregivers. Work disruption and out-of-pocket cost fall on the years of lowest accumulated wealth, which is the mechanism in Access, affordability, and financial toxicity. Fear of recurrence and body image after mastectomy at 30 are covered in Distress, anxiety, depression, and fear of recurrence and Body image and identity.

In practice

Ask about children by name and age. It changes what the patient is optimising for and it is not recorded anywhere in the chart.

Treat adherence as a clinical outcome with its own follow-up, not as patient behaviour.

Document who is at home. The partner of a 35-year-old patient is doing childcare, income, and caregiving at once.

References

All 67 references
  1. Partridge AH, Hughes ME, Warner ET, et al. Subtype-Dependent Relationship Between Young Age at Diagnosis and Breast Cancer Survival. J Clin Oncol 2016 34:3308-14. PMID 27480155
  2. Dunn J, Steginga SK. Young women's experience of breast cancer: defining young and identifying concerns. Psychooncology 2000 9:137-46. PMID 10767751
  3. Gorman JR, Bailey S, Pierce JP, Su HI. How do you feel about fertility and parenthood? The voices of young female cancer survivors. J Cancer Surviv 2012 6:200-9. PMID 22179785
  4. Ganz PA, Greendale GA, Petersen L, Kahn B, Bower JE. Breast cancer in younger women: reproductive and late health effects of treatment. J Clin Oncol 2003 21:4184-93. PMID 14615446
  5. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review. J Natl Cancer Inst 2012 104:386-405. PMID 22271773
  6. Baucom DH, Porter LS, Kirby JS, Gremore TM, Keefe FJ. Psychosocial issues confronting young women with breast cancer. Breast Dis 2005 23:103-13. PMID 16823173
  7. Hickey M, Peate M, Saunders CM, Friedlander M. Breast cancer in young women and its impact on reproductive function. Hum Reprod Update 2009 15:323-39. PMID 19174449
  8. Oktay K, Harvey BE, Partridge AH, et al. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2018 36:1994-2001. PMID 29620997
  9. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013 31:2500-10. PMID 23715580
  10. Oktay K, Turan V, Bedoschi G, Pacheco FS, Moy F. Fertility Preservation Success Subsequent to Concurrent Aromatase Inhibitor Treatment and Ovarian Stimulation in Women With Breast Cancer. J Clin Oncol 2015 33:2424-9. PMID 26101247
  11. Oktem O, Oktay K. Fertility preservation for breast cancer patients. Semin Reprod Med 2009 27:486-92. PMID 19806518
  12. Dunn L, Fox KR. Techniques for fertility preservation in patients with breast cancer. Curr Opin Obstet Gynecol 2009 21:68-73. PMID 19125006
  13. Redig AJ, Brannigan R, Stryker SJ, Woodruff TK, Jeruss JS. Incorporating fertility preservation into the care of young oncology patients. Cancer 2011 117:4-10. PMID 21235031
  14. Moffat R, Güth U. Preserving fertility in patients undergoing treatment for breast cancer: current perspectives. Breast Cancer (Dove Med Press) 2014 6:93-101. PMID 25114587
  15. Lee S, Ozkavukcu S, Heytens E, Moy F, Oktay K. Value of early referral to fertility preservation in young women with breast cancer. J Clin Oncol 2010 28:4683-6. PMID 20876425
  16. Moore HC, Unger JM, Phillips KA, et al. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med 2015 372:923-32. PMID 25738668
  17. Lambertini M, Moore HCF, Leonard RCF, et al. Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient-Level Data. J Clin Oncol 2018 36:1981-1990. PMID 29718793
  18. Cruz MR, Prestes JC, Gimenes DL, Fanelli MF. Fertility preservation in women with breast cancer undergoing adjuvant chemotherapy: a systematic review. Fertil Steril 2010 94:138-43. PMID 19339000
  19. Blumenfeld Z, Evron A. Preserving fertility when choosing chemotherapy regimens - the role of gonadotropin-releasing hormone agonists. Expert Opin Pharmacother 2015 16:1009-20. PMID 25826240
  20. Del Mastro L, Lambertini M. Temporary Ovarian Suppression With Gonadotropin-Releasing Hormone Agonist During Chemotherapy for Fertility Preservation: Toward the End of the Debate?. Oncologist 2015 20:1233-5. PMID 26463868
  21. Lambertini M, Peccatori FA, Moore HC, Del Mastro L. Reply to the letter to the editor 'Can ovarian suppression with gonadotropin releasing hormone analogs (GnRHa) preserve fertility in cancer patients?' by Rodriguez-Wallberg et al. Ann Oncol 2015 27:548-9. PMID 26646756
  22. Sukumvanich P, Case LD, Van Zee K, et al. Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: a prospective study. Cancer 2010 116:3102-11. PMID 20564648
  23. Quinn GP, Block RG, Clayman ML, et al. If you did not document it, it did not happen: rates of documentation of discussion of infertility risk in adolescent and young adult oncology patients' medical records. J Oncol Pract 2015 11:137-44. PMID 25549654
  24. Yee S, Abrol K, McDonald M, Tonelli M, Liu KE. Addressing oncofertility needs: views of female cancer patients in fertility preservation. J Psychosoc Oncol 2012 30:331-46. PMID 22571247
  25. Yeomanson DJ, Morgan S, Pacey AA. Discussing fertility preservation at the time of cancer diagnosis: dissatisfaction of young females. Pediatr Blood Cancer 2013 60:1996-2000. PMID 23836521
  26. Peate M, Meiser B, Friedlander M, et al. It's now or never: fertility-related knowledge, decision-making preferences, and treatment intentions in young women with breast cancer--an Australian fertility decision aid collaborative group study. J Clin Oncol 2011 29:1670-7. PMID 21444865
  27. Smith LH, Dalrymple JL, Leiserowitz GS, Danielsen B, Gilbert WM. Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997. Am J Obstet Gynecol 2001 184:1504-12; discussion 1512-3. PMID 11408874
  28. Gwyn K, Theriault R. Breast cancer during pregnancy. Oncology (Williston Park) 2001 15:39-46; discussion 46, 49-51. PMID 11271981
  29. Middleton LP, Amin M, Gwyn K, Theriault R, Sahin A. Breast carcinoma in pregnant women: assessment of clinicopathologic and immunohistochemical features. Cancer 2003 98:1055-60. PMID 12942575
  30. Nichols HB, Schoemaker MJ, Cai J, et al. Breast cancer risk after recent childbirth: a pooled analysis of 15 prospective studies. Ann Intern Med 2019 170:22-30. PMID 30534999
  31. Lyons TR, O'Brien J, Borges VF, et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 2011 17:1109-1115. PMID 21822285
  32. Goddard ET, Bassale S, Schedin T, et al. Association between postpartum breast cancer diagnosis and metastasis and the clinical features underlying risk. JAMA Netw Open 2019 2:e186997. PMID 30646210
  33. Yang WT, Dryden MJ, Gwyn K, Whitman GJ, Theriault R. Imaging of breast cancer diagnosed and treated with chemotherapy during pregnancy. Radiology 2006 239:52-60. PMID 16484353
  34. Kuerer HM, Gwyn K, Ames FC, Theriault RL. Conservative surgery and chemotherapy for breast carcinoma during pregnancy. Surgery 2002 131:108-10. PMID 11812971
  35. Annane K, Bellocq JP, Brettes JP, Mathelin C. Infiltrative breast cancer during pregnancy and conservative surgery. Fetal Diagn Ther 2005 20:442-4. PMID 16113569
  36. Gentilini O, Cremonesi M, Trifirò G, et al. Safety of sentinel node biopsy in pregnant patients with breast cancer. Ann Oncol 2004 15:1348-51. PMID 15319240
  37. Keleher A, Wendt R, Delpassand E, Stachowiak AM, Kuerer HM. The safety of lymphatic mapping in pregnant breast cancer patients using Tc-99m sulfur colloid. Breast J 2004 10:492-5. PMID 15569204
  38. Pandit-Taskar N, Dauer LT, Montgomery L, St Germain J, Zanzonico PB, Divgi CR. Organ and fetal absorbed dose estimates from 99mTc-sulfur colloid lymphoscintigraphy and sentinel node localization in breast cancer patients. J Nucl Med 2006 47:1202-8. PMID 16818956
  39. Khera SY, Kiluk JV, Hasson DM, et al. Pregnancy-associated breast cancer patients can safely undergo lymphatic mapping. Breast J 2008 14:250-4. PMID 18476883
  40. Mondi MM, Cuenca RE, Ollila DW, Stewart JH, Levine EA. Sentinel lymph node biopsy during pregnancy: initial clinical experience. Ann Surg Oncol 2007 14:218-21. PMID 17066225
  41. Filippakis GM, Zografos G. Contraindications of sentinel lymph node biopsy: are there any really?. World J Surg Oncol 2007 5:10. PMID 17261174
  42. Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and pregnancy. Semin Oncol 1989 16:337-46. PMID 2678485
  43. Ebert U, Löffler H, Kirch W. Cytotoxic therapy and pregnancy. Pharmacol Ther 1997 74:207-20. PMID 9336023
  44. Germann N, Goffinet F, Goldwasser F. Anthracyclines during pregnancy: embryo-fetal outcome in 160 patients. Ann Oncol 2004 15:146-50. PMID 14679135
  45. Hahn KM, Johnson PH, Gordon N, et al. Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer 2006 107:1219-26. PMID 16894524
  46. García-Manero M, Royo MP, Espinos J, Pina L, Alcazar JL, López G. Pregnancy associated breast cancer. Eur J Surg Oncol 2009 35:215-8. PMID 18550321
  47. Mir O, Berveiller P, Ropert S, et al. Emerging therapeutic options for breast cancer chemotherapy during pregnancy. Ann Oncol 2008 19:607-13. PMID 17921242
  48. Gonzalez-Angulo AM, Walters RS, Carpenter RJ, et al. Paclitaxel chemotherapy in a pregnant patient with bilateral breast cancer. Clin Breast Cancer 2004 5:317-9. PMID 15507181
  49. Gainford MC, Clemons M. Breast cancer in pregnancy: are taxanes safe?. Clin Oncol (R Coll Radiol) 2006 18:159. PMID 16523825
  50. Watson WJ. Herceptin (trastuzumab) therapy during pregnancy: association with reversible anhydramnios. Obstet Gynecol 2005 105:642-3. PMID 15738038
  51. Bader AA, Schlembach D, Tamussino KF, Pristauz G, Petru E. Anhydramnios associated with administration of trastuzumab and paclitaxel for metastatic breast cancer during pregnancy. Lancet Oncol 2007 8:79-81. PMID 17196514
  52. Sekar R, Stone PR. Trastuzumab use for metastatic breast cancer in pregnancy. Obstet Gynecol 2007 110:507-10. PMID 17666645
  53. Witzel ID, Müller V, Harps E, Janicke F, Dewit M. Trastuzumab in pregnancy associated with poor fetal outcome. Ann Oncol 2008 19:191-2. PMID 18084047
  54. Fanale MA, Uyei AR, Theriault RL, Adam K, Thompson RA. Treatment of metastatic breast cancer with trastuzumab and vinorelbine during pregnancy. Clin Breast Cancer 2005 6:354-6. PMID 16277887
  55. Waterston AM, Graham J. Effect of adjuvant trastuzumab on pregnancy. J Clin Oncol 2006 24:321-2. PMID 16401684
  56. Shrim A, Garcia-Bournissen F, Maxwell C, Farine D, Koren G. Favorable pregnancy outcome following Trastuzumab (Herceptin) use during pregnancy--Case report and updated literature review. Reprod Toxicol 2007 23:611-3. PMID 17399946
  57. Pant S, Landon MB, Blumenfeld M, Farrar W, Shapiro CL. Treatment of breast cancer with trastuzumab during pregnancy. J Clin Oncol 2008 26:1567-9. PMID 18349415
  58. Kelly H, Graham M, Humes E, et al. Delivery of a healthy baby after first-trimester maternal exposure to lapatinib. Clin Breast Cancer 2006 7:339-41. PMID 17092403
  59. Amant F, Vandenbroucke T, Verheecke M, et al. Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy. N Engl J Med 2015 373:1824-34. PMID 26415085
  60. Moran MS, Colasanto JM, Haffty BG, Wilson LD, Lund MW, Higgins SA. Effects of breast-conserving therapy on lactation after pregnancy. Cancer J 2005 11:399-403. PMID 16259870
  61. Partridge AH, Niman SM, Ruggeri M, et al. Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer. N Engl J Med 2023 388:1645-1656. PMID 37133584
  62. Kranick JA, Schaefer C, Rowell S, et al. Is pregnancy after breast cancer safe?. Breast J 2010 16:404-11. PMID 20522097
  63. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy After Breast Cancer: A Systematic Review and Meta-Analysis. J Clin Oncol 2021 39:3293-3305. PMID 34197218
  64. Arecco L, Blondeaux E, Bruzzone M, et al. Safety of pregnancy after breast cancer in young women with hormone receptor-positive disease: a systematic review and meta-analysis. ESMO Open 2023 8:102031. PMID 37879234
  65. Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 2010 28:4120-4128. PMID 20585090
  66. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005 353:487-97. PMID 16079372
  67. McGale P, Dodwell D, Challenger A, et al. Second cancers in 475 000 women with early invasive breast cancer diagnosed in England during 1993-2016: population based observational cohort study. BMJ 2025 390:e083975. PMID 40865997